CATS Proceedings Printout - ICPE - 7th International Congress on

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© Graz Tourismus
BOOK OF
ABSTRACTS
June 16-17, 2014
Graz, Austria
www.icpe-graz.org
Organizing Institutions:
Graz University of Technology
Institute for Process & Particle Engineering,
Graz University of Technology
Research Center
Pharmaceutical
Engineering
Co-sponsoring and Supporting Organizations & Societies:
APV, International Association for
Pharmaceutical Technology, Germany
BioNanoNet Research Association
Austria
Medical University of Graz, Austria
University of Graz, Austria
Sponsors of the ICPE2014:
Thank you very much for sponsoring the ICPE2014!
ICPE 2014
Table of Contents
Keynote Lecture
1 Mechanistic models and model analysis tools to support PAT
system development
1
Krist Gernaey
Keynote Lecture
1 High energy formulations for poorly water soluble drugs –
developments and challenges
2
Thomas Rades
Advanced Formulation Design
1 Phase Behavior of Pharmaceutical Systems
3
Gabriele Sadowski, Anke Prudic, Raphael Paus
2 Study of the polymer swelling kinetics using MRI
4
Michaela Gajdosova
3 Tailored protein release from biodegradable
multiblock-copolymer implants prepared by hot melt extrusion
5
Milica Stankovic
4 DPI performance of tailor-made spray dried mannitol and
salbutamol sulphate particles
6
Mathias Mönckedieck, Jens Kamplade, Phanuel Fakner,
Hartwig Steckel, Peter Walzel
Advanced Platform Technologies
1 Die Face Pelletizing of Sticky HME Formulations
7
Daniel Treffer, Gerold Koscher, Johannes Khinast
2 Comminutive Pelletizing - Continuous Production of Hot-melt
Extruded Pellets
8
Reinhardt-K. Muerb
3 Stirred media milling of an organic model compound in
ethanol
9
Denise Steiner, Jan Henrik Finke, Sandra Breitung-Faes, Arno Kwade
4 Freezing of Pharmaceutical Proteins: Benefits of Process
Characterization at Reduced Scales
Ulrich Roessl, Birgit Pittermann
I
10
ICPE 2014
Keynote Lecture
1 Progressing to i-pharmaceuticals - Drug delivery science
driven by technology & patients
11
Sven Stegemann
Advanced Formulation Design
1 Effects of Particle Size and Structure on the Drug Loading
Capacity of Lipid Nanoparticles
12
Eva Kupetz, Heike Bunjes
2 Miscibility, processing, and stability considerations of
spray-dried amorphous solid dispersions: A tale of naproxen-PVP
system
13
Amrit Paudel
3 The Stability of Amorphous Solid Dispersions - What can We
Learn from Mathematical Models?
14
Michael Brunsteiner
4 Compressing of granules into minitablets and tablets – is
there any difference?
15
Adrian Kamola
Advanced Platform Technologies
1 Integration of ecological aspects in sustainable
pharmaceutical production in multi-purpose plants
16
Mandy Wesche, Michael Häberl, Marco Kohnke, Stephan Scholl
2 A Critical Eye on Controlled Nucleation during Lyophilization
17
Ilona Konrad, Raimund Geidobler, Angelika Freitag, Wolfgang Friess,
Andrea Hawe, Gerhard Winter
3 Bacterial Ghost Platform Technology for Pharmaceutical
Protein Production
18
Timo Langemann
4 NANEX: A Rational Design of the Manufacturing of a Solid
Oral Nanoparticle Formulation
19
Ramona Baumgartner
Pharmaceutical Modeling and Simulation
1 Two-dimensional PBM for simultaneous modelling of drying
and breakage of pharmaceutical granules
20
Séverine Mortier
2 A Novel Simulation Approach for Hot Melt Extrusion
Andreas Eitzlmayr, Josip Matic, Gerold Koscher
II
21
ICPE 2014
3 A decision making framework for optimal implementation of
equipment management in manufacturing execution system
22
Saana Sandström, Julia Matilainen, Anne Juppo, Christian Rothkopf
Process Analysis and Quality Assurance
1 Improvement of adherence and safety of senior patients
through multi-frequency RFID technology supported medication
23
Elena Stocker
2 Fermentation Modeling in a PAT Environment
24
Johannes Scheiblauer
3 QbD 2.0: Efficient use of R&D for the design of robust
manufacturing processes
25
Sean Bermingham
Keynote Lecture
1 Critical discussion about the influence of roll compaction/
dry granulation on tablet properties
26
Peter Kleinebudde
1 Simulation of an overall lab scale tablet production
27
Sebastian Trebbien, Ina Weinsheimer, Alexandra Weitz,
Peter Langguth, Frank Stieneker
2 Image-Based Real Time Crystal Shape Observer
28
Holger Eisenschmidt
3 Investigating the uniformity of an active coating process
using DEM simulations
29
Gregor Toschkoff, Georg Scharrer, Sarah Just, Klaus Knop,
Peter Kleinebudde, Dejan Djuric, Adrian Funke, Johannes G. Khinast
1 Development of a multivariate FTIR spectroscopic method to
monitor microstructural changes of gelatin during capsule
manufacture
30
Fabian Polyak, Gabriele Reich
2 Total Surveillance! Inline Monitoring of Tablets with NIR
Chemical Imaging
31
Patrick R. Wahl, Stephan Sacher, Peter Kerschhaggl
3 Combining image analysis with Raman spectroscopy for QBD
Paul Davies
III
32
ICPE 2014
Keynote Lecture
1 The European Pharmaceutical Industry – Past success,
present challenge and future potential
33
Richard Torbett
Keynote Lecture
1 Perspectives in Process Analysis
34
Rudolf Kessler
1 Process modelling of dry foam drying kinetics
35
Pranay Kumar Ghosh, Emmanuela Gavi, Angela Dischinger,
Susanne Page
2 Prediction of bulk compaction properties based on
deformational characteristics of single crystals determined by
nanoindentation
36
Stane Srcic, Nina Lah
3 Investigation of polymer-API systems distribution behavior
in the mold during injection molding process by numerical (CFD)
methods
37
Herwig Juster
4 Probabilistic Modeling of Wet Collisions in Sheared Particle
Beds
38
Bhageshvar Mohan, Stefan Radl
5 Experimental and model-based investigation of twin screw
granulation: towards more profound process knowledge
39
Ashish Kumar, Krist Gernaey
1 Application of combined UV/VIS spectroscopy and computed
tomography in analysis of granules
40
Ondrej Kaspar
2 Multispectral UV Imaging for High-Speed Quality Control in
the Manufacturing Process of Tablets
41
Marten Klukkert, Albrecht Sakmann, Sönke Rehder,
Jens Michael Carstensen, Thomas Rades, Claudia S. Leopold
3 Fast Insight into Solid State Transformations using
Synchrotron X-ray Diffraction
Johan Boetker, Jukka Rantanen, Thomas Rades, Anette Müllertz,
Adrian Hawley, Ben Boyd
IV
42
ICPE 2014
4 Coating Thickness Prediction by in-line Raman spectra:
43
Applicability of Spatial Filtering Velocimetry as reference method
Friederike Folttmann
5 Measuring the particle size evolution of disintegrating
tablets
44
Julian Quodbach, Peter Kleinebudde
1 Fully Coupled Multiphase Simulation of a Bottom-spray
Wurster Coater Using a Hybrid CPU/GPU CFD/DEM approach
45
Charles Radeke
1 Terahertz Spectroscopy: A New Tool for Predicting the
Stability of Amorphous Drugs
46
Axel Zeitler
Continuous Manufacturing
1 Continuous manufacturing of solid dosage forms from the
point of view of an equipment supplier
47
Reiner Lemperle
2 Experimental study on the particle size distribution of
granules produced by twin screw granulation
48
Jurgen Vercruysse, Margot Fonteyne, Urbain Delaet, Ivo Van Assche,
Thomas De Beer, Jean Paul Remon, Chris Vervaet
3 The Plug & Play Reactor: A Versatile Tool for Synthesis in
Continuous Flow Mode
Heidrun Gruber-Wölfler, Georg J. Lichtenegger, Klemens Obermaier,
Hannes Kitzler, Johannes G. Khinast
V
49
ICPE 2014
Mechanistic models and model analysis tools to
support PAT system development
K.V. Gernaey
CAPEC-PROCESS, Department of Chemical and Biochemical Engineering, Technical
University of Denmark (DTU), Building 229, DK-2800 Lyngby, Denmark
Email for correspondence: kvg@kt.dtu.dk
Considering the typical development cycle of a drug, two obvious ways of increasing profit are:
(1) more rapid process development, and thus maximization of the time between product
release and patent expiration; and (2) optimising the full-scale production system to achieve a
more efficient process. In both cases, increased use of mechanistic models can be
advantageous. A mechanistic model should in this respect be considered as a convenient
representation of the available process knowledge. In a process development context, a
mechanistic model can be used to screen different combinations of operating conditions, such
that only the most promising combinations have to be validated experimentally. In this way, the
number of experiments can be reduced, or the available experimental resources can be used
more efficiently. With respect to full-scale production, a mechanistic model of (part of) a
production system can be used to investigate how to operate the system more efficiently, e.g.
by adding on extra controllers or by changing set points of controllers, without the need to
disturb the full-scale system.
The mapping of the design space of a process, inspired by the PAT guidance released by the
FDA in 2004, increasingly justifies the development of mechanistic models of the process as
well, to capture the often non-linear relations between process variables and final product
quality. Here specifically, model analysis – for example by means of uncertainty and local/global
sensitivity analysis – and simulation studies with such models can be helpful in designing
experiments to map the design space, or to propose a design of a PAT system, to test control
strategies etc. In this context, mechanistic models and model analysis methods can contribute
significantly to streamline the process development phase research efforts.
This lecture will illustrate the use of mechanistic models in the context of pharmaceutical
process development and operation with examples. Examples will have focus on fermentation
process development, on separation processes and also on secondary manufacturing.
Moreover, the use of mechanistic models to support PAT system design and scaling up of
processes will be discussed, and examples from other research areas will be highlighted to
illustrate how mechanistic models could be used increasingly in the future in the context of
pharmaceutical process development and operation.
1
ICPE 2014
High energy formulations for poorly water soluble
drugs – developments and challenges
T. Rades
Research Chair in Pharmaceutical Design and Drug Delivery, University of Copenhagen,
Faculty of Health and Medical Sciences, Department of Pharmacy, Universitetsparken 2, 2100
Copenhagen, Denmark
Email for correspondence: thomas.rades@sund.ku.dk
An increasingly important bottleneck for the development of drugs to medicines is the poor
aqueous solubility of many small molecular weight drugs in the pipeline of pharmaceutical
companies. To increase the solubility of drugs, and thus their bioavailability, feasible
approaches include the conversion of crystalline drugs to their respective amorphous forms,
and the formulation of drugs in lipid based drug delivery systems (LBDDS). In both of these
systems the drug is present in a high energy form, either in the formulation (amorphous forms )
or after administration (LBDDS).
Amorphous systems show an increased dissolution rate and solubility compared to their
crystalline counterparts and thus improved bioavailability, especially for so-called “brick dust”
molecules. This approach may be pursued either for the pure drug, or more commonly using
drug/polymer mixtures, resulting in amorphous glass solutions.
LBDDS are particularly suitable for so-called “grease ball” molecules and provide higher
bioavailability through solubilisation of the drug in various colloidal particles after administration.
The nature of the colloidal particles, and thus their solubilisation capacity changes as lipolysis
progresses.
In this presentation, emphasis will be placed on the fact that the amorphous form does not
represent a well-defined solid state, but that the resulting amorphous form will have different
properties (including different physical stabilities) depending on the preparation method (e.g.
quench-cooling, spray drying, milling) and the parameters used in the preparation process (e.g
cooling rate of the melt, milling time). Examples for our own work in this field will be given.
Also new concepts to develop amorphous drugs, such as the use of drug-drug co-amorphous
combinations, the use of amino acids as small molecular weight excipients to increase stability
of amorphous drugs and our recent attempts to coat amorphous particles with polymers, to
decrease surface crystallisation will be discussed.
LBDDS can also be prepared with the drug supersaturated in the lipid formulation, resulting in
higher drug load and higher bioavailability. Care however needs to be taken when developing
such dosage forms as precipitation of the drug (either in crystalline or amorphous forms) may
occur. Again, examples for our own work in this field will be given.
Since these high energy forms present specific challenges over and above “conventional” solid
dosage forms. This means that additional challenges need to be addressed if such dosage
forms are to be manufactured in a QbD/PAT environment and when considering continuous
manufacturing possibilities.
2
ICPE 2014
Phase Behavior of Pharmaceutical Systems
G. Sadowski, A. Prudic, R. Paus
TU Dortmund, Department of Chemical and Biochemical Engineering,
Laboratory of Thermodynamics
Email for correspondence: gabriele.sadowski@bci.tu-dortmund.de
Active pharmaceutical ingredients (APIs) are often complex compounds exhibiting very low
aqueous solubility. Because of this, they only slowly dissolve in the body when administered as
crystalline solids, which leads to a low bioavailability. Several approaches to increase the
bioavailability of APIs have been presented in literature.
One of them is salt formation by ionization of functional groups which can be achieved by
adding an acid or a base and therewith changing the pH in the solution. The observable
increase in solubility depends on the acid constant of the API itself as well as on the amount
and nature of the acid or base added.
Another possibility is to form a so-called amorphous solid dispersion in which the API is
integrated into a polymer which acts as carrier matrix. In this matrix, the API is integrated in its
amorphous form rather than in the crystalline state which increases the dissolution rate of the
API. However, often these solid dispersions are not thermodynamically stable and therefore
amorphous phase separation and even recrystallization of the API might occur during storage.
This depends on the thermodynamic phase behaviour which is to a great extend influenced by
e.g. the kind of API and polymer, by temperature and relative humidity.
Due to this complexity, the above-mentioned approaches are so far usually found by trial-anderror procedures. Thermodynamic understanding and modeling of the underlying phenomena,
however, is a valuable tool to improve and to intensify this process.
The talk will give an overview about the thermodynamic phase behaviour of systems containing
pharmaceuticals. The influence of temperature, co-solvents, additives and pH on the solubility
of APIs in water as well as in organic solvents will be discussed, whereas the latter is of
particular interest during API production. Particular emphasis will be placed on the phase
behaviour of solid dispersions including the influence of relative humidity on their phase
behavior.
All phenomena will be discussed on the basis of experimental data for various systems. Finally,
it will be shown that thermodynamic modelling today allows for reliable correlations and even
predictions of the phase behaviour of API solutions as well as for solid dispersions. It can thus
drastically reduce the experimental effort for developing the optimal API formulation and
processing.
3
ICPE 2014
Study of the polymer swelling kinetics using MRI
M. Gajdošová *, N. Sarvašová , D. Pěček , F. Štěpánek
Department of Chemical Engineering, Institute of Chemical Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic, Tel.: +420 220 443 048
*E-mail for correspondence: gajdosom@vscht.cz
Through the recent years, there has been a steady increase in employing various imaging
techniques in pharmaceutical research. Amongst others, Magnetic Resonance Imaging (MRI)
has also been utilized mainly due its ability to provide us with the direct visualization of several
physicochemical processes, such as tablet dissolution, in real time. As a non-destructive
method, it can be likewise used as a means to study the swelling of the polymer matrices. Since
such matrices are nowadays widely used to control the release of API, it became essential to
describe the polymer swelling kinetics and find the relationship between the type of used
polymer and the dissolution profile of API.
The aim of our research was to monitor the dissolution kinetics of polymeric matrixes with the
different ratio of hydrophilic and lipophilic components using MRI technology. For this purpose,
six different types of tablets prepared by the direct pressing were studied. The experiments
were performed in flow arrangement within specially designed plastic flow cell with a tablet
holder placed inside the MRI scanner. Each measurement proceeded under specific conditions,
namely phosphate buffer saline pH 6 as a medium, medium temperature 37°C, the flow rate of
medium 4 ml/min, the time of experiment 8 hours. As a contrast agent, for improving the
visibility of erosion front, composite nanoparticles SiO2/FeOx were used. Each tablet was
measured three times and the thickness of gel layer was evaluated in three different regions.
Results from MRI experiments were compared to the results obtained with texture analyser, and
then the relationship between polymer swelling and drug release was evaluated.
In summary, MRI proved to be a suitable imaging technique for the polymer swelling
quantification. For the future measurements, the effect of different additives on the polymer
swelling kinetics will be evaluated. The results of this research should lead to unique database,
containing the list of possible polymer matrices and their effects on the dissolution profile of API,
existence of which would notably simplify the formulation of dosage forms with the desired drug
release.
4
ICPE 2014
Tailored protein release from biodegradable
multiblock-copolymer implants prepared by hot melt
extrusion
M.Stanković *a, J. Tomar a, C. Hiemstra b, R. Steendam b, H. W.Frijlink a, W. L.J.Hinrichs a
a
b
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen,
A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands
InnoCore Pharmaceuticals, L.J. Zielstraweg 1, 9713 GX, Groningen, The Netherlands
E-mail for correspondence: m.stankovic@rug.nl; milica.stankovic@rcpe.at
The research on the development of parenteral depot formulations for sustained delivery of
proteins has expanded enormously during the last few decades. Numerous emulsificationbased encapsulation techniques have been used to prepare such formulations. However, when
manufactured via these processing methods proteins are exposed to aqueous-organic solvent
interphases and/or hydrophobic surfaces, which can result in denaturation of proteins. Hot melt
extrusion (HME) is a solvent-free method offering many advantages over the other
encapsulation techniques. It is a fast and reproducible process with good mixing capabilities.
Poly(DL-lactide-co-glycolide) (PLGA) has been widely applied as a release controlling
biodegradable polymer in microparticle and implant-based depot formulations for peptides and
proteins. However, PLGA can only be extruded at temperatures higher than 90°C, which can be
highly detrimental for protein integrity.
To overcome this problem, we synthesized biodegradable poly(ε-caprolactone-poly(ethylene
glycol))-block-poly(ε-caprolactone), x[PCL-PEG]-b-y[PCL]) multiblock copolymers with different
block ratios and with a low melting temperature (49 - 55 ˚C), with x/y being 30/70, 50/50 and
70/30 (w/w) [1]. The effect of block ratio and thus the PEG content of the polymers (i.e. 22.5,
37.5 and 52.5 wt%) as well as the effect of protein molecular weight (Mw) (1.2, 5.8, 14, 29 and
66 kDa being goserelin, insulin, lysozyme, carbonic anhydrase and albumin, respectively) on
protein release was investigated. Proteins were first spray-dried with polysaccharide inulin as a
stabilizer to obtain a powder of uniform particle size. Subsequently, spray-dried inulin-stabilized
proteins were incorporated into small diameter polymeric implants by HME at temperatures as
low as 49 - 55 ˚C. A degradation study on polymer only implants was additionally performed to
study the in vitro degradation kinetics of these novel multiblock copolymers.
All incorporated proteins fully preserved their structural integrity as determined after extraction
from the implants. It was found that the release rate of the protein increased with decreasing
Mw of the protein and with increasing the PEG content of the polymer. Swelling and
degradation rate of the copolymer increased with increasing PEG content. In conclusion,
proteins can be in incorporated in [PCL-PEG]-b-[PCL] multi-block copolymers by HME without
loss of their integrity and the release of the proteins from these implants can be tailored by
varying the PEG content of the polymer (results of this study have been published in [2].
Acknowledgment: This research was performed within the framework of the Northern Drug
Targeting and Delivery Cluster (EFRO Grant)
[1]
M. Stanković, H. De Waard, R. Steendam, C. Hiemstra, J. Zuidema, H.W. Frijlink, W.L.J.Hinrichs,
Low temperature extruded implants based on novel hydrophilic multiblock copolymer for long-term
protein delivery, Eur. J. Pharm. Sci. 49 (2013) 578–587.
[2]
M. Stanković, J. Tomar, C. Hiemstra, R. Steendam, H.W. Frijlink, W.L.J. Hinrichs, Tailored protein
release from biodegradable poly(ε-caprolactone-PEG)-b-poly(ε-caprolactone) multiblockcopolymer implants., Eur. J. Pharm. Biopharm. (2014) http://dx.doi.org/10.1016/j.ejpb.2014.02.012
5
ICPE 2014
DPI performance of tailor-made spray dried mannitol
and salbutamol sulphate particles
M. Mönckedieck*, J. Kamplade**, P. Fakner**, H. Steckel***, P. Walzel**
* Research Center Pharmaceutical Engineering, Inffeldgasse 13, A-8010 Graz, Austria
** TU Dortmund, Emil-Figge-Str. 68, 44227 Dortmund, Germany
*** Kiel University, Grasweg 9a, 24118 Kiel, Germany
Email for correspondence: mmoenckedieck@pharmazie.uni-kiel.de
INTRODUCTION:
Carrier-based formulations are well established for the use in DPIs. Interparticle interactions
between carrier and drug need to be strong enough to ensure uniformity of dosing, but low
enough to facilitate detachment of the drug during inhalation. Particle properties like surface
morphology, size and porosity play a crucial role in the prediction of the resulting fine particle
fraction (FPF, 1-5 µm). This project deals with spray dried drug (salbutamol sulphate, SBS) and
carrier (mannitol) particles, which were tailor-made by adjusting appropriate process parameters
[1]. Our goal is to obtain an essential understanding of how different surface morphologies and
sizes of either carrier or different APIs affect the DPI performance for lung inhalation [2].
EXPERIMENTAL METHODS:
Mannitol was spray dried in different qualities with a non-commercial pilot scale spray dryer at
TU Dortmund. SBS was prepared using a Buechi Mini Spray Dryer B-290 (Buechi Labortechnik
AG, Switzerland). Interactive mixtures were prepared with a Turbula blender (Willy A. Bachofen
AG, Germany) and DPI performance was investigated by determination of the FPF with a Next
Generation Impactor (NGI, Copley Scientific Limited, UK) using the Novolizer as a device.
RESULTS & DISCUSSION:
Figure 1: Binary mixture of mannitol
carrier and SBS drug particles (both spray
dried); (A): mannitol dried at an outlet
temperature of 70°C and SBS with x50.3 =
2.3 µm; (B): mannitol dried at an outlet
temperature of 97°C and SBS with x50.3 =
3.7 µm
Particle properties were altered for both drug and carrier components on the basis of particle
size and surface morphology. The various resulting mixtures reveal significant differences in the
FPF. Spheric mannitol carrier particles in combination with smaller SBS particles (FPF: 27.3%;
Fig. 1A) show a better performance than indented mannitol carrier mixed with larger SBS
particles (FPF 11.5%; Fig. 1B). It could be shown that the entrainment of the powder into air is
dependent on the particle surface of the carrier material. SBS from spherical carrier particles
with low indentations appears to be better disaggregated compared to blends consisting of
carrier material with rough surface properties (see Fig. 1).
CONCLUSION:
The DPI performance of interactive blends can be tailored by selecting appropriate drying
conditions to gain components with desired properties including tailored particle-particle
interactions.
ACKNOWLEDGEMENTS:
The authors would like to thank the Deutsche Forschungsgemeinschaft (DFG) for funding this
project (SPP1423) and Roquette Frères for providing the mannitol (Pearlitol 160C).
REFERENCES:
[1]
[2]
Littringer, E., et.al., European Journal of Pharmaceutics and Biopharmaceutics, 194-204 (2012)
Littringer, E., et.al., Powder Technology, 193-200 (2013)
6
ICPE 2014
Die Face Pelletizing of Sticky HME Formulations
1
D. Treffer1, G. Koscher2, J. Khinast1,2
Institute for Process and Particle Engineering, TU Graz, 8010 Graz, Inffeldgasse 13/III
2
Research Center Pharmaceutical Engineering, 8010 Graz, Inffeldgasse 13/II
Email for correspondence: daniel.treffer@tugraz.at, khinast@tugraz.at
Hot melt extrusion is a continuous process with increasing importance for the pharmaceutical
industry [1]. An extruder processes a formulation into homogeneous strands of molten material
and offers, thereby, robust production opportunities for solid dispersions. Solid dispersions are
requested to face current drug development challenges such as poor water solubility or
modified release of the active pharmaceutical ingredient (API). The continuous emerging
material is shaped in the downstream process into the product of the extrusion line. Various
options are available. Often, pellets are requested as intermediates for capsule filling, tablet
compaction or injection molding. Pellets can be obtained by hot die face pelletizing or strand
pelletizing. They differ in terms of material temperature where the cutting takes place. During
strand pelletizing the material is drawn as cylindrical strands through a cooling section and
chilled near or below the softening point and cut by a rotating knife. Thus, solid bodies are cut
resulting in cylindrical-shaped pellets. Die face pelletizing is performed with a rotating knife
pressed on the extrusion die plate. Thus, the material is in a viscous state during cutting and
can deform due to surface tension into rounded pellet [2], [3]. Rounded pellets lead to better
flowability and enhance dosing accuracy in subsequent handling steps. However, this
downstream process was limited to few formulations because of stickiness [4], although a
similar principle is used in the plastics industry for several decades to process a broad variety of
materials. The plastics industry uses underwater pelletizing systems, where the stickiness of the
melt is suppressed by higher cooling intensities. In the pharmaceutical field, water-cooled
system are not suitable due to water solubility of the API and high purity requirements of the
products.
The objective of the presented study was a fundamental understanding of polymer melt
stickiness and its prevention during die face pelletizing. The impact of heat transfer on adhesion
properties has been analyzed and a hypothesis on melt stickiness derived. The hypothesis
relates heat transfer properties to the materials phase transition temperature. The proposed
hypothesis was confirmed with probe tack investigations at controlled heat transfer conditions.
This realization triggered a novel die plate design, which thermally decouples the die face from
the melt flow channel. Thus, the surface temperatures of the pelletizer are low as compared to
underwater pelletizing so that stickiness is prevented. The novel die plate’s heat balance has
been simulated and optimized in-silico and subsequently built and tested as a real prototype.
The die plate prototype was implemented into an extrusion line consisting of an 18 mm twinscrew extruder (Coperion ZSK 18) and a hot die face pelletizer (Automatik Plastics Machinery
GmbH, Sphero®-THA). The setup has successfully been applied to process different
pharmaceutical polymers which are commonly known for their sticky behavior. It has been
proven that the new design enables processing of sticky materials so that a broader range of
formulations can benefit from the advantages of die face pelletizing.
References:
[1]
[2]
[3]
[4]
M. A. Repka, N. Langley, and J. DiNunzio, Eds., Melt Extrusion - Materials, Technology and Drug
Product Design. New York, Heidelberg, Dordrecht, London: Springer, 2013.
E. Roblegg, E. Jäger, A. Hodzic, G. Koscher, S. Mohr, A. Zimmer, and J. Khinast, “Development
of sustained-release lipophilic calcium stearate pellets via hot melt extrusion.,” Eur. J. Pharm.
Biopharm., vol. 79, no. 3, pp. 635–645, Nov. 2011.
S. Bialleck, “Herstellung von Polysaccharidpellets mittels Schmelzextrusion,” Rheinischen
Friedrich-Wilhelms-Universität Bonn, 2011.
D. Treffer, P. Wahl, D. Markl, G. Koscher, E. Roblegg, and J. Khinast, “Hot Melt Extrusion as a
Continuous Pharmaceutical Manufacturing Process,” in Melt Extrusion: Equipment and
Pharmaceutical Applications, M. Repka, Ed. Springer Publishers, 2013.
7
ICPE 2014
Comminutive Pelletization Continuous Production of Hot Melt Extruded Pellets
R.-K. Mürb
Automatik Plastics Machinery GmbH, Grossostheim, Germany
E-mail for correspondence: Reinhardt-KarstenMuerb@maag.com
Hot-melt pelletizing becomes more and more of interest along with the increasing importance of
the hot-melt extrusion process for the pharmaceutical world, especially for novel drug
development of class-II and class-III substances. Although physical basics had been
established in the plastics processing chain for many years, adaptation to the needs of the
pharmaceutical environment experienced considerable progress within the last years and offers
great opportunities now.
The contribution highlights similarities and differences of hot-melt extrusion in comparison to
conventional dry or wet extrusion and sheds some light on the physics behind the process of
hot-melt pelletizing as well as engineering and layout aspects. The impact of continuous
production is highlighted as well.
8
ICPE 2014
Stirred Media Milling of an Organic Model
Compound in Ethanol
D. Steiner, J.-H. Finke, S. Breitung-Faes, A. Kwade
Institute for Particle Technology, Technische Universität Braunschweig/Germany
E-mail for correspondence: d.steiner@tu-braunschweig.de
It is presumed that more than 40 % of active pharmaceutical ingredients (APIs) being
identified through combinatorial screening programs are poorly water-soluble [1]. The
formulation of these drugs becomes particularly challenging if they are poorly soluble in both
aqueous and organic media, like e.g. intraconazole and carbamazepine. Different strategies
have been developed in the recent years in order to increase the bioavailability of these
APIs. One strategy focuses on the particle size reduction to produce nanosuspensions by
wet grinding or high pressure homogenization. With decreasing particle size the dissolution
rate of the particles increase, leading to a higher bioavailability of the API [2]. In the last
years the grinding behavior of different APIs and organic model drugs in aqueous
suspensions has been studied in detail [1].
The increasing number of APIs which are poorly soluble in water and organic solvents
extend the choice of fluids in which the wet grinding can be performed. Ethanol based
suspensions could provide different behaviors during wet grinding in mills or the postprocessing of nanosuspensions compared to aqueous suspensions. Spray drying e.g. is a
common method for the transformation of API suspensions into a dry powder. Due to the
lower boiling point of ethanol (78 °C) compared to water (100 °C) the drying process of this
organic solvent based formulation could be performed at lower temperatures which means
an advantage for the processing of thermosensitive APIs.
This study focuses on the grinding of an organic model material (lactose monohydrate) in
ethanol. The particle stabilization against (re-)agglomeration has been investigated in a
planetary ball mill (PM 400, Retsch GmbH), modified according to Juhnke [3], with 1 ml
grinding chambers. Yttrium-stabilized zirconium oxide grinding beads (x50 = 475 μm) were
used for the grinding experiments. The mill was operated at 400 rpm for 4 hours. Thereby,
the stabilizing performance of different additives (polymers and surfactants) has been
investigated. The resulting particle size was determined with laser diffraction (Helos,
Sympatec GmbH).
Furthermore, the grinding process of the stabilized particle suspension was scaled-up from
1 ml to 500 ml processed in a stirred media mill with a 140 ml grinding chamber in circle
mode (MiniCer, Netzsch GmbH). Herein, the grinding behavior was investigated regarding
the influences of the tip speed, solid content and grinding bead size and material. The
resulting suspensions were analyzed with dynamic light scattering (Nanophox, Sympatec
GmbH). The stress model was used to draw a comparison and explain the differences of the
grinding behaviors between the grinding results of ethanol-based and water-based organic
suspensions as well as the behavior of inorganic particles ground in ethanol.
1. Patravale, V.B., Date, A.A., Kulkarni, R.M. “Nanosuspensions: a promising drug delivery strategy”.
Journal of Pharmacy and Pharmacology, 56, 827-840 (2004)
2. Noyes, A. A., Whitney, W. R. “The Rate of Solution of Solid Substances in Their own Solutions”. Am
Chem Soc, 19, 930–934, 1897
3. Juhnke, M. et al. “Accelerated Formulation Development for Nanomilled Active Pharmaceutical
Ingredients Using a Screening Approach”. Chem. Eng. Technol., 33 (9), 1412-1418 (2010)
9
ICPE 2014
Freezing of Pharmaceutical Proteins: Benefits of
Process Characterization at Reduced Scales
B. Pittermann*, U. Roessl+
*Zeta Biopharma, Lieboch, Austria
+
Research Center Pharmaceutical Engineering GmbH, Graz Austria
Email for correspondence: Birgit.Pittermann@zeta.com
Freezing is a convenient and widely applied unit operation for stabilizing bulk solutions of
pharmaceutical proteins during storage and transportation. Despite its use for large amounts of
highly concentrated protein preparations, freezing and thawing (F/T) processes have rarely
been investigated at industrial scales.
Zeta lab-scale and pilot-scale freezers were designed to facilitate F/T process characterization
at reasonable scales and cost. Since every protein must be expected to react differently upon
F/T stresses, the Zeta lab-scale and pilot-scale freeze containers promise invaluable
improvements in efficiency compared to testing at original scales.
We show that process characterization is possible at intermediate scales in order to investigate
criticality of different operational parameters. Experimental design can be used for efficient and
significant testing of protein stability attributes. Considerations occurred with regard to Qualityby-Design (QbD)-principles.1
In addition, the lab-scale and pilot-scale freezers enable detailed investigations of F/T
processes. A specialized Computational Fluid Dynamics (CFD)-model can be used to predict
temperature and phase transition for freezing inside of the Zeta containers and provide valuable
information about solute distribution in the frozen state.2 Employing in-situ Raman spectroscopy,
a method was developed for secondary structure monitoring of proteins in the frozen state,
which has been applied to a F/T process in a Zeta pilot-scale freezer.3
The presented devices and methods were developed in close collaboration between Zeta
Biopharma and the RCPE and allow for studying and optimizing F/T processes at various
scales. In a joint presentation we will introduce the most expedient features of the Zeta freezer
systems and demonstrate that the investigation of F/T processes at intermediate scale offers
significant advantages over simple empirical process development at production scale.
1.
Roessl, U., Humi, S., Leitgeb, S. & Nidetzky, B. Pilot-scale freezing of L-lactic dehydrogenase:
Investigating the impact of processing conditions on protein stability. In Press (2014).
2.
Roessl, U., Jajcevic, D., Leitgeb, S., Khinast, J. G. & Nidetzky, B. Characterization of a
Laboratory-Scale Container for Freezing Protein Solutions with Detailed Evaluation of a Freezing Process
Simulation. J. Pharm. Sci. (2013).
3.
Roessl, U., Leitgeb, S., Pieters, S., De Beer, T. & Nidetzky, B. Protein secondary structure
determination in ice: Raman spectroscopy-based process analytical tool for frozen storage of
biopharmaceuticals. In Press (2014).
10
ICPE 2014
Progressing to i-pharmaceuticals
Drug delivery science driven by technology & patients
S. Stegemann
Capsugel, Bornem (Belgium) & RCPE, Graz (Austria)
Email for correspondence: Sven.stegemann@tugraz.at
Over the past two decades more than 600 new drugs were brought to the market allowing the
effective treatment of the most major chronic diseases effectively. In addition to this different
drug delivery systems and administration routes have emerged from drug delivery science to
increase the efficacy of the drugs.
On the other hand, increasing life expectancy and the baby boomers coming into age, the
treated patient population has significantly evolved too; patients beyond 85 and even 95 years
will rather be the norm than the exception and must be considered as new patient populations.
This is even more true considering that chronic diseases occur with age and drug therapy is
becoming an integral part of our later life, with a high likelihood to develop into “polypharmacy”
when multiple chronic diseases occur.
Despite the increasing complexity of drug therapy the responsibility of the medication
management is shifted to the patients when the pharmacist is handing over the drug products,
forgetting that the majority of patients are lay persons. It is not surprising that medication errors
and inappropriate alteration have been identified as a growing area of concerns for drug safety
and efficacy. With our patient information leaflets we are trying to make the patients fit for the
product even so we know that heath literacy is often insufficient in the general patient population
especially with our medical and technical language and abbreviations. Therefore, regulatory
authorities are looking into ways to move from the concept of “efficacy” to “effectiveness” to
assure that the drug products approved reach the therapeutic outcomes seen in the randomized
clinical trials [1].
In order to overcome the challenge of poor adherence and therapeutic outcomes, drug delivery
technology will have to move from a theoretical conceptual design to a patient centric product
design by including the real patients in the development. Factors that need to be considered in
the design of patient centric products are based on the expected targeted patient population,
within their own living environment and day structure. The major patient factors that need to be
taken into account are the cognitive, sensory, motoric and swallowing capabilities of the patient
[2, 3], but also the prediction of the context in which these drug therapies will be applied e.g.
disease clusters/predicted co-morbidities, polypharmacy, home setting etc. Based on this, the
design features are determined for a specific product to make it most suited for the targeted
patient and will intuitively be used in the intended way. Combining drug delivery technology
meeting patients’ therapeutic needs with and patient centered drug product design that is
intuitively used as intended like i-phones and other products from the consumer industry will
significantly increasing safety and effectiveness to the benefit of the patient and society.
1.
Eichler H-G., Abadie E., Beckenridge A., Flamion B.,Gustafsson L.L., Leufkens H, Rowland M.,
Schneider C.K., Bloechel-Daum B.: Bridging the efficacy-effectiveness gap: a regulator’s
perspective on addressing variability of drug response. Nature Rev Drug Disc 10(7) 495 – 506
(2011)
2.
Stegemann S, Ecker F, Maio M, Kraahs P, Wohlfahrt R, Breitkreutz J, Zimmer A, Bar-Shalom D,
Hettrich P, Broegmann B: Geriatric drug therapy: neglecting the inevitable majority. Aging Res
Rev 9, 384 – 398 (2010)
3.
Stegemann S, Gosch M, Breitkreutz J.: Swallowing dysfunction and dysphagia is an
unrecognized challenge for oral drug therapy. Int J Pharm 430: 197-206 (2012)
11
ICPE 2014
Effects of Particle Size and Structure on the Drug
Loading Capacity of Lipid Nanoparticles
E. Kupetz, H. Bunjes
Institut für Phrmazeutische Technologie, Technische Universität Braunschweig,
Mendelssohnstraße 1, 38106 Braunschweig, Germany
Email for correspondence: heike.bunjes@tu-braunschweig.de
Lipid nanocarriers are being intensively investigated as carriers for poorly water soluble drugs
and several drug products based on this concept have reached the market. There is, however,
still only limited knowledge on the relations between the composition and structure of these
carrier particles and their drug loading capacity. In order to obtain deeper insight into the
structure-function-relationships of lipid drug carrier nanoparticles a screening procedure was
developed which allows to obtain data on the drug carrier capacity of different types of
nanoparticulate carriers within comparatively short time [1]. This method is based on the
incubation of pre-formed nanocarrier dispersions with the respective drug substance and was,
for example, successfully applied to find suitable carriers for an investigative drug candidate [2].
Beyond its use for the identification of suitable carrier systems, the method can also be
employed to obtain more fundamental information, like, e.g., effects of carrier particle size and
structure on the achievable drug load. In this work, the influence of these parameters was
studied for lipid nanoemulsions and -suspensions. Conclusions about drug localization were
drawn from the relations between lipid mass, specific particle surface area and drug load in the
respective dispersions.
Emulsions and suspensions comprised trimyristin as lipid matrix and poloxamer 188 as
emulsifier. Well defined dispersions with different particle sizes were prepared by premix
membrane extrusion [3] or high pressure melt homogenization, respectively. The pre-formed
nanodispersions were passively loaded with amphotericin B, curcumin, dibucaine, fenofibrate,
mefenamic acid, propofol and a porphyrin derivative. Drug load and lipid content were quantified
by UV spectroscopy and high performance liquid chromatography, respectively.
The passive loading procedure was successful for all drugs in emulsions and suspensions with
higher drug loads being achievable for the emulsion particles in most cases. However,
amphotericin B and curcumin could be loaded at higher concentrations into lipid
nanosuspensions than into corresponding nanoemulsions. It strongly appeared that for solid
particles drug molecules exclusively associated at the particle surface under these conditions.
Emulsion droplets could accommodate drugs in the lipid core as well as at the surface the ratio
being drug specific. As a general rule, smaller particles led to higher drug loads than larger
ones. Propofol and the porphyrin derivative displayed eutectic interaction with the lipid and
crystal growth after loading, respectively, which made conclusions on their localization difficult.
th
1.
K. Rosenblatt, H. Bunjes, Poster presentation # 126, 6 PBP World Meeting, Barcelona 2008.
2.
E. Kupetz, L. Preu, C. Kunick, H. Bunjes, Eur. J. Pharm. Biopharm. 85 (2013) 511–520.
3.
S. Joseph, H. Bunjes, J. Pharm. Sci. 101 (2012) 2479–2489.
12
ICPE 2014
Miscibility, processing, and stability considerations of
spray-dried amorphous solid dispersion: A tale of
naproxen-PVP system
Amrit Paudela,*, Yves Loysona, Guy Van Den Mootera
a
Drug Delivery and Disposition, KU Leuven, Belgium
*Current address: Research Centre Pharmaceutical Engineering (RCPE), Graz, Austria
Email for correspondence: amrit.paudel@rcpe.at
Aim: To rationalize the current trial and error practice of manufacturing spray-dried amorphous
solid dispersions (SDD)[1], a thorough investigation was designed with a selected model poorly
water soluble drug, naproxen and a solid dispersion carrier, polyvinylpyrrolidone (PVP).
Materials and Methods: The predictability of the equilibrium solid solubility and
heteromolecular interaction parameter of naproxen in PVP of different chain length by different
Flory Huggins (FH)-based mixing thermodynamic models was envisaged[2]. Next study related
drug-polymer interactions in solution to the molecular miscibility profiles of resulting solid
dispersions and to the latter with the solid-state hydrogen (H) bonding behavior in the
dispersions[3]. Finally the influence of feed solution properties[4] and critical spray-drying
process parameters[5] on the physical structure, physical stability and in vitro dissolution
behavior of SDD prepared from the naproxen-PVP was investigated.
Results and discussion: Comparison of the experimental drug-polymer binary phase behavior
(kinetic miscibility) with the solid solubility and intermolecular interaction predicted by FH mixing
models revealed that SDD are highly supersaturated with respect to the estimated solid
solubility of the drug in the polymer. Also, currently used mixing models lacking the accounts of
H-bonding were unable to discriminate the PVP chain length effect on the phase behavior of
SDD. Spray-drying solvent composition was shown to be another contributor for the particular
phase structure of the end product. Moreover, addition of an anti-solvent for the polymer
resulted in SDD with superior miscibility and physical stability. Next, the phase behavior and
intermolecular interactions between naproxen-PVP were contrasted in solid dispersions
prepared by slow solvent evaporation and those prepared by quench cooling. A persuasive
difference was evidenced in the composition-dependent miscibility and in the intermolecular
interactions. In addition, the spray drying temperature and atomizing conditions proved to be the
key process parameters influencing the miscibility, stability and in vitro performance of the
spray-dried dispersions. Faster evaporating conditions viz., higher inlet temperature and/or
higher atomization airflow rate resulted into heterogeneous amorphous dispersions of the
selected systems which, in contrary, possessed higher physical stability against moistureinduced phase separation and recrystallization. Furthermore, higher compression force induced
demixing in SDD beyond a certain drug loading and the extent of this behavior was inherited by
the processing conditions of SDD manufacturing[5].
Conclusion: Understanding the physical chemistry of drug-carrier miscibility, impact of spray
drying processing parameters on various physical/chemical processes (evaporation, drying,
atomization, phase distribution, crystallization etc) is crucial for the structural development of
physicochemically stable SDD.
References:
1. Paudel et al (2013). Manufacturing of solid dispersions of poorly water soluble drugs by spray drying:
Formulation and process considerations, Int. J. Pharm. 453:253-284.
2. Paudel et al (2010). Theoretical and experimental investigation on the solid solubility and miscibility of
naproxen in poly (vinylpyrrolidone), Mol. Pharmaceutics 7:1133-1148.
3. Paudel et al (2013). Relating hydrogen-bonding interactions with the phase behavior of naproxen/PVP
K 25 solid dispersions: Evaluation of solution-cast and quench-cooled films, Mol. Pharmaceutics 9:
3301-3317.
4. Paudel and Van den Mooter (2012). Influence of solvent composition on the miscibility and physical
stability of naproxen/PVP K 25 solid dispersions prepared by cosolvent spray-drying, Pharm. Res.
29:251-270.
5. Paudel et al (2013). An investigation into the effect of spray drying temperature and atomizing
conditions on miscibility, physical stability, and performance of naproxen–PVP K 25 solid dispersions,
J. Pharm. Sci. 102:1249-1267.
13
ICPE 2014
The Stability of Amorphous Solid Dispersions - What
can We Learn from Mathematical Models?
M. Brunsteiner, A. Paudel, J. Khinast
Research Center Pharmaceutical Engineering Gmbh, Graz
Email for correspondence: michael.brunsteiner@rcpe.at
The increasing number of poorly water soluble drug candidates in pipelines represents a
challenge for formulation science. A strategy for obtaining formulations for oral delivery with
improved solubilities is based on the preparation of amorphous solid dispersions (ASD). [1] The
major issue impeding a widespread application of this strategy is the limited physical stability of
ASDs. Here we compare a number of approaches that can be used to estimate the impact of
the choice of excipient on the relative stabilities of ASD-based formulations. Using Molecular
Dynamics simulations of ASDs comprising different API-excipient combinations we calculate a
number of in-silico descriptors of these systems, including the strength of intermolecular
interactions (hydrogen bonding, cohesive energy densities), and molecular mobilities. We
analyze correlations between such descriptors and relative stabilities of ASDs, and discuss
strategies for obtaining in-silico descriptors that provide improved predictive power and insights
into the physics at the basis of ASD stabilities.
1.
Chau Le-Ngoc Vo, Chulhun Park, and Beom-Jin Lee. Current Trends and Future Perspectives of
Solid Dispersions Containing Poorly Water-Soluble Drugs. European Journal of Pharmaceutics and
Biopharmaceutics, 85(3 Pt B):799–813, 2013.
14
ICPE 2014
Compressing of granules into minitablets and tablets
– is there any difference?
A. Kamola1, K. Owcarz1, H. Kotlowska2, S. Przerada3, M. Sznitowska2
Student Chapter of the International Society for Pharmaceutical Engineering, Department of
Pharmaceutical Technology, Medical University of Gdansk, Gdansk, Poland
2
Department of Pharmaceutical Technology, Medical University of Gdansk, Gdansk, Poland
3
Pharmaceutical Works Polpharma SA, Starogard Gdanski, Poland
Email for correspondence: msznito@gumed.edu.pl
1
INTRODUCTION
Minitablets (1-3 mm in diameter) are promising new dosage forms which can be used to adjust
dosage by multiplication or to modify drug release rate or for taste masking in pediatrics [1]. Like
conventional tablets (T), minitablets (MT) can be compressed directly from powder mixtures or
after granulation [2]. In the study T and MT were prepared from different granules with the aim
to indicate whether some properties of the granules can be more important in the compression
of MT than in tabletting of T.
METHODS
Five formulations of the placebo granules, based on lactose and microcrystalline cellulose, were
prepared by wet granulation. For tabletting the granules were used as un-fractionated (size up
to 1000 µm) or as a fraction below 250 µm. The granules were characterized by flowability,
angle of repose, compressibility index and Hausner ratio. Particle size distribution was
determined by sieve analysis. PRUV (sodium stearyl fumarate) was added as a lubricant in
concentration of 1% or 3% w/w. MT (thicknes/diameter ratio 0.8 or 1.3) were produced with a
rotary tablet press equipped with a single or multiple 2 mm punches. For comparison, T with a
diameter 5 mm and 7 mm (thicknes/diameter ratio 0.8 and 0.7, respectively) were compressed.
Compression pressure of 160 and 250 MPa, and pre-compression force of 100 and 500 N were
used. MT and T were tested for mass uniformity, crushing strength (measured with a texture
analyzer) and friability.
RESULTS
According to compressibility index and Hausner ratio, the granules showed good, fair or poor
flowability. However, MT with acceptable mass uniformity (RSD below 10%) were obtained from
all tested granules, independent of the size of granules. The crushing strength was about 10 N
for smaller MT, 20 N for “thicker” MT, and 30-60 N for T. In spite of such difference friability of
MT was generally less than 0.4%. The mechanical strength of both, MT and T, depended on the
compression force, but no effect of the pre-compression force was noted. The tensile strength of
T and MT was similar and also similar increase of the mechanical strength was achieved in MT
and T by decreasing a content of the lubricant from 3% to 1%.
CONCLUSION
The size of the granules did not affect the process of the compression of MT. The relationship
between the granules flowability or compression pressure and MT hardness was similar like
observed for T. Similarly, the content of lubricant influenced the hardness of MT and T in the
same manner. It was concluded that for production of MT no special requirements for the quality
of granules are necessary.
Acknowledgements: The research is financially supported by The National Centre of Research
and Development, Poland
REFERENCES
1. Ernest T.B., Craig J., Nunn A., Salunke S., Tuleu C., Breitkreutz J., Alex R., Hempenstall J. 2012.
Preparation of medicines for children – A hierarchy of classification. Int. J. Pharm. 435, 124-130.
2. Tissen C., Woertz K., Breitkreutz J., Kleinebudde P. 2011. Development of mini-tablets with 1
mm and 2 mm diameter. Int. J. Pharm. 416, 164-170.
15
ICPE 2014
Integration of ecological aspects in sustainable
pharmaceutical production in multi-purpose plants
1
M. Wesche1, M. Häberl2, M. Kohnke2, S. Scholl1
Technische Universität Braunschweig, Institute for Chemical and Thermal Process
Engineering, Braunschweig, Germany
2
Merck KGaA, Darmstadt, Germany
Email for correspondence: mandy.wesche@tu-braunschweig.de
Sustainability has become a major topic in the product and process development strategy for
many companies in the chemical, special chemicals and pharmaceutical industry [1, 2] as
shown in initiatives or collaborative research programs like Chemie³ or F³-Factory. Besides
social and economical aspects ecological considerations are gaining increasing attention as
part of the improvement of existing and the design of new processes and production sites.
In pharmaceutical production the manufacturing facilities are often operated as multi-purpose
plants. Individual production processes for different products are set up modularly by combining
the relevant unit operations in the process. In an existing multi-product plant the portfolio of
feasible unit operations and available equipment is fixed and new production processes have to
fit into this portfolio. Thus, none of the processes use specifically tailored equipment. It can be
assumed that these processes exhibit large potentials in regard to energy and resource
efficiency.
This contribution will present an approach for a modular based modeling method that allows the
assessment of processes in such multi-purpose plants. It considers the special challenges
arising from the use of multi-purpose plants:
1. The acquisition of consumption data of a single process taking into account central
equipments of the multi-purpose plant.
2. The allocation of the ecological expenditures resulting from the provision and disposal of
the multi-purpose plant as well as the service and maintenance over lifetime to the
different processes manufactured in the plant.
3. The identification and quantitative assessment of potential ecological improvement for a
specific process.
The application of the developed approach will be shown for a typical pharmaceutical
production process. The approach is based on the Three Level Model, which considers three
different levels of detail for process modeling: unit operation, process and production site [3]. It
forms the foundation for a process reflection in material flow based simulation tools, for example
umberto® of ifu Hamburg GmbH. Using standardized building blocks for equipment components,
such as stirred vessels or dryers and process steps, such as cooling or inertization, reduces the
time demand and increases the flexibility for the modeling of different processes. The
transparent reflection of all components, mass and energy flows allows a systematic process
analysis including the identification of unit operations with significant ecological relevance.
Furthermore allocation approaches with different levels of detail have been considered and the
individual influence of the assignment accuracy has been determined. The combination of
calculated consumption data in the model and the allocated plant expenditure enable a holistic
ecological assessment of production process in multi-product plants. The presented approach
supports a continuous consideration and improvement of ecological aspects in the optimization
of existing as well as the development of new manufacturing processes.
[1] Grundemann, L., Gonschorowski, V., Fischer, N., Scholl, S.: Cleaning waste minimization for multiproduct plants: transferring macro batch to micro conti manufacturing. J. Cleaner Prod. 24, 92-101(2012).
[2] Huebschmann, S. et al.: Decision Support Towards Agile Eco-Design of Microreaction Processes by
Accompanying (Simplified) Life Cycle Assessment, Green Chem. 13, 1694 – 1707 (2011).
[3] Wesche, M., Häberl, M., Kohnke, M., Scholl, S.: Ecological Assessment of Pharmaceutical Production
Processes in Multi Product Plants. Short-paper of the 9th PBP World Meeting, Lisbon, April 2014.
16
ICPE 2014
A Critical Eye on Controlled Nucleation during
Lyophilization
I. Konrad1,2, R. Geidobler2, A. Freitag1, W. Friess2, A. Hawe1, G. Winter2
1
Coriolis Pharma Research GmbH, D-82152 Martinsried, Germany
2
Ludwig-Maximilians-University, D-81377 Munich, Germany
Department of Pharmacy, Institute for Pharmaceutical Technology and Biopharmaceutics
Email for correspondence: Ilona.Konrad@coriolis-pharma.com
Controlled nucleation gains importance for the pharmaceutical industry, because of the
economical advantage of shortened primary drying time due to larger pores formed at higher
nucleation temperatures [1], Our work is a critical evaluation of the implementation of controlled
nucleation in pharmaceutical development and production with focus on protein drugs.
Several methods to induce controlled nucleation are available on the market, e.g. Millrock
Freeze Booster® [2], Praxair Depressurization Method [3], Veriseq Nucleation Station [4] or the
Ice Fog method recently described by Geidobler et al. [5]. The different methods have been
reviewed regarding scalability, applicability in aseptic environments and necessary retrofits in
another work of Geidobler et al. [6]. Three different ice fog methods (Millrock Freeze Booster®,
Veriseq Nucleation Station and the method by Geidobler et al.) will be compared with respect to
process parameters like primary drying time as well as product quality aspects, like
reconstitution times and product stability.
It has been shown [7] that controlled nucleation is beneficial for highly concentrated protein
formulations (BSA 193 mg/ml, mAB 161 mg/ml), to reduce primary drying time and shorten
reconstitution times of these protein formulations from ~ 15 min to less than 5 min. The process
established in [7] has already been transferred to the Millrock Freeze Booster®, leading to
similar physico-chemical product characteristics and a comparable reduction of primary drying
time.
The combination of controlled nucleation with aggressive primary drying of highly concentrated
protein formulations confirmed the previously published results regarding physico-chemical
properties and faster reconstitution times after controlled nucleation. Furthermore, aggressive
primary drying substantially reduces drying time independent of the freezing protocol (controlled
as well as random nucleation).
Controlled nucleation has the potential to become an increasingly important method in freezedrying, because of economic benefits of reduced process times and improved product quality
with respect to reconstitution times. Further investigations on the impact of controlled nucleation
on more crucial product quality attributes such as long term stability will be addressed in the
future.
1. Hottot A, Vessot S, et al. Chem. Eng. Process. Process Intensif. 2007;46:666–74.
2. Weija L. Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice
fog distribution, Patent US2012/02722544 A1. 2012.
3. Gasteyer TH, Sever RR, et al. Method of inducing nucleation of a material, Patent US20070186567A1.
2007.
4. Kaltenegger P, Lee R, et al. Neuartiges Verfahren zur Steuerung der Eiskeimbildung. Technopharm.
2012;2:420–4.
5. Geidobler R, Mannschedel S, et al. A New Approach to Achieve Controlled Ice Nucleation of
Supercooled Solutions During the Freezing Step in Freeze-Drying. 2012;101:4409–13.
6. Geidobler R, Winter G. Controlled ice nucleation in the field of freeze-drying: fundamentals and
technology review. Eur. J. Pharm. Biopharm. 2013;85:214–22.
7. Geidobler R, Konrad I, et al. Can Controlled Ice Nucleation Improve Freeze-Drying of HighlyConcentrated Protein Formulations? J. Pharm. Sci. 2013;102:3915–9.
17
ICPE 2014
Bacterial Ghost Platform Technology for
Pharmaceutical Protein Production
T. Langemann*/***, A. Meitz*, P. Sagmeister**, C. Herwig**
* RCPE GmbH, Graz; ** Technische Universität Wien, *** BIRD-C GmbH, Wien
Email for correspondence: timo.langemann@bird-c.at
Pharmaceutical proteins are commonly produced using recombinant DNA technology with
mainly microbial or mammalian hosts1. Bacterial Ghosts (BGs) are empty non-living cell
envelopes that are produced from Gram-negative bacteria - e.g. Escherichia coli - by protein Emediated lysis2. Protein E induces formation of a discrete lysis tunnel through which the
cytoplasm (CPS) is expelled while the periplasm (PPS) is sealed and its contents retained. Prior
to E-lysis heterologous proteins can be expressed either in the CPS or the PPS2.
Expressing recombinant human protein in the CPS of E. coli often results in misfolded protein
monomers which form insoluble inclusion bodies (IB). After E-lysis, which removes all
cytoplasmic components, the IB have to be solubilized and the protein refolded into a bioactive
dimeric form3. Exporting the protein into the PPS allows for proper protein folding due to an
oxidizing environment and a family of proteins assisting disulphide bond formation4. In this case,
refolding is obsolete and the functional dimer can be directly purified from the PPS of the BGs.
The concept of the platform technology is depicted in the figure below (1: PPS, 2: CPS).
We have shown the applicability of the described platform technology with E. coli strain C41
BGs and a dimeric recombinant human growth factor (rhGF) as target protein. We were able to
produce the target protein in both compartments (CPS/PPS) of the bacteria and subsequently
induce E-lysis for release of the cytoplasm. We have found soluble dimer of rhGF after E-lysis in
preparations from the periplasmic expression system. For expression of rhGF as IB in the
cytoplasm we have established a robust refolding procedure that allows for independent control
of the critical process parameters dissolved oxygen concentration and redox potential with a
refolding yield of > 70%. Analytics for identification of the rhGF was done via specific Western
Blot, quantification of rhGF monomer and dimer was done using analytical size exclusion
chromatography (SEC). Functionality of the dimeric rhGF was shown in a bioactivity assay with
similar performance as the commercial reference product. With these results the described
system has proven to be a promising alternative for production of recombinant pharmaceutical
proteins in E. coli.
1.
Ferrer-Mirales, N. et al.: Microbial factories for recombinant pharmaceuticals. Microb Cell Fact,
2009. 8 (17)
2.
Langemann, T. et al.: The Bacterial Ghost platform system: production and applications. Bioeng
Bugs, 2005. 1 (5), p. 326-336
3.
Singh, S.M. et al.: Solubilization and refolding of bacterial inclusion body proteins. J Biosci
Bioeng, 2005. 99 (4), p. 303-310
4.
Hannig, G. et al.: Strategies for optimizing heterologous protein expression in Escherichia coli.
Trends Biotechnol, 1998. 16 (2), p 54-60
18
ICPE 2014
NANEX: A Rational Design of the Manufacturing of a
Solid Oral Nanoparticle Formulation
R. Baumgartner *, J. Khinast *,**, E. Roblegg ***
* Research Center Pharmaceutical Engineering GmbH, Graz, Austria
** Institute for Process and Particle Engineering, Graz, University of Technology, Austria
*** Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology,
Karl-Franzens University Graz, Austria
Email for correspondence: eva.roblegg@uni-graz.at
More than 40% of today´s drugs suffer from low stability, poor solubility and/or limited ability to
cross certain biological barriers. Thus, the implementation of new platform technologies that
manage these challenges as early as possible is without controversy.
On that account, a one-step process (i.e., NANEX) was developed, which enables the
conversion of a stabilized aqueous nanosuspension (i.e., Phenytoin nanosuspension prepared
via media milling and stabilized by Tween® 80) into a solid oral formulation with improved
solubility behavior by tailoring a conventional process (i.e., hot-melt extrusion) 1,2.
The aim of this study was firstly, to evaluate materials that are suitable for incorporating
aqueous suspensions during hot melt extrusion and secondly, to gain a comprehensive
process-understanding. Therefore, three distinct polymers (Soluplus®, Kollidon® VA 64,
Hypromellose acetate succinate/Kolliphor® P188 (HPMCAS/KP188)) were used. The process
parameters, such as screw configuration, throughput and screw speed, were adapted to the
process requirements. The maximum amount of water that was added to the molten matrix
material without blocking the degassing unit (due to insufficient adhesion of the molten mass to
the screw) was determined and the residual moisture contents of the extrudates were measured
via Karl-Fischer titration.
The results demonstrated that the amount of water fed to the material was strongly dependent
on the filling degree of the screw, which, in addition, is a function of the throughput and the
screw speed. The lower the filling degree was the higher was the amount of added water.
Based on these findings, stabilized Phenytoin nanosuspensions were fed directly to the molten
polymers and obtained nano-extrudates were investigated regarding nanocrystaldistribution/verification via electron microscopy (EM) and atomic force microscopy. Finally,
dissolution studies were conducted.
Summing up, it can be stated, that all tested polymers were appropriate for incorporating
water/aqueous nanosuspensions homogeneously. Moreover, the results of Karl-Fischer
titrations clearly demonstrated that the excess-water was removed entirely via devolatilization.
EM investigations of the Phenytoin-loaded nano-extrudates showed that the nanocrystals were
embedded de-aggregated in the extrudates and dissolution studies confirmed an increase in the
solubility behavior of nanocrystalline Phenytoin from the prepared nano-extrudates,
independent on the polymer.
It can be concluded that NANEX represents a promising new platform technology in the design
of novel drug delivery systems that improves the performance of critical drugs.
1. Baumgartner R, Khinast JG, Roblegg E. Manufacturing of a Solid Oral Phenytoin Nanoparticle
Formulation via Nano-extrusion (NANEX).submitted. 2014
2. Khinast J, Baumgartner R, Roblegg E. Nano-extrusion: a One-Step Process for Manufacturing of Solid
Nanoparticle Formulations Directly from the Liquid Phase. AAPS PharmSciTech. 2013.
19
ICPE 2014
Two-dimensional PBM for simultaneous modelling of
drying and breakage of pharmaceutical granules
S.T.F.C. Mortier*,1,2, K.V. Gernaey3, T. De Beer**,2, I. Nopens1
1
BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of
Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
2
Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical
Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000
Ghent, Belgium
3
Department of Chemical and Biochemical Engineering, Technical University of Denmark,
Building 229, 2800 Kgs. Lyngby, Denmark
Email for correspondence: * Severine.mortier@ugent.be
** Shared last authorship
The production of pharmaceutical tablets is the result of different subprocesses. The use of a
wet granulation technique during tablet production requires subsequent drying of the wet
granules, which can be achieved using several techniques. This choice potentially influences
the properties of the granules and, hence, their further downstream processing. Here, a
fluidized bed dryer is studied, which is part of a full continuous from-powder-to-tablet line, i.e.
the ConsiGmaTM.
The development of mechanistic models is increasingly important, for example due to the
ongoing transition from batch to continuous production processes and its accompanied need for
improved process understanding. Models play a significant role in the latter, and, moreover,
they facilitate process optimization and the development of control strategies.
During drying the fluidizing granules are prone to break up potentially resulting in smaller sized
granules. The combination of breakage and drying can be modeled using a Population Balance
Model (PBM). A PBM is a tool to analyse particles that are interacting with each other and the
continuous phase. A one-dimensional PBM describing the evolution of the moisture content
distribution during drying was developed in previous research. In this contribution, this model
has been extended towards a two-dimensional PBM. The model now allows predicting the
evolution of the granule size distribution as well as the moisture content distribution during
drying. Several breakage mechanisms have been implemented. A differentiation can be made
between granule breakage and surface erosion. Whereas in the first case two or more smaller
particles are formed with a noticeable size, in the latter case fine dust is formed while the size of
the mother particle remains almost identical. Several mechanisms have been theoretically
investigated, i.e. erosion, the formation of two equal fragments, etc. Another important aspect is
the rate of breakage. Both the breakage rate and the breakage mechanism will be influenced by
several variables. The gas velocity during fluidization will have an impact on the breakage rate,
where a higher gas velocity will increase the breakage rate. Furthermore, it can be expected
that dryer particles will be more subjected to erosion compared to wetter particles. The form and
the size of the particles will both influence the rate and the mechanism of breakage. Spherical
particles are less prone to breakage compared to elongated particles.
In this study, the breakage behaviour during drying has been investigated theoretically by
simulating the PBM for different breakage mechanisms and rates. The effect of the parameters
in the kernels has been analysed in detail.
20
ICPE 2014
A Novel Simulation Approach for Hot Melt Extrusion
A. Eitzlmayr*, J. Matić**, G. Koscher**, J. Khinast*,**
*Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse
13/III, 8010 Graz, Austria
**Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/III, 8010 Graz, Austria
Email for correspondence: khinast@tugraz.at
Hot melt extrusion attracts increasing importance as pharmaceutical manufacturing operation. It
provides potential to overcome the bioavailability challenge of poorly soluble drug molecules via
solid solutions. The continuous process characteristics, and the unification of different functions
in a single device (e.g., melting, distributive and dispersive mixing, degassing) provide high
potential for increased efficiency and reduced operation costs.
The most common extrusion devices in pharmaceutical manufacturing are co-rotating twinscrew extruders. In contrast to different types (e.g., single-screws, counter-rotating twin-screws,
multi-screws) the co-rotating twin-screws are frequently preferred due to their mixing
performance and self cleaning screw profiles. The typically used modular screw design provides
high flexibility for operation.
Extrusion processes are well known from the polymer and food industry since many years.
Nevertheless, the simulation of these processes is still highly challenging due to the complex
geometry of extruder screws and the variety of the involved phenomena. E.g., for conventional,
mesh-based CFD (Computational Fluid Dynamics) methods the rotation of the screws requires
sophisticated remeshing techniques [1]. Similarly, the free surface flow in partially filled sections
is extremely challenging for mesh based simulation methods. Moreover, the typical polymer
melts are non-Newtonian (shear-thinning, often viscoelastic) and their rheological properties are
temperature dependent. The temperature is strongly inhomogeneous due to the high viscosity
and the related dissipation, resulting in a nonlinear, coupled system of the underlying equations.
The melting zone is even much more complicated, since the material there exhibits the entire
spectrum from granular to molten state on a scale that required an extremely high resolution.
In order to develop a comprehensive approach which provides sufficient potential to address
these goals, we investigated the applicability of the Smoothed Particle Hydrodynamics (SPH)
method. SPH is a Lagrangian particle method for the simulation of fluids, i.e., it represents the
flow by the movement of small fluid elements [2]. Thus, SPH is mesh-free, which is a significant
advantage compared to mesh-based CFD methods in this application. Furthermore, SPH does
inherently represent free surface flows and convective mixing. Since the typical methods to
model wall boundaries in SPH (e.g., boundary particles, ghost particles) were not sufficient for
the complex geometry of extruder screws, we developed a novel wall interaction, which allows
the interaction of fluid elements with a flat wall surface (e.g., generated by CAD software in the
*.STL format) without using additional particles. We implemented our approach into the opensource particle simulator LIGGGHTS (www.liggghts.com) and validated a twin-screw conveying
element using literature data generated with conventional CFD [3]. In the same simulations, we
studied mixing phenomena in completely filled and partially filled states.
Up to now, our work is based on the rheology of a Newtonian fluid. In the next step, we want to
implement more complex rheologies and the thermal energy equation to account for the
temperature distribution. Furthermore, we are going to characterize mixing phenomena for
important types of screw elements.
1.
A. Sarhangi Fard et al., Int. J. Numer. Meth. Fl. 68 (2012), 1031-1052.
2.
J.J. Monaghan. Rep. Prog. Phys. 68 (2005) 1703-1759.
3.
M. Bierdel, in K. Kohlgrüber, Co-Rotating Twin-Screw Extruders, Carl Hanser, Munich, 2008.
21
ICPE 2014
A decision making framework for optimal
implementation of equipment management in
manufacturing execution system
S. Sandström*,**, J. Matilainen*, A. Juppo**, C. Rothkopf*
* Pharmaceutical Development & Supplies, PTD Biologics Europe,
F. Hoffmann-La Roche Ltd, Basel, Switzerland
** Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Finland
Email for correspondence: christian.rothkopf@roche.com
Manufacturing execution systems (MES) are increasingly adapted in pharmaceutical industry
[1]. Implementation solutions differ, however, and there is no single solution which would be the
optimal one for all facilities. Each manufacturing facility has their unique properties and needs
which have to be reflected in the implementation. A successful MES project will bring plenty of
benefits such as more efficient use of resources and automated data transfer, but the roll out
phase might turn to be problematic if the processes of the organization have not been analysed
thoroughly enough at decision making [2]. This creates the need for a systematic analysis of
possible to-be implementation scenarios which is based on the value-drivers of the organization
and considers the decision from multiple viewpoints.
This study presents a holistic value driver-based framework with a mathematical weighing
method to allow for a systematic and scientifically justified decision for identification of the
optimal implementation depth of equipment management (EQM) in MES. A modified Delphi
method [3] was utilized in this study to create the framework. The framework was developed
based on literature and brainstorming sessions with experts and validated by means of a Delphi
questionnaire round with expert panel consisting of professionals representing the major
stakeholders of MES system in a pharmaceutical manufacturing facility. Classical additive
weighting method [4] was applied to create the mathematical basis for valuation and
comparison of the scenarios. The robustness of mathematical method was tested by means of
a sensitivity analysis.
The presented method not only addresses the costs but also takes into account intangible
factors. Intangible factors include aspects such as GMP quality and user acceptance which are
not directly transferable into quantitative units but are crucial both for pharmaceutical industry
and the success of the implementation project. The framework describes the decision in the
form of a value tree with three main branches, namely GMP, cost and process/organization
which cover the main viewpoints important for the decision. The presented method also allows
the weighing of different factors according to current needs of the facility and decision in
question. Hence, the presented framework leads the decision maker through a systematic and
comprehensive analysis of different to-be scenarios for EQM implementation.
As a use case, the presented framework was applied in a parenterals clinical manufacturing
facility to evaluate four different to-be scenarios and the highest ranked scenario was chosen by
site management for the next implementation step. The results from the use case indicate that
the method is a valuable tool in a decision making process, and encourage the further utilization
of the tool in future implementation decisions.
1. Savage D. Has MES reached maturity in the pharmaceutical industry?. Pharmaceutical Engineering
2013; 33(4); 1-7.
2. Poulsen L. Verbesserung des Unternehmenserfolgs durch MES. TechnoPharm. 2014; 4(1): 49-53.
3. Linna A, Korhonen M, Mannermaa JP, Airaksinen M, Juppo AM. Developing a tool for the preparation
of GMP audit of pharmaceutical contract manufacturer. Eur J Pharm Biopharm. 2008; 69(2):786-792.
4. Farid SS, Washbrook J, Titchener-Hooker NJ. Combining multiple quantitative and qualitative goals
when assessing biomanufacturing strategies under uncertainty. Biotechnol Prog. 2005; 21(4):11831191.
22
ICPE 2014
Improvement of adherence and safety of senior
patients through multi-frequency RFID technology
supported medication
E. Stocker (a), S. Heidenbauer (a), S. Sacher (a), G. Holweg (b), T. Herndl (b), G.
Breitfuss (c), J. G. Khinast (a),(d)
(a) Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz,
Austria
(b) Infineon Technologies AG - Development Center Graz, Babenbergerstraße 10, 8020
Graz, Austria
(c) evolaris next level GmbH, Hugo-Wolf-Gasse 8, 8010 Graz, Austria
(d) Institute for Process and Particle Engineering, Graz University of Technology,
Inffeldgasse 13, 8010 Graz, Austria
Email for correspondence: elena.stocker@tugraz.at
According to statistics published by the world health organization WHO 50% of patients do
not adhere to a pharmacotherapy prescribed by their physician. Although not only patients
health is endangered, but also enormous costs for the health care system are caused [1].
However, adherence can be easily and efficiently supported due to appropriate aids - even in
the existing managed health care systems.
Therefore, the eSecMed project is aimed to develop prototypes of smart drug packaging and
a virtual medicine cabinet application. Generally the packaging is equipped with a multifrequency RFID chip and antenna. In combination with a smart phone app senior patients’
adherence and safety will be enhanced.
A prototype is developed, based on the analysis of all relevant requirements including
application, technology, project environment and senior patients’ needs. The experimental
concept focuses on common indication cases for elder patients such as hypertension,
diabetes mellitus type II, hypercholesterolemia and short duration treatable acute
inflammation.
The goal of the chosen case study scenarios is to emphasize on the entire pharmaceutical
supply chain up to the patient. Medication adherence will be increased and undesirable side
effects and harmful interactions of drugs minimized. In addition counterfeiting security and
drug traceability will be improved.
As a result of the scientific work done so far, the current state of the concept is presented
which includes highly prioritized thematic emphases along the pharmaceutical supply chain.
[1] H. Bale, “How the pharmaceutical industry can help in enhancing adherence to long-term
therapies,” in World Health Organization - Adherence to long-term therapies: evidence for action,
2003, pp. 156–157.
23
ICPE 2014
Fermentation Modeling in a PAT Environment
J. Scheiblauer, M. Joksch, S. Scheiner*
Siemens CT RTC SET BSN-AT, A-1210 Vienna
*Institute for Mechanics of Materials and Structures,
Vienna University of Technology (TU Wien), A-1040 Vienna
Email for correspondence: johannes.scheiblauer@siemens.com
Saccharomyces cerevisiae (or baker’s yeast) has not only been used for baking bread and
brewing beer, it is also used as a model organism for eukaryotic cells and a possible host for
the production of recombinant proteins. Due to its various fields of application, gaining detailed
knowledge on the kinetics of the yeast cell metabolism is a desirable goal.
Cells of Saccharomyces cerevisiae metabolize glucose via glycolysis to pyruvate which is then
either oxidized (TCA circle, reaction 1) or reduced to ethanol (reaction 2). Due to the higher
yield of adenosine triphosphate (ATP), the cells prefer the oxidative pathway over the reducing
one. However, given the limited oxygen uptake rate, only a limited amount of pyruvate can be
oxidized. As so-called Crabtree-positive yeast, Saccaromyces cerevisiae processes (after the
respiration pathway, reaction 1, is saturated) the remaining pyruvate anaerobically: If the
glucose concentration S in the medium exceeds a critical value Scrit, ethanol is formed – even if
there is sufficient dissolved oxygen present. After the entire glucose is consumed, the formerly
produced ethanol is metabolized oxidatively (diauxic growth, reaction 3).
Reaction 1: C6H12O6 + 6O2 -> 6CO2 + 6H2O
Reaction 2: C6H12O6 -> 2C2H5OH + 2CO2
Reaction 3: C2H5OH + 3O2 -> 2CO2 + 3H2O
We present a mathematical model, based on first principles [1,2], which covers the described
metabolism and allows for predicting the evolutions of the biomass, substrate, ethanol, and
dissolved oxygen concentrations during batch and fed-batch cultivations. The developed
process model is part of a complete fermentation control system that is currently operated at
Siemens Corporate Technology.
The respiratory quotient RQ is defined as the fraction of produced carbon dioxide over
consumed oxygen. If the glucose concentration S is below the critical value Scrit, a true glucoseoxidative state (reaction 1) with RQ=1 is expected. In case of S > Scrit, both reactions 1 and 2
take place: thus RQ > 1 (its exact depending on the amount of glucose overflow). For the
ethanol consumption state, our model predicts RQ = 2/3 (reaction 3).
Additionally, the implemented PAT concept is based on several probes for CO2 and O2 levels in
the gas and/or liquid phase, standard probes for pH value and temperature profiling, as well as
an NIR spectrometer. By means of the process control system (SIMATIC PCS7) and the PAT
software solution (SIPAT) sensor information, process model predictions, as well as statistical
information from previous runs, e.g. golden batch models, can be integrated to guarantee a
complete PAT environment for fermentation processes. This integration is the subject of
ongoing research activities.
1.
Pham, H.T.B., Larsson, G., Enfors, S.-O. (1998) Growth and Energy Metabolism in Aerobic FedBatch Cultures of Saccharomyces cerevisiae: Simulation and Model Verification. Biotechnology and
Bioengineering, Vol. 60, 4, 474-482.
2.
Sonnleitner, B., Käppeli, O. (1986) Growth of Saccharomyces cerevisiae is controlled by its
limited respiratory capacity: Formulation and verification of a hypothesis. Biotechnology and
Bioengineering, Vol. 28, 6, 927-937.
24
ICPE 2014
QbD 2.0: Efficient use of R&D for the design of
robust manufacturing processes
S.K. Bermingham
Process Systems Enterprise Ltd
Email for correspondence: s.bermingham@psenterprise.com
The fact that QbD has not lived up to its hype is not simply a result of the high expectations
fostered by the industry and regulatory bodies, but more significantly a result of the inherently
resource intensive statistical methodology (QbD 1.0) currently adopted by the pharmaceutical
industry.
This talk will argue that only a mechanistic model-based methodology (QbD 2.0) can both
reduce the size of the lab-scale experimental programme and avoid having to carry out more or
less the same experimental programme at typically two pilot scales and the manufacturing
scale. QbD 2.0 can deliver on these benefits by introducing the “sound science” mentioned in
the QbD definition as it relates to the physics and chemistry governing drug manufacture and
drug delivery steps.
In QbD 1.0, the only a priori knowledge used in the formulation of the (statistical) model is the
input-output structure, e.g. the CPPs and the CQAs. In QbD 2.0, the a priori knowledge used to
formulate the (mechanistic) model includes well-established physics and chemistry such as the
laws of conservation. Through the increase in a priori knowledge the amount of information
required to parameterise the model decreases and at the same time the ability to extrapolate
greatly increases.
This more efficient approach to QbD will be illustrated using three case studies from industry1,2.
Figure 1: Evolution in use of experiments to support design of robust products and processes.
1
B. Gettelfinger, S. Glassmeyer, M. Pinto, S. Bermingham. Model-Based Scale-up of Impact Milling. AIChE 2011
paper 55b
2
C. Burcham, M.A. Lovette, C,S, Polster, S.K. Bermingham, H. Mumtaz. Utilization of Population Balance Models to
Develop a Continuous Crystallization Process. AIChE 2012 papers 187g & 187h
25
ICPE 2014
Critical discussion about the influence of
roll compaction/ dry granulation on tablet properties
P. Kleinebudde
Heinrich-Heine-University Düsseldorf, Institute of Pharmaceutics and Biopharmaceutics
Email for correspondence: kleinebudde@hhu.de
Tableting of dry granulated materials results often a reduced compactability compared with
direct tableting of not granulated materials. Several reasons for this phenomenon are discussed
in the literature. Work hardening was claimed as one mechanism to explain the phenomenon1.
Since work hardening refers to changes in the crystal structure it may not be applicable in many
cases. Instead granule hardening was proposed2. The roll compaction/ dry granulation results in
granule hardening, which is indicated by a higher yield pressure. Other authors postulated a
major influence of particle size growth as dominant mechanism for the reduced compactability3.
Beside mechanisms, which are directly connected to roll compaction/ dry granulation, it is well
known since a long time that lubricants can also affect compactability. In many studies a
constant fraction of lubricant is used for direct compaction and tableting of granules. Dependent
on the deformation mechanism of the particles this can influence the outcome of the study since
the available surface area can be significantly different. In order to distinguish between different
mechanisms of reduced compactability, it is important to design the study properly.
The presentation will pick up several studies from the literature focusing on this topic and
discuss these references critically. In some cases the design of a study was not suitable for
strong conclusions. Other studies allow more unbiased conclusions4. A new data set is
presented, which allows distinguishing between the effects of lubrication, granule hardening and
particle size. Furthermore, a huge influence of the mechanical properties of the starting material
has to be taken into account. By discussing the ratio under the compactability curves of direct
tableting and dry granule tableting it is possible to distinguish the different materials.
References
1. Malkowska S, Khan KA. Effect of re-compression on the properties of tablets prepared by dry
granulation. Drug Dev. Ind. Pharm. 9:331-347 (1983).
2. Sun C, Himmelspach MW. Reduced tabletability of roller compacted granules as a result of
granule size enlargement. J. Pharm. Sci. 95:200-206 (2006).
3. Patel S, Dahiya S, Sun CC, Bansal AK. Understanding size enlargement and hardening of
granules on tabletability of unlubricated granules prepared by dry granulation. J. Pharm. Sci.
100:758-766 (2011).
4. Herting MG, Kleinebudde P. Studies on the reduction of tensile strength of tablets after roll
compaction/dry granulation, Eur. J. Pharm. Biopharm. 70:372-379 (2008).
26
ICPE 2014
Simulation of an overall lab scale tablet
production
S. Trebbien*, A. Weitz*, I. Weinsheimer*, Prof. Dr. P. Langguth*, Dr. F. Stieneker**
*Department of Pharmaceutical Technology, J.G.-University, Mainz, Germany
**IFAP AG, Hofmattstr. 3, 5085 Sulz (Schweiz)
Email for correspondence: Trebbien@uni-mainz.de
Simulation and modelling are broadly used tools in the pharmaceutical production industry (1).
Nevertheless simulating an overall production process of pharmaceuticals in early stages is
rarely mentioned in the research area of pharmaceutical technology. Therefore we did a study
to analyze possible benefits of using simulations in early stage lab scale production of tablets.
The necessary preparations for using the Simulation Software FlexSim to find an optimised
overall tablet production were examined and shown in a lab scale case study. Target of the
case study was to show how to approach a simulation with constructivist didactics and to
examine an optimized tablet production. After investigating
different ways to produce one kilogram of tablets within the
given resources and available equipment at the
department, we found by simulation, that two days are
minimum necessary to perform all process steps with two
persons as limiting resource and 1600 tablets as target
outcome volume. The paper shows the process of
constructing a simulation and the resulting simulation of an
overall pharmaceutical lab scale tablet production with
FlexSim.
We used concept maps for the constructivist didactics of
the simulation choose to simulate the following production
hardware which determines the basic process steps:
weigh, mesh, mixer and granulator, tablet compressor,
tablet coater, primary blister packaging and final packaging
in paper boxes. Finally the working simulation was
equipped with analytic tools for every main process step to
further analyze and optimize the performance of the
simulated pathway.
Figure 1: Concept map of the simulation
Figure 2: Snapshot of the resulting Simulation. Translation will be provided.
1.
Trebbien et al., Life-Cycle-Management, Pharm. Ind. 74, Nr. 7, 1163–1170 (2012), ECV,
Aulendorf (Germany).
27
ICPE 2014
Image-Based Real Time Crystal Shape Observer
H. Eisenschmidt1, K. Sundmacher1,2
Otto-von-Guericke University, Magdeburg
2
Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg
Email for correspondence: sundmacher@mpi-magdeburg.mpg.de
1
Real time monitoring of crystallization processes is an important task, which opens the way
for the determination and quantification of the governing kinetic phenomena, as well as for
feedback control of crystallization processes. While the state of the continuous phase can be
quantified with state of the art laboratory equipment, monitoring of the dispersed phase in a
quantitative manner is still challenging. This is in particular true for the online measurement
of the crystal shape distribution, which is a decisive product property.
For this purpose, video microscopy has received much attention over the last two decades,
since this technology gives an immediate impression of the state of the dispersed phase.
However, for a quantitative evaluation of the recorded videos, large data sets have to be
processed and the 3 dimensional shapes of the observed crystals have to be reconstructed
from the obtained projections. In our contribution, we present an efficient approach for this
shape reconstruction. Here, the boundary curves of all visible single crystals are
parameterized by Fourier descriptors, which are compared to a precomputed database of
possible crystal projections [1,2]. This approach is applied to potassium dihydrogen
phosphate (KDP) crystals dissolved in water, see Figure 1 left, and is shown to be robust to a
finite image resolution as well as to imperfections of the crystal projections.
The estimation scheme is further used, to construct an observer for the real time
measurement of crystal shape distributions. For this purpose, videos of a length of 10
seconds are continuously collected, and the last recorded video is passed to the shape
estimation routines. By tracking of the evolution of the seed crystal distribution, crystals can
instantaneously be classified as seed crystals, nucleated crystals or agglomerates, see
Figure 1 right. Thus, an immediate and quantitative insight into the crystallization process
can be provided. Finally, the obtained observation results are passed to a Kalman filter. This
serves to reduce the measurement noise and thus, to enable the identification of
crystallization kinetics as well as feedback control of crystallization processes.
Figure 1: Left: recorded images of KDP crystals (gray) together with the estimated shapes of
all visible single crystals (color), right: estimate of the crystal shape distribution.
1.
C. Borchert, K. Sundmacher, Chemical Engineering Science, 2012, 70, 87-98
2.
C. Borchert, E. Temmel, H. Eisenschmidt, H. Lorenz, A. Seidel-Morgenstern, K. Sundmacher,
Crystal Growth & Design, 2014, 14, 952-971
28
ICPE 2014
Investigating the uniformity of an active coating
process using DEM simulations
G. Toschkoff1, G. Scharrer1, S. Just2, K. Knop2, P. Kleinebudde2, D. Djuric3, A. Funke4, J.
G. Khinast5,*
1
Research Center Pharmaceutical Engineering GmbH, Graz, Austria
Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Düsseldorf, Germany
3
L.B. BOHLE Maschinen + Verfahren GmbH, Ennigerloh, Germany
4
Bayer Global Chemical and Pharmaceutical Development, Bayer Pharma AG, Berlin, Germany
5
Institute for Process and Particle Engineering, Graz University of Technology, Graz, Austria
*Email for correspondence: khinast@tugraz.at
2
Pan coating is a commonly used unit operation to apply a functional layer around tablet cores. A
special application is active coating, where the coating layer itself contains an active
pharmaceutical ingredient (API). In this case, the variation of coating mass between tablets has
to be consistently small, thus a high degree of process understanding is needed. In addition to
experimental investigations, there is a strong trend towards numerical simulations1,2.
In this work, the application of an active coating was investigated: Gastrointestinal therapeutic
systems (Adalat® GITS, Bayer Pharma AG, Germany) were coated with an aqueous
suspension containing candesartan cilexetil as API. A lab pan coater (BFC 5, L.B. Bohle,
Germany) was used.
Both experiments and Discrete Element Method (DEM) simulations were performed, using the
same Design of Experiments. The geometry of the coating apparatus was provided by the
manufacturer (Figure 1). The material properties came from measurements3.
Figure 1: Snapshot of the Discrete Element Method simulation of the coating drum.
Summarizing, it was aimed to capture the coating process in the simulation as good as
possible, which in turn allows for detailed investigations. A main result is that a lower CoV
(better uniformity) can be reached by using more nozzles, followed by decreasing the spray
rate, increasing rotation speed, and decreasing fill level. In general, fundamental insights into
the nature of the process were gathered; based on this, guidelines on how to improve the
uniformity were defined. For the resulting settings, the coating uniformity was consistently well
within regulatory specifications.
References
1.
Ketterhagen, W. R., am Ende, M. T. & Hancock, B. C. Process modeling in the pharmaceutical
industry using the discrete element method. J. Pharm. Sci. 98, 442–70 (2009).
2.
Toschkoff, G. & Khinast, J. G. Mathematical modeling of the coating process. Int J Pharm (2013).
doi:10.1016/j.ijpharm.2013.08.022
3.
Just, S. et al. Experimental analysis of tablet properties for discrete element modeling of an active
coating process. AAPS PharmSciTech 14, 402–11 (2013).
29
ICPE 2014
Development of a multivariate FTIR spectroscopic
method to monitor microstructural changes of gelatin
during capsule manufacture
F. Polyak, G. Reich
University of Heidelberg, IPMB, Department of Pharmaceutical Technology and
Biopharmaceutics, INF 366, 69120 Heidelberg, Germany
Email for correspondence: f.polyak@uni-heidelberg.de
Purpose:
1. To evaluate the potential of FTIR spectroscopy for the analysis of temperature-induced and
time-dependent microstructural changes of gelatin during gelation. These changes, affecting gel
strength and elasticity, are crucial to machinability and capsule product performance (Reich,
2004).
2. To provide a multivariate approach for improved process understanding that enables spectral
changes to be continuously monitored and correlated to rheological properties.
3. To develop a spectroscopic method suitable for real-time PAT application.
Methods:
Aqueous solutions (30-40% w/w) of various gelatin types of different Bloom strength and
viscosity were measured with an oscillatory rheometer coupled with an ATR-FTIR spectrometer.
A linear cooling ramp from 70 to 25°C was applied. The spectra were acquired in one minute
intervals with 24 scans at 4 wavenumber resolution. Structural information was obtained from
the Amide I region using the wavenumbers from 1645 to 1592 cm-1. Due to the polydispersity of
hard and soft capsule gelatin types and grades, a multivariate approach, e.g., a principal
component analysis (PCA) was applied to highlight the substantial spectral changes. Score line
plots were used to monitor temperature- and time-dependent profiles.
Results:
PCA revealed strong correlation between changes of the Amide I bands and the viscoelastic
properties of gelatin measured by oscillation rheology. The score line plot of the first principal
component (PC-1) was found to correspond to the time course of the rheological characteristics.
Differences in the temperature- and time-dependent progress of the storage modulus G’
between gelatins of different Bloom strength and/or viscosity could be monitored through score
line plots. This indicates that FTIR spectroscopy is able to detect microstructural differences
associated with the sol/gel transition of different gelatin types and grades used in hard and soft
capsule shell formulations.
Conclusion:
FTIR spectroscopy coupled with rheology offers a promising approach to provide new insights
in temperature- and time-dependent microstructural changes related to the gelation process of
highly concentrated gelatin formulations used in hard and soft capsule production.
Spectroscopy in combination with multivariate data analysis enables a more thorough
understanding of structural changes associated with the viscoelastic behavior of such
formulations. The spectroscopic method thus provides potential as a PAT tool for formulation
development and process optimization in hard and soft gelatin capsule design and manufacture.
1. Reich, G., Formulation and physical properties of soft capsules, Chapter 11 in: Pharmaceutical
Capsules, eds. F. Podczeck and B. Jones, Pharmaceutical Press, London, (2004)
30
ICPE 2014
Total Surveillance! Inline Monitoring
of Tablets with NIR Chemical Imaging
P.R. Wahl*, O. Scheibelhofer*, S. Sacher*, P. Kerschhaggl**, J.G. Khinast*,***
* Research Center Pharmaceutical Engineering (RCPE) GmbH, Graz, Austria
** EVK DI Kerschhaggl GmbH, Raaba/Graz, Austria
*** Graz University of Technology, Institute of Process and Particle Engineering, Graz, Austria
Email for correspondence: khinast@tugraz.at
The composition and uniformity of active ingredients and excipients as well as tablet hardness
are critical quality attributes of tablets. Typically these attributes are tested offline with low
sample sizes (10 to 30 tablets), e.g. by dissolution and crushing strength. Here we present an
in-line NIR chemical imaging system, capable of analyzing the entire product stream.
The tablets were manufactured using a Fette 102i tablet press. After ejection the whole tablet
stream was further transported on a conveyor belt to assure ideal representation to the imaging
system (Figure 1).
Figure 1: Conveying of tablets to the
imaging system after compaction
Figure 2: Chemical Image of all manufactured tablets with 5% API content
The captured “images” (spectra) were first segmented into tablets and background using PCA
projection. Each tablet consisted of 20 – 50 spectra (depending on size, velocity and optics).
Chemical images of each tablet’s surface were obtained by PLS (Figure 2 and Figure 3). The
mean API content and standard deviation was calculated, yielding information about the intra
and inter-tablet content uniformity. The maximum throughput was experimentally verified to be
at about 500,000 tablets per hour.
Changing the compaction force leads to different surface roughness and scattering properties of
the tablets. The superposition of physical and chemical effects for the obtained spectra has its
advantages and disadvantages. It is a pain in model development, but a clear gain in
information - as long as these effects can be separated.
Figure 3: Mapping of tablets with API content ranging from 1% to 11% showing API clusters.
31
ICPE 2014
Combining image analysis with Raman spectroscopy
for QBD
P. Davies
Malvern Instruments France
Email for correspondence: contact@malvern.com
Increasing demands drive operators from the pharmaceutical industry to get more details on the
properties of the particles. This is possible thanks to imaging technologies that analyze the size
and shape of the particles. Automated image analyzers capture two-dimensional images of
particles dispersed beforehand to allow direct measurement of the particle size. A pictorial
representation of the particle size can be an important factor, especially if one tries to predict
their behavior during the manufacturing process or during the quality control of the finished
product. Particle shape can influence a variety of properties, as the behavior during dissolution
of the actives, or their ability to be blended with the excipients .
In addition to the size and shape of the particles, Raman spectroscopy can be used to identify
the presence of one or several chemical components or contaminents and thus achieve the
identification of particles covered with a layer of another product .
The Morphologi G3, is both an analyzer and a particle counter based on image analysis. The
measurement size range is from 0.5 microns to 10 millimeters. The integrated powder disperser
is designed to disperse any type of powders without breaking the elementary particles. After the
dispersion phase, several tens of thousands to one million particles of powder or particles in
suspension can be analyzed within a few minutes. Each particle image will be saved with the
possibility of returning to position the lens just above a selected particle. The advantage of this
function is to drive a Raman microprobe to analyze the surface of the particles and to assess
the quality of coating or remove a suspect particle (contaminant, aggregate, foreign particles)
and identify it in a precise way with any other technology.
The Morphologi G3 validated 21 CFR measures particles using numerous geometric and
morphological parameters such as width, length, perimeter, area, circularity, aspect ratio,
convexity, the elongation, strength, color coded gray level and standard deviation of the gray
level which reflects the heterogeneity of the particle surface under incident light
A simple way to perform a supervised analysis is to work directly on the scattergram manually
or to use automated classification using the data partitioning (clustering). Another possibility to
improve the device to be more selective in the classification is to equip the Morphologi G3 of a
chemical identification system using Raman spectroscopy. The addition of a chemical spectrum
can be very useful for the identification of particles that are not identified just by their size, shape
or color. Raman technology can identify the presence of one or more chemical components one
a surface. A Raman spectrum can be acquired for each particle and these spectra can be
compared to a library of of the pure components spectra and a value of correlation score is then
calculated to describe how the measured spectra correspond to those recorded on pure
components. In case of mixture of components as a single granule, the sensor with a resolution
of 3 microns will identify particles coated or composed of several elements that are
indistinguishable by image analysis.
Reference :
L. H. Kidder, K. S. Haber, J. Dubois et E. N. Lewis, Raman spectroscopy directed by image analysis
for characterising Carrier/API association of a “Dry Powder Inhaler”, Respiratory Drug Delivery
Orlando 2010
Food and Drug Administration. Generic Drugs: Questions and Answers” Food and Drug
Administration, August 2011,
http://www.fda.gov/drugs/resourcesforyou/consumers/questionsanswers/ucm100100.htm
32
ICPE 2014
The European Pharmaceutical Industry – Past
success, present challenge and future
potential
R. Torbett
EFPIA – European Federation of Pharmaceutical Industries and Associations
Email for correspondence: Richard.torbett@efpia.eu
This presentation will focus on what Europe can do to ensure it retains its status as
one of the global hubs for pharmaceutical industry research and development. In
doing so it will present a vision for a new type of ‘integrated life sciences strategy’ for
the EU that should create much greater coherence than we have today between
three areas of policy: health, finance and science & competitiveness.
The presentation will review past history, recent challenges and potential future
trends on three interconnected issues:
1. Health outcomes – The pharmaceutical industry has an impressive track
record of contributing to better health outcomes, with significant increases in
life expectancy experienced in all European countries across the last 60
years. But major healthcare inequalities persist and across Europe. Looking
to the future, an ageing population with its associated increase in chronic
disease prevalence will mean that health systems are likely to come under
ever increasing strain.
2. Financial Sustainability – If Europe is to meet its future healthcare
objectives and retain pharmaceutical innovation in the areas most valued by
society all sides need to build explicit strategies for managing financial
sustainability now. This includes the need to improve the predictability of
spend and the development of systems that ensure rational use of all medical
technologies.
3. A thriving life sciences eco-system – Europe currently remains an
importance global centre for the pharmaceutical industry with around €30bn
of private sector R&D spending. Small and large firms work in an
interconnected network with universities, hospitals and other partners.
Although we have many of the foundations of success there are signs that
Europe is losing competitiveness in some areas. More needs to be done to
ensure Europe retains its leadership in life sciences research to fuel the wider
eco-system.
Public policy around these three issues usually takes places in a disconnected way
with different communities of experts, policymakers and success measures. This
leads to a lack of coherence. In this presentation, I will put forward EFPIA’s ideas on
how we can develop a more integrated approach that can help patients, the science
community as well as the industry.
33
ICPE 2014
Perspectives in Process Analysis
R. W. Kessler, K. Rebner
Center of Excellence for Research and Education in Process Analysis and Technology (PA&T)
Hochschule Reutlingen-Reutlingen University, Alteburgstr. 150, 72762 Reutlingen, Germany
Email for correspondence: rudolf.kessler@reutlingen-university.de
Process analysis is a transdisciplinary technology. Process chemists, process engineers,
chemometricians, and many other technologists must work together and put more emphasis on
the essentials of science of each discipline. Process Analysis includes process design (Quality
by Design (QbD)) and technology, process analytics (Process Analytical Technology (PAT)),
process control units as well as the economic evaluation of the process including supply chain
management.
Spectroscopy will play an important role in the transition of a re-active industrial production
into a pro-active industrial system. To an increasing extent, spectroscopic techniques are
integrated into real life production and are extending knowledge of the information from
conventional sensors or even replacing them. Spectroscopic sensors are, in that sense,
complex systems providing detailed information on the molecular structure of components. As
spectroscopic techniques can simultaneously detect all morphological and chemical features,
the complete fundamental functionality of a compound is inherent in every spectrum. However,
redundant and unnecessary information must be excluded from the spectral features by means
of complex data analysis.
The lecture will introduce state of the art concepts and strategies in the processing industry
and will discuss some current challenges for the application of process analytical spectroscopy
like: sensitivity and selectivity, integrating first principles when analysing scattering systems,
working in aqueous solutions, etc. [1]. In the second part of the lecture, some selected possible
“next generation” technology will be explained and their relevance for the future industrial
revolution to personalize products will be evaluated [2]. New concepts for project oriented
learning (POL) must be introduced in modern education to take into account these trends.
Process analysis will thus play a more important role in the future of the processing industry
than it has in the past. According to the Industry 4.0 concept of the German government, the
future of industrial automation will be “arbitrarily modifiable and expandable (flexible), connect
arbitrary components of multiple producers (networked), enabling its components to perform
tasks related to its context independently (self-organizational) and emphasizes ease of use
(user-oriented)”. Spectroscopy will be an important toolbox and enabling technology to realize
this concept.
Literature:
1.
D. Oelkrug, E. Ostertag, R. W. Kessler: Quantitative Raman spectroscopy in turbid matter:
reflection or transmission mode?, Anal. Bioanal. Chem., 2013, 405:3367–3379
2.
R. W. Kessler: Perspectives in process analysis. J. Chemometrics, 2013, 27: 369–378. doi:
10.1002/cem.2549
34
ICPE 2014
Process modelling of dry foam drying kinetics
P. K. Ghosh, E. Gavi, A. Dischinger, S. Page
Formulation Research and Development, F. Hoffmann-La Roche Ltd, Switzerland
Email for correspondence: pranay_kumar.ghosh@roche.com
INTRODUCTION: Dry foam technology was developed to overcome insufficient oral
bioavailability of poorly soluble and wettable active pharmaceutical ingredients (APIs) [1]. The
paste, containing the API, is firstly subjected to reduced pressure at room temperature, where
foaming and pore development takes place. Complete drying of the foam is then achieved in a
second phase at moderately accelerated temperatures. Conventionally, a vacuum belt dryer
(VBD) is employed for the drying process on a larger scale. To extract information on drying
kinetics of the paste, a magnetic suspension balance (MSB) can be used on a smaller scale.
The current work applies a mathematical model to predict the amount of evaporated water
(EVW) in a VBD process by using drying kinetics data obtained from small scale MSB
experiments.
MATERIALS AND METHODS: Pastes containing 15.5% Indomethacin, 2.1% Sodium dodecyl
sulfate and 82.4% Maltodextrin DE 21 calculated on dry mass served as model formulation. The
paste water content (PWC) varied in the experiments in the range of 17% to 25%, based on wet
mass. The small scale experiments were performed on MSB equipment from Rubotherm,
Germany, while the large scale experiments were carried on a Drylab vacuum belt dryer from
Bucher, Switzerland. 0.4 g and 100g of paste was used in MSB and VBD experiments
respectively. The sample chamber temperature respectively the plate temperature in the VBD,
were set to 20°C and 40°C while the pressure was varied from 20 to 80mbar at both scales.
EVW at the end of 30 min was recorded at both scales.
Diffusion of moisture through the dry foam is considered as the rate limiting step for the studied
drying process and was modelled with Fick’s second law of diffusion [2]. In the adopted model
the drying kinetics depends upon the effective diffusivity of the moisture and the height of the
dry foam. The effective diffusivity of moisture through the dry foam at a given PWC can be
estimated from the EVW value obtained from experiments performed on MSB, whereas the
height of the foam on the VBD belt is treated as a fitting parameter.
RESULTS AND DISCUSSION:
In contrast to a MSB process, where the foam is constrained in a basket, in a VBD process the
foam is unconstrained and free to spread across the VBD belt. Therefore, the height of dry foam
on the VBD belt is independently modeled as a function of the corresponding PWC, whereas it
is considered constant in the MSB process. Two VBD experiments with dry foam consisting
21% and 25% PWC were used to obtain the correlation between height and PWC on a VBD
belt. In order to validate the developed models, the approach was tested for the ability to predict
EVW in a VBD process with dry foam consisting 17% PWC at 20°C and 40°C. Height of the dry
foam on the VBD belt was calculated based on the developed correlation. The corresponding
effective diffusivity at 20°C and 40°C was estimated from MSB experiments. Using the above
information, the predicted EVW values for the VBD process was found in close agreement with
the corresponding experimentally determined EVW values.
1. A. Sprunk, S. Page, P. Kleinebudde. Influence of process parameters and equipment on dry foam
formulation properties using indomethacin as model drug. Int. J. Pharm., 455(1-2):189-96, 2013.
2. S. Jaya and H. Das. A Vacuum Drying Model for Mango Pulp, Drying Technology: An
International Journal, 21:7, 1215-1234, 2003.
The experimental data are derived from the PhD thesis of A. Sprunk under supervision of Prof.
Kleinebudde from the Heinrich-Heine-University Düsseldorf.
35
ICPE 2014
Nanomechanical properties of single pharmaceutical
crystals
M. Egart1, B. Janković1, I. Ilić1, N. Lah2, S. Srčič1
1
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, Ljubljana, Slovenia
Email for correspondence: biljana.jankovic@ffa.uni-lj.si
2
Introduction: In particular, more than 90 % of small molecule drugs are delivered in crystalline
form (Variankaval et al., 2008). Therefore, a comprehensive understanding of mechanical
properties and their dependence from crystal structure is a critical step to overcome
manufacturing challenges associated with designing solid dosage forms. Nanoindentation is
able to make a link between the structures of molecular solids and their single crystal
mechanical properties and to use it to predict bulk mechanical properties (Varughese et al.,
2013; Janković et al., 2013; Roberts, 2011). The main goal of this research was to assess the
mechanical properties of different APIs (famotidine, nifedipine, olanzapine, piroxicam) at the
single crystal level and relate them to the characteristics of their crystal structures.
Materials and Methods: The mechanical properties of oriented single crystals were determined
using instrumented nanoindentation (continuous stiffness measurement) (Oliver and Pharr,
2004). Thermodynamically stable single crystals were prepared according to procedure
described in the literature. Solid states were identified by single crystal x-ray diffractometry. The
face indexing of individual crystal was performed using CrysAlis PRO software (Agilent
technologies).
Results and Discussion: Mechanical properties such as Young`s modulus (E) and indentation
hardness (H) were consistent with the molecular packing of the solid forms investigated with
respect to the crystal orientation. Mechanically interlocked structures were characteristic for
most forms what is resulting in isotropic mechanical properties. The presence of slip planes was
detected for famotidine B only and this implies to plastic behaviour. This was confirmed with
essentially lower indentation hardness in comparison to famotidine form A.
Conclusion: According to the results, the nanomechnical measurements can be used for
quantitative assessing of molecular crystals mechanical attributes. Young`s modulus and
indentation hardness can thus represent valuable and effective tool in preformulation studies as
only a small amount of material is needed for evaluation of materials` mechanical properties
with high precision.
References
1. S. Varughese, M. S. R. N. Kiran, U. Ramamurty, G. R. Desiraju, Nanoindentation in Crystal
Engineering: Quantifying Mechanical Properties of Molecular Crystals, Angew. Chem. Int. Ed. 52
(2013) 2701-2712.
2. R. J. Roberts, Particulate analysis – Mechanical Properties, in Solid state Characterization of
Pharmaceuticals, (Eds. R. A. Storey and I. Ymen), John Wiley & Sons, Southern Gate UK 2011, pp.
357-369.
3. N. Variankaval, A. S. Cote, M. F. Doherty, From Form to Function: Crystallization of Active
Pharmaceutical Ingredients, Amer. Inst. Chem. Eng. 54 (2008) 1682 -1688.
4. B. Janković, M. Škarabot, Z. Lavrič, I. Ilić, I. Muševič, S. Srčič, O. Planinšek, Consolidation trend
design based on Young`s modulus of clarithromycin single crystals, Int. J. Pharm. 454 (2013) 324332.
5. W. C. Oliver, G. M. Pharr, Measurement of hardness and elastic modulus by instrumented
indentation: Advances in understanding and refinements to methodology, J. Mater. Res. 19 (2004) 320.
36
ICPE 2014
Investigation of polymer-API systems distribution
behavior in the mold during injection molding
process by numerical (CFD) methods
H.R. Juster, T. Distlbacher, G. Steinbichler
Institute of Polymer Injection Moulding and Process Automation, Johannes Kepler University,
Science Park 2, Altenbergerstrasse 69, 4040 Linz, Austria
E-mail for correspondence: herwig.juster@jku.at
It has been already proven that solid dispersions are able to greatly enhance the bioavailability
of several active pharmaceutical ingredients (API´s) [1]. Nevertheless, current methods to
prepare API based solid dispersions involve complex multi-step procedures and the usage of
high amount of additives. As a result, the whole process shows rather low efficiency at elevated
costs [2].
The Hot-melt extrusion (HME) has emerged as a potentially more efficient and benign technique
for manufacturing solid dispersion systems. In HME, various solid dispersions can be produced
in the absence of solvents through a fast and continuous low-cost process that is still multistep
based [3]. Injection molding technique, which is well known from polymer processing industry,
may be a new way to produce drug dosage forms with enhanced solubility in a one step equally
efficient procedure. This is a discontinuous production process, where the melt is injected into a
predefined-shape mold that is used for cooling down the melt until it reaches the solid state. The
plastification step is performed by screws, similarly to HME. The melt flows from the
antechamber of the plasticizer unit to the cavities of the mold. At this point, the melt splits into
the melt volumes necessary for each cavity. Important to control is the distribution homogeneity
of the drug within the polymer matrix by the end of the injection molding process.
In this study Computational Fluid Dynamics (CFD) methods were used to visualize the injection
molding process of a drug delivery system consisting of Soluplus ® / Fenofibrate, 90/10 (%w,w).
The molding simulation package utilized was SIGMASOFT® [4]. Through process simulation,
the distribution behavior of the API within a single mold cavity and the distribution behavior of
API along all the six mold cavities can be visualized and better understood. Furthermore, the
location of regions of high shear rates, shear heating and shear stress distribution can be
identified and analysed. Finally, on the basis of such analysis, an optimization of the distribution
in the cavities can be performed. In this study, we used a virtual mold consisting of six tablets
(diameter of 13mm and height of 4mm). These tablets were connected to a six-way star
distributor. This way, with one injection molding circle, six tablets can be produced.
The system here studied represents a one-phase system. For analysing the API distribution,
tracers were set to follow the melt into the cavities. The injection volume rates have been varied
from 5 cm 3/s to 15 cm 3/s. Apart of the tracer analysis, a statistical analysis was also done by
using the Shannon Entropy S model [5]. The higher S, the better is the distribution of the API in
the cavity.
It was possible to analyse the distribution of the API during injection into each cavity of the
mold. The different injection flow rates show similar distribution behavior (Shannon Entropy is
always between 1.5 to 2.5). Therefore, it was possible to produce more output by reducing the
cycle time increasing the flow rates.
1.
2.
3.
4.
5.
Lipinski, C.A., Curr Drug Dis. 2001, 4
Dhirendra K., Lewis S., Udupa N., Atin K., Journal of Pharmaceutical Sciences 2009, 22
Breitenbach, J., Wiesner, B., The use of polymers in pharmaceutical melt extrusion, ExAct 2008,
20
SIGMA Engineering, URL: http://www.sigmasoft.de (20.04.2014)
Phelps, J.H., Tucker, C.L., Chemical Engineering Science 2006,61
37
ICPE 2014
Probabilistic Modeling of Wet Collisions in Sheared
Particle Beds
B. Mohana, J.G.Khinasta,b, S.Radla
a
b
Research Center for Pharmaceutical GmbH, Graz, Austria
Email for correspondence: radl@tugraz.at
Abstract
Wet granular materials are used in numerous industrial processes such as mixing, coating,
granulation etc. However, the development of simple liquid transport models for such processes
is a challenging task. Here we focus on detailed simulations of the formation and rupture of
liquid bridges in a sheared particle bed by implementing a probabilistic model for predicting wet
collisions. We use the Discrete Element Method (DEM) supplemented with a variety of
microscopic liquid transport models that model liquid transfer associated with each particleparticle contact point.
We present results for the wet collision coordination number that were obtained with a simple
probabilistic model taking into account the finite surface coverage of liquid. We then compare
the proposed wet collision coordination number with the (classical) contact coordination number
for a wide range of effective liquid film thicknesses. Our results help in quantifying the liquid
transfer rate in cases where particles are non-uniformly coated with a liquid layer. Such a
quantitative understanding is of key importance for process control in applications such as tablet
coating or granulation.
38
ICPE 2014
Experimental and model-based investigation of twin
screw granulation: towards more profound process
knowledge
A. Kumar1,2, K.V. Gernaey3, T. De Beer2*, I. Nopens1
1. BIOMATH, Dept. of Mathematical Modelling, Statistics and Bioinformatics, Faculty of
Bioscience Engineering, Ghent University, Belgium
2. Laboratory of Pharmaceutical Process Analytical Technology, Dept. of Pharmaceutical
Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Belgium
3. Center for Process Engineering and Technology, Department of Chemical and Biochemical
Engineering, Technical University of Denmark, Denmark
Email for correspondence: Ingmar.Nopens@Ugent.be, *Shared last authorship
Twin-screw granulation (TSG) is a promising technology for continuous wet granulation, as it
achieves mixing by a combination of screw configuration and process settings (e.g. feed rate,
screw speed, etc.) to produce a certain end-product specification in a short time. However, to
optimise and control this new technology, understanding of the mixing and the dominating
granulation sub-processes is needed. This study is an initial step in combining experimental
observations and mathematical models for gaining such knowledge regarding continuous twin
screw granulation. The residence time distribution (RTD) in a TSG provides interesting
information to understand its mixing behaviour. However, in order to predict the mixing
precisely, modelling of the RTD is desirable. In this study, an analytical model based on
classical chemical engineering method for dynamic transport modelling was developed. The
simulation data were compared with the experimental residence times obtained from near
infrared chemical imaging to validate the model (Fig. 1.a). In addition, the change in GSD and
dynamics along the TSG barrel in order to understand the function of individual screw modules
and their interaction was investigated experimentally. Dynamic image analysis was performed
to evaluate the changes in size of granules sampled from different locations in the barrel. The
results from the two studies have been utilised to develop a population balance model (PBM) for
a continuous TSG (Fig. 1.b). The focus is on the modelling of the rate processes considered
dominant in the kneading element regions of the granulator, namely aggregation and breakage.
The results demonstrated by this experimental and modelling study will be further used as a
basis for development of multi-dimensional PBM involving particle properties (size, porosity and
saturation etc.).
Figure 1: (a) NIR chemical map of API to measure resudence time distribution and (b) varification of particle
size distribution predicted using PBM
39
ICPE 2014
Application of combined UV/VIS spectroscopy and
computed tomography in analysis of granules
O. Kaspar1, V. Tokarova1, S. Oka2, R. Ramachandran2, F. Stepanek1
1
Department of Chemical Engineering, Institute of Chemical Technology Prague, Technická 3,
166 28 Prague 6, Czech Republic
2
Department of Chemical & Biochemical Engineering, Rutgers, The State University of New
Jersey, Piscataway, NJ, USA
Email for correspondence: Frantisek.Stepanek@vscht.cz
The X-ray micro-tomography (micro-CT) technique combined with UV/VIS spectroscopy
and image analysis has been used to visualize the microstructure of granules and the dynamic
evolution of porosity during granule dissolution. Granules have been produced by high shear
wet granulation (HSWG), which is currently the most common route undertaken. A mechanistic
understanding of the correlation between the properties of the primary powder and granules can
lead to enhanced and efficient process development in tablet manufacturing.
Using acetaminophen (paracetamol) as the active pharmaceutical ingredient (API) and
microcrystalline cellulose (Avicel PH-200) as an excipient, the porosity of the granules was
systematically influenced by the granulation process parameters (binder/solids ratio, impeller
speed and wet massing time). The CT measurement allows us to study localization of the API
(acetaminophen) in the matrix of granule (cellulose) and evaluate the diffusion mechanism of
API from granules into surroundings for different process variables [1]. This approach could be
very beneficial in optimization of granulation process and properties of the final product.
1.
Kaspar, O., et al., Combined UV/vis and micro-tomography investigation of acetaminophen
dissolution from granules. International Journal of Pharmaceutics, 2013. 458(2): p. 272-281.
40
ICPE 2014
Multispectral UV Imaging for High-Speed Quality
Control in the Manufacturing Process of Tablets
M. Klukkert,1 A. Sakmann,1 S. Rehder,2 J.M. Carstensen,3 T. Rades,4 C.S. Leopold,1
1
University of Hamburg, 2Bayer Health Care Supply Center Kiel 3Technical University of
Denmark, 4University of Copenhagen
Email for correspondence: klukkert@chemie.uni-hamburg.de
Purpose. To investigate the applicability of UV imaging in combination with multivariate image
analysis as a non-destructive, high-speed technique for content control of blisters, identity
control of tablets and determination of the coating layer intactness within the primary packing
material of the tablets.
Methods. Acetylsalicylic acid (ASS) tablets (MCC, starch, aerosil, and MgSt) were compacted
(rotary tablet press, 8 mm faceted punches) and subsequently coated with Kollicoat® IR (drum
coater). Those compacts as well as Baytril® (B, API: enrofloxacine) and Drontal® Plus (D, APIs:
febantel, praziquantel, pyrantel pamoate) tablets were imaged within sealed blisters (sealing
foil: polyvinyl chloride (PVC) or polychlorotrifluoroethylene (PCTFE)) using a six-wavelength UV
imaging instrument (VideometerLab) with a CCD camera to capture the diffusely reflected light.
Image analysis and statistics were performed using an in-house written Matlab® script.
Results. UV imaging has been shown to be a fast analyzing technique as images of more than
70 tablets (8 mm ø) were acquired within 30 s (spatial resolution: 77.9 µm). The UV images of
blistered tablets (Figs. 1a and 2a) reveal translucency of PVC and PCTFE foils for the emitting
UV light. According to the UV spectra (Fig. 1b), D and B show distinct absorbance profiles
through the sealing foils. To determine the suitability of UV imaging to detect cross
contamination in an automatized manner, PCA was applied on the spectral dataset. The PC2
scores images (Fig. 1c) reveal clear a differentiation of the two tablet formulations as pixels
belonging to B are markedly higher in intensity than those related to D.
To evaluate the intactness of the coating layer of ASS formulations, PCA was performed on
each tablet separately. The resulting PC1 scores images (Fig. 2b) were separated into nonoverlapping concentric subunits followed by calculation of the within-subunit variation (relative
standard deviation, rSD) of score intensities (Fig. 2c). The plots of the rSDs of the respective
subunits vs. their radius reveal a nearly constant within-subunit variation throughout the surface
for intact tablet coatings. In contrast, splintered coatings are clearly detected as they result in a
markedly increased rSD of the enclosing subunit, which exceeds the previously determined
threshold that is indicative for an intact coating layer (Fig. 2c, red lines).
Conclusion. Multispectral UV imaging in combination with multivariate image analysis is a fast,
non-destructive, and sensitive technique to verify the content of blisters, detect cross
contamination and evaluate the coating integrity of sealed tablets in an automatized manner.
P
B
Figure 1: a) UV images (313 nm) of tablets
(1: Drontal® Plus, 2: Baytril®); b) UV spectra of D
and B and PC2 loadings plot; c) PCA scores
images of PC2.
Figure 2: Columns correspond to ASS tablets with intact (3) or
splintered (4) coating and the image analysis pathway (5); a) UV
images (313 nm) of sealed tablets; b) PCA scores images of PC1;
c) relative SD of PC1 scores of concentric subunits vs. their radius.
41
ICPE 2014
Fast Insight into Solid State Transformations using
Synchrotron X-ray Diffraction
J. Boetker1, J. Rantanen1, T. Rades1, A. Müllertz1, A. Hawley2, B. Boyd3
1
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark
2
3
SAXS/WAXS Beamline, Australian Synchrotron, Clayton, VIC, Australia
Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville,
VIC, Australia
Email for correspondence: johan.botker@sund.ku.dk
PURPOSE
The purpose of these experiments was to assess the solvent mediated solid state
transformation of a model compound, carbamazepine (CBZ), by synchrotron X-ray diffraction.
Different media were used to approximate biorelevant conditions to understand the impact of
solution components on transformation rates.
METHOD
CBZ (form III) was acquired from Hawkins, Inc. (Minneapolis, MN, USA). Milli-Q water, bile salt
(sodium taurodexoycholate sodium salt, 20 mM STDC) in aqueous solution, FaSSIF (1.25 mM
DOPC and 5.00 mM STDC), FeSSIF (5.00 mM DOPC and 20.00 mM STDC) and an aqueous
SDS solution (1% SDS and 5 mM DOPC) were used as solvent media. The crystal form of the
dispersed drug particles was determined at down to 5 sec time intervals at the SAXS/WAXS
beam line at the Australian Synchrotron, Clayton, Australia. The sample environment consisted
of a custom build rig setup [1].
RESULTS
Time resolved synchrotron X-ray diffractograms were obtained by dispersing CBZ anhydrate
form III in either Milli-Q water or different biorelevant media (FaSSIF, FeSSIF, bile salt or SDS
containing media). The diffraction of the CBZ anhydrate form III was observed to vanish after
approximately 3 to 30 min depending on the medium used. Furthermore, the synchrotron X-ray
diffractograms provided direct verification of the formation of the CBZ dihydrate form. The
conversion rates of CBZ anhydrate form III to CBZ dihydrate were shown to be affected by the
dissolution media with the conversion being the fastest in SDS solution, intermediate in either
water or FaSSIF/FeSSIF and relatively slow in bile salt.
CONCLUSION
The presence of SDS clearly sped up the polymorphic transformation of carbamazepine relative
to water. In contrast, bile salt clearly slowed the transition, indicating the specific interaction of
bile salt with the carbamazepine solid form. Future studies will be directed at quantifying the
adsorption behaviour of surfactants in these systems to support the kinetics of the
transformations determined in this study.
[1] Boetker, J.; Rades, T.; Rantanen, J.; Hawley, A.; Boyd, B. J. Structural Elucidation of Rapid SolutionMediated Phase Transitions in Pharmaceutical Solids Using in Situ Synchrotron SAXS/WAXS. Mol
Pharmaceutics 2012, 9, (9), 2787-2791.
42
ICPE 2014
Coating Thickness Prediction by in-line Raman
spectra: Applicability of Spatial Filtering Velocimetry
as reference method
F. Folttmann, K. Knop, P. Kleinebudde, M. Pein
Heinrich-Heine University Düsseldorf, Institute of Pharmaceutics and Biopharmaceutics,
Email for correspondence: miriam.pein@hhu.de
The use of in-line Raman spectroscopy for the quantitative film thickness evaluation on pellets
has been introduced in 2010 [1]. However, an adequate reference method for in-line film
thickness determination has not yet been established. A spatial filtering velocimetry (SFV) probe
might be a promising tool for this purpose, as it has recently been applied for in-line particle size
determination in fluidized bed granulation processes [2-4].
A SFV probe for in-line particle sizing (Parsum®GmbH) and a Raman probe (Kaiser Optical
Systems) were used for pellet coating monitoring in a fluidized bed coater (Glatt) in the current
study. Data were captured per minute over a total process time of 247 min. The median of the
SFV volume size distribution was defined as particle size. A film thickness was calculated from
the particle size of uncoated and coated pellets. The final film thickness of 40 µm was reached.
Resulting Raman spectra were SNV (standard normal variate) normalized. The spectra and the
film thicknesses were correlated using the PLS (partial least squares) regression method
(SIMCA 13.0®, Umetrics).
Two coating runs were performed under the same conditions. Coating run 2 was used for
calibration, coating run 1 for external validation. The resulting RMSEP (root mean square error
of prediction) of 3.79 (Table 1, model 1) indicates a low predictive power of the calibration
model to foretell the film thickness on Raman spectra obtained in an independent coating run.
The high RMSEP might be due to effects of the measurement techniques. In coating run 1, an
artefact in particle sizing occurred in the beginning of the spraying phase (Fig.1, left). Moreover
the spectral information showed an offset of one wavenumber (Fig.1, right). Eliminating the
spectral offset resulted in a decreased RMSEP (Table 1, model 2). However, the RMSEP
decreases much more by eliminating the artefact in pellet sizing by optimization of the raw data
(Table 1, model 3). By correlating both optimized datasets, the lowest prediction error of 3.03
was achieved.
Figure 1. SFV particle size (D50) (left), 3 out of 247 normalized Raman spectra per run (right) of
coating run 1 (black) and 2 (grey) spectral excerpt 917-984 cm-1
In summary, the validation by an external dataset showed that artefacts in SFV based pellet
sizing led to a relatively high predictive error of the calibration model. The observed spectral
offset of one wavenumber had a lower impact on the RMSEP. The applicability of in-line SFV as
reference method for coating thickness prediction by in-line Raman spectroscopy during a
Wurster coating process was generally proven. However, further studies are required to assess
the quality of the calibration.
Table 1. PLS models
Model
number
1
2
3
4
Coating
number
(calibration)
2
2
2
2
Coating
number
(validation)
1
1a
1b
43
1ab
Spectral
range [cm-1]
R2
RMSECV
RMSEP
150-1750
150-1750
150-1750
150-1750
0.992
0.992
0.992
0.992
1.19
1.19
1.19
1.19
3.79
3.64
3.06
3.03
[1] A. Bogomolov et al., J.
Chemometrics, 24 (2010) 544-557
[2] A. Burggraeve et al., Eur. J.
Pharm. Biopharm., 76 (2010) 138-14
[3] A. Burggraeve et al., Eur. J.
Pharm. Biopharm.,83 (2013) 2-15
[4] S. Schmidt-Lehr et al., Pharm.
Ind., 69 (2007) 478-484
ICPE 2014
Measuring the particle size evolution of
disintegrating tablets
J. Quodbach, P. Kleinebudde
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf
Email for correspondence: julian.quodbach@hhu.de
Information about the particle size distribution (PSD) of particles generated during tablet
disintegration could be useful for formulation scientists, especially, if it was possible to record
the change in particle size over a period of time. Until now, the fragility of tablet particles
prevented the particle size determination. In this study, an approach is presented to
continuously acquire particle size data of disintegrating tablets.
Tablet particles are usually destroyed or severely altered
when they pass a pump. Nevertheless, this process is
necessary to transport the disintegration medium through a
measuring instrument. This problem is overcome by
introducing a propelling circuit (Figure 1, dark gray) driven
by a double membrane pump (Lutz DMP ¼”, Lutz Pumpen
GmbH). This circuit is separated from a measuring circuit
(Figure 1, light gray) in which the particles are transported
through a measuring device (Parsum Inline-Probe IPP
77-S, Parsum GmbH). Tablets disintegrate in the main,
funnel-shaped water reservoir in a tablet holder made of
coarse mesh. In this reservoir the water circulates similarly
to a cyclone to separate the particles from the water. The
particles sediment in the funnel and are drawn in the
measuring circuit which passes through the Parsum-probe.
The measuring circuit is driven by an under pressure
Figure 1: Setup of measurement
caused by the velocity difference between measuring and
apparatus
propelling circuit, which ends in the hose of the
measurement circuit behind the Parsum-probe (Figure 1). The water for the propelling circuit
flows from the top of the glass funnel through a sediment filter. The filter system is added to
prevent particles from re-entering the measurement circuit.
The ring buffer (moving average) of the Parsum-probe is set to 1000 particles and a particle
size distribution is saved every 5 s. In Figure 2, the results of two formulations are shown
exemplarily. The only difference between the formulations is the brand of the used disintegrant
(polacrilin potassium). The results suggest, that the disintegrant used in the right graph is more
efficient because less large and more small particles result after short time. For the first time, it
is possible to record continuously the PSD of disintegrating tablets.
Figure 2: Particle size distributions of tablets containing two different brands of polacrilin potassium
44
ICPE 2014
Fully Coupled Multiphase Simulation of a Bottomspray Wurster Coater Using a Hybrid CPU/GPU
CFD/DEM approach
E. Siegmann, A.C. Radeke, J.G. Khinast
Research Center Pharmaceutical Engineering, Graz
Email for correspondence: Johannes.khinast@rcpe.at
Where most of the DEM simulations focus on dry material handling, some highly important
applications involve liquid chemical sprays. Here, granular material is sprayed and coated.
Using an in-house DEM code, a lab-scale Wurster coater with one million particles was
simulated for at least 60 seconds of processing time. The particles are coated continuously by a
bottom spray nozzle and grow according to their residence time in the spray zone. The
commercial code AVL FIRE® was used to simulate the liquid phase and our in-house GPU
DEM code XPS was used for the modelling of the solid phase.
By statistical means values like residence time distribution and size distribution of the particles
were monitored.
Keywords:
Discrete element modelling, Spray, Coating
45
ICPE 2014
Terahertz Spectroscopy: A New Tool for Predicting
the Stability of Amorphous Drugs
Juraj Sibik1, Korbinian Loebmann2, Thomas Rades2, J. Axel Zeitler1,*
Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
2
Department of Pharmacy, University of Copenhagen, Denmark
Email for correspondence: jaz22@cam.ac.uk
1
Terahertz spectroscopy is gaining popularity in pharmaceutical research due to its ability to
probe inter-molecular dynamics in a unique way. Crystalline solids exhibit unique spectral
fingerprints in the terahertz region, allowing their identification [1], while amorphous solids and
liquids show no distinct spectral features. Yet, the difference in the frequency dependence of
absorption of amorphous solids and liquids can be quantified and information on the relaxation
dynamics may be extracted [2,3]. At the moment the terahertz studies of amorphous materials
still remain limited.
In the present work we summarise our recent findings from studies of amorphous drugs by
terahertz spectroscopy. Three different glass-forming drug systems were examined: naproxen,
indomethacin and paracetamol. The thermal range covered both temperatures below and above
glass transition temperature Tg. Several key observations with relevance to pharmaceutical
industry were made.
We have previously shown that the terahertz absorption generally exhibits three different
thermal regions: (i) at temperatures below 0.65 Tg the absorption is induced almost entirely by
coupling the terahertz photons into vibrational density of states, (ii) at temperatures between
0.65 - 1.0 Tg the Johari Goldstein (JG) secondary relaxation develops and contributes to the
terahertz losses, and (iii) at temperatures above Tg the primary relaxation develops and
contributes towards the terahertz absorption [2,3].
On the sample of naproxen we show that the crystallisation of glasses are directly enhanced by
JG relaxation above 0.65 Tg. The samples of indomethacin and paracetamol are then used as a
proof of principle system opening a possibility of terahertz spectroscopy as a tool of the stability
predictions of amorphous drugs. Lastly, the crystallisation kinetics of paracetamol is examined
above Tg [4].
We propose that terahertz spectroscopy could be a useful new technology to assess the
stability of pharmaceutical drug molecules: the measurement of the dielectric relaxation
dynamics at terahertz frequencies allows to directly quantify the absolute strength of molecular
movement that persists at temperatures below the Tg and how this is affected by temperature
changes.
1. Zeitler, J. A., Taday, P. F., Newnham, D. A, Pepper, M., Gordon, K. C., and Rades, T. Terahertz
pulsed spectroscopy and imaging in the pharmaceutical setting - a review. J. Pharm. Pharmcol., 59,
209–223 (2007)
2. Sibik, J., Shalaev, E. Y. and Zeitler, J. A. Glassy dynamics of sorbitol solutions at terahertz
frequencies, Phys. Chem. Chem. Phys. 15, 11931-11942 (2013).
3. Sibik, J., Elliott, S. R. and Zeitler, J. A. Thermal decoupling of molecular-relaxation processes from the
vibrational density of states at terahertz frequencies in supercooled hydrogen-bonded liquid,
submitted.
4. Sibik, J., Sargen, M.J., Franklin, M., and Zeitler, J.A. Crystallization and phase changes in
paracetamol from the amorphous solid to the liquid phase, Mol. Pharm. in press
DOI:10.1021/mp400768m (2014).
46
ICPE 2014
Continuous manufacturing of solid dosage forms
from the point of view of an equipment supplier
H. Spittka, R. Lemperle
Gebrüder Lödige Maschinenbau GmbH
Email for correspondence: spittka@loedige.de, lemperle@loedige.de
Lödige is well experienced in designing continuous process equipment and subsystems for
mixing and granulating processes for a couple of different industries since 1950. Lödige already
supplied some continuous systems for specific applications for the pharmaceutical industry
since 1991 where relative large production volumes were required.
The interest for this type of process grew considerably due to the PAT initiative and the “Quality
by design” approach in the pharmaceutical industry.
As a supplier of continuous or semi continuous subsystems or systems, Lödige can basically
provide the following machinery for the production of solid dosage forms, working either
individually or combined in the complete process unit:
1. Continuous mixers
2. Continuous granulators
3. Continuous dryers
The required throughputs are 10 – 500 kg/h for continuous mixing processes and 5 – 500 kg/h
for continuous mixing, granulation and drying processes.
The available machines and systems need a much smaller footprint as comparable batch
machines. Because of this it is often easy to install such systems in existing sites.
For the wet granulation processes Lödige recommends to use continuous horizontal mixers
rotating at high speed so called ring layer mixers.
In this type of mixer nearly identical rheological properties as in batch high shear mixers will be
achieved.
This process solution developed by Lödige is not an extrusion process but a high shear
granulation generating a very close particle size distribution.
Dosing of the active agent and the other components into the continuous mixer is a decisive
aspect for implementing continuous systems.
Flow properties of the different components required trails and individual design of all
components of the unit as the loss in weight feeders during the design phase of continuous
processes.
Another important aspect when designing continuous systems is the quality control of the most
critical process steps. For this purpose NIR measurement methods or similar and process
parameters like speed of the mixing shaft, temperatures and weighing precision can be used for
the process validation.
The continuous systems manufactured by Lödige ensure a yield up to 98.5 % depending on
process and products.
47
ICPE 2014
Experimental study on the particle size distribution of
granules produced by twin screw granulation
J. Vercruysse*, M. Fonteyne**, U. Delaet***, I. Van Assche***, T. De Beer**, J.P. Remon*, C.
Vervaet*
*Laboratory of Pharmaceutical Technology, Ghent University, Belgium
**Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Belgium
***Department of Pharmaceutical Development, Janssen Pharmaceutica, Belgium
Email for correspondence: Chris.Vervaet@ugent.be
Twin screw granulation (TSG) has been reported by different research groups as an attractive
technology for continuous wet granulation. In contrast to fluidised bed granulation, granules
produced via this technique typically have a broad and bimodal particle size distribution (PSD)
leading to inferior flow properties [1-2]. Previous research work [3] indicated that the bimodal
PSD after twin screw granulation was not specifically linked to insufficient mixing of powder and
liquid phase during the short residence time of material inside the screw chamber, but rather to
the granulation mechanism inherent to the technique. The aim of the current study was to vary
granulator screw configuration and formulation parameters in order to obtain a narrower and
monomodal PSD.
Experiments were performed using a 25-mm co-rotating twin screw granulator (part of the
ConsiGmaTM-25 system, a fully continuous from-powder-to-tablet manufacturing line from GEA
Pharma Systems). Besides the screw elements conventionally used for TSG (i.e. conveying and
kneading elements), other types of screw elements (e.g., distributive mixing elements) were
evaluated. Formulation parameters such as type of filler (α-lactose monohydrate, MCC, corn
starch), binder (PVP, HPMC, pregelatinized starch) and binder addition method (wet vs. dry)
were studied. Addition of a surfactant (sodium laurylsulphate) to the granulation liquid was
evaluated. Furthermore, milling of granules (Quadro® comil®) was performed at different milling
speeds (300-3000 rpm). PSD (sieve analysis) and angle of repose of granules were
determined.
Using distributive mixing elements on the granulator screws, agglomerates (>2000µm) were
broken up to smaller granules (250-1400µm) without formation of extra fines (<150µm).
Therefore, screws consisting of kneading elements combined with distributive mixing elements
resulted in a narrower and monomodal PSD, compared to screws with kneading elements only.
The liquid-to-solid ratio (L/S ratio) yielding an acceptable granule size distribution depended on
the aqueous solubility of the filler: a higher L/S ratio was required with a low soluble filler (corn
starch). Due to the short residence time of material inside the screw chamber, the binder
efficiency was highly dependent on the swelling rate of the binder. If the binder was dissolved in
the granulation liquid prior to wet granulation, the amount of fines was lower. Addition of a
surfactant to the binder solution improved wetting of powders and yielded larger granules. At
higher milling speed, more fines were formed during milling, reducing the flow properties as
indicated by a higher angle of repose.
In conclusion, by adapting screw configuration as well as formulation and milling parameters,
the PSD of granules produced with TSG could be adjusted. However, PSD obtained for twin
screw granulated material was still broader (250-1400µm), compared to fluidised bed
granulation (150-500µm).
1.
A.S. El Hagrasy et al., Twin screw wet granulation: influence of formulation parameters on
granule properties and growth behavior, Powder Techn. 238 (2012) 108-115.
2.
R.M. Dhenge et al., Twin screw wet granulation: granule properties, Chem. Eng. J. 164 (2010)
322–329.
3.
J. Vercruysse et al., Visualization and understanding of the granulation liquid mixing and
distribution during continuous twin screw granulation using NIR chemical imaging, Eur. J. Pharm.
Biopharm. (2013) http://dx.doi.org/10.1016/j.ejpb.2013.10.012.
48
ICPE 2014
The Plug & Play Reactor: A Versatile Tool for
Synthesis in Continuous Flow Mode
H. Gruber-Wölfler, G.J. Lichtenegger, K. Obermaier*, H. Kitzler*, J.G. Khinast
Graz University of Technology, Institute of Process and Particle Engineering, Graz, Austria
* One-A Engineering Austria GmbH, Vöcklabruck, Austria
Email for correspondence: woelfler@tugraz.at
Continuous processing has been considered as highly attractive alternative to batch
manufacturing in the pharmaceutical industry for many years. It offers several advantages, such
as reduced capital and operational costs, as well as real-time quality control for increased
process reliability, reproducibility and safety. Furthermore, the switch from a synthetic batchmode to a flow-through concept has other various advantages. For example, scale-up can be
conducted by use of parallel reactors and assembling a line of reactors multistep synthesis can
be achieved by minimum or no purification in between two reaction steps. Up to now, batch
processing still dominates pharmaceutical manufacturing. However, the pharmaceutical industry
is currently attempting a transition towards continuous manufacturing in several areas, driven by
the “PAT” and the “Critical-path” initiatives of the FDA (Federal Drug Administration).
We present the development of a so-called “Plug & Play Reactor”. This “minireactor” includes
an exchangeable reaction module, which is filled with heterogeneous catalysts. Thus, the Plug
& Play reactor can be used for gas/solid, liquid/solid as well as gas/liquid/solid reactions.
Furthermore, it allows the monitoring of the reaction progress and the reaction parameters inand online and can be easily implemented in existing reaction processes.
The performance of this new reactor will be presented using two model reactions. Both
reactions involve heterogeneous catalysts which are implemented as fixed bed in the Plug &
Play reactor. As a consequence, an extra step to separate the catalytic active compounds from
the reaction mixture is not necessary.
The first reaction involves the synthesis of acetyl salicylic acid – the API of Aspirin. The
traditional synthesis of this compound includes the use of sulfuric acid as catalyst for the
esterification. In our approach, commercially available ion-exchange particles (Amberlite 120 IR)
are used as heterogeneous catalyst implemented in the Plug & Play reactor.
The second model reaction is the cross-coupling of different aryl halides with phenyl boronic
acid via the Suzuki-Miyaura reaction [1]. For these kind of reactions heterogeneous Pd-catalysts
developed by us [2, 3] are used. The obtained products are important compounds for
pharmaceutical products or liquid crystals.
The results of both model reactions show that the developed setups lead to improved
practicability and flexibility of the processes. Thus, our novel reaction system constitutes a
promising alternative to existing batch applications.
[1] N.Miyaura, A.Suzuki, Chem. Rev. 95 (1995) 2457.
[2] H.Gruber-Woelfler, P.F.Radaschitz, P.W.Feenstra, W.Haas, J.G.Khinast, Journal of Catalysis 286
(2012) 30.
[3] G.J.Lichtenegger, P.A.Deshpande, H.Gruber-Wölfler, J.G.Khinast, Oral Presentation, 47.
Jahrestreffen Deutscher Katalytiker, Weimar, Germany (2014).
49
ICPE 2014
Author Index
Kessler, Rudolf 34
Khinast, Johannes 7
Khinast, Johannes G. 29, 49
Kitzler, Hannes 49
Kleinebudde, Peter 26, 29, 44
Klukkert, Marten 41
Knop, Klaus 29
Kohnke, Marco 16
Konrad, Ilona 17
Koscher, Gerold 7, 21
Kumar, Ashish 39
Kupetz, Eva 12
Kwade, Arno 9
B
Baumgartner, Ramona 19
Bermingham, Sean 25
Boetker, Johan 42
Boyd, Ben 42
Breitung-Faes, Sandra 9
Brunsteiner, Michael 14
Bunjes, Heike 12
C
Carstensen, Jens Michael 41
D
L
Davies, Paul 32
De Beer, Thomas 48
Delaet, Urbain 48
Dischinger, Angela 35
Djuric, Dejan 29
E
Lah, Nina 36
Langemann, Timo 18
Langguth, Peter 27
Lemperle, Reiner 47
Leopold, Claudia S. 41
Lichtenegger, Georg J. 49
Eisenschmidt, Holger 28
Eitzlmayr, Andreas 21
M
Matic, Josip 21
Matilainen, Julia 22
Mönckedieck, Mathias 6
Mohan, Bhageshvar 38
Mortier, Séverine 20
Müllertz, Anette 42
Muerb, Reinhardt-K. 8
F
Fakner, Phanuel 6
Finke, Jan Henrik 9
Folttmann, Friederike 43
Fonteyne, Margot 48
Freitag, Angelika 17
Friess, Wolfgang 17
Funke, Adrian 29
O
Obermaier, Klemens 49
G
P
Gajdosova, Michaela 4
Gavi, Emmanuela 35
Geidobler, Raimund 17
Gernaey, Krist 1, 39
Ghosh, Pranay Kumar 35
Gruber-Wölfler, Heidrun 49
Page, Susanne 35
Paudel, Amrit 13
Paus, Raphael 3
Pittermann, Birgit 10
Polyak, Fabian 30
Prudic, Anke 3
H
Q
Häberl, Michael 16
Hawe, Andrea 17
Hawley, Adrian 42
Quodbach, Julian 44
R
J
Radeke, Charles 45
Rades, Thomas 2, 41, 42
Radl, Stefan 38
Rantanen, Jukka 42
Rehder, Sönke 41
Reich, Gabriele 30
Remon, Jean Paul 48
Roessl, Ulrich 10
Rothkopf, Christian 22
Juppo, Anne 22
Just, Sarah 29
Juster, Herwig 37
K
Kamola, Adrian 15
Kamplade, Jens 6
Kaspar, Ondrej 40
Kerschhaggl, Peter 31
51
ICPE 2014
S
Sacher, Stephan 31
Sadowski, Gabriele 3
Sakmann, Albrecht 41
Sandström, Saana 22
Scharrer, Georg 29
Scheiblauer, Johannes 24
Scholl, Stephan 16
Srcic, Stane 36
Stankovic, Milica 5
Steckel, Hartwig 6
Stegemann, Sven 11
Steiner, Denise 9
Stieneker, Frank 27
Stocker, Elena 23
T
Torbett, Richard 33
Toschkoff, Gregor 29
Trebbien, Sebastian 27
Treffer, Daniel 7
V
Van Assche, Ivo 48
Vercruysse, Jurgen 48
Vervaet, Chris 48
W
Wahl, Patrick R. 31
Walzel, Peter 6
Weinsheimer, Ina 27
Weitz, Alexandra 27
Wesche, Mandy 16
Winter, Gerhard 17
Z
Zeitler, Axel 46
52
POSTER
ICPE 2014
Table of Contents
Lunch Break / Poster Session
Monday, June 16, 12:50 - 13:50, Foyer "Alte Technik":
1
Rapid enzyme based detection systems display upcoming
infections in chronic wounds
1
Doris Schiffer
2
The adhesion of composite microparticles in 3D
differentiated model solid media
2
Nina Sarvasova
3
An effective tool of particle targeting to a cancer cell by
the antibody-antigen interaction
3
Viola Tokarova
4
Effects of the Drying Temperature on the Final Properties
of Calcium Stearate Micro-Pellets
4
Simone Schrank, Birthe Kann, Maike Windbergs, Ben Glasser
5
The development and use of a piezoelectric impact probe
for pellet flow evaluation in a Wurster coater
5
Matevž Luštrik
6
Flow regimes inside the Wurster coater draft tube
6
Matevž Luštrik
7
Issues on protein drug formulation filtration
7
Benjamin Werner, Gerhard Winter
8
crystals
8
Stane Srcic
9
Nanoemulsification: Initial Junction of Lipid and Aqueous
Phase in High Pressure Microsystems
9
Jan Henrik Finke, Thomas Gothsch, Stefan Beinert, Claudia Richter,
Jan-Wilhelm Thies, Andreas Dietzel, Stephanus Büttgenbach,
Christel Charlotte Müller-Goymann, Arno Kwade
10 Development of critical quality attributes control strategies
in a continuous high shear wet granulation process
10
Niels Nicolaï, Ingmar Nopens
11 Preparation and characterization of lipid nanocarriers
containing ceramides
Lucie Vidlarova
I
11
ICPE 2014
12 Manufacturing of Poloxamer 188-stabilized Lipid
Nanoemulsions by Premix Membrane Emulsification
12
Sandra Gehrmann
13 Targeted drug delivery through surface functionalization of
human serum albumin nanoparticles
13
Alexandra Rollett, Andrea Heinzle, Tamara Reiter, Anna Repic,
Hannes Stockinger, Georg M. Guebitz
14 Solid-state Compatibility Screening of Excipients Suitable
14
for Development of Indapamide Sustained Release Solid Dosage
Formulation
Packa Antovska, Gjorgji Petrusevski, Bosilka Stefanova,
Sonja Ugarkovic, Petre Makreski
15 Permeability studies of the TCM formulation Si Miao San,
its modifications and main compounds
15
Christine Reisinger
16 A Refined Model for the Filling Rate of a Liquid Bridge
16
Mingqiu Wu, Johannes Khinast, Stefan Radl
Lunch Break / Poster Session
Tuesday, June 17, 12:50 - 13:50, Foyer "Alte Technik":
1
Mini-tablets: an option for multiple unit dosage forms
17
Florian Priese, Caterina Funaro, Giusi Mondelli,
Anastasiya Zakhvatayeva, Bertram Wolf
2
Estimation of particle concentration in a Wurster coater
draft tube via optical transmittance
18
Rok Šibanc, Rok Dreu
3
Development of a Drug Abuse-Alcohol-Resistant
Formulation Produced via Hot-Melt Extrusion
19
Nicole Jedinger
4
The role of surface hydrophilicity/hydrophobicity of
nano-TiO2 in buccal uptake behaviour
20
Birgit Teubl
5
Development of Lipophilic Hot-Melt Extruded
Alcohol-Resistant Pellets Containing Nicomorphine
21
Nicole Jedinger
6
PAT in High-Shear Granulation Processes using In-line
Particle Size Measurements
Gerd Kutz, Carina Hüttner, Stefan Dietrich
II
22
ICPE 2014
7
Diafiltration in a manufacturing process of liposome
embedded DNAzymes.
23
Kay Marquardt
8
Surface coverage of surface modified glass beads as model
carriers in dry powder inhalers influences the FPF
24
Sarah Zellnitz, Hartmuth Schroettner, Nora Anne Urbanetz
9
Characterization and synthesis of alginate microparticles
using microfluidics device
25
Anna Pittermannova
10 Feedback Control for a Continuous Crystallization Process
26
Maximilian Besenhard, Cheng-Da Ho, Peter Neugebauer,
Raffael Eder, Johannes Khinast
11 The influence of residual water on the reconstitution
behavior of lyophilized human fibrinogen
27
Verena Wahl, Stefan Leitgeb, Peter Laggner, Johannes Khinast
12 Novel Strategy for Downstream Process Development along
QbD Principles
28
Andrea Meitz
13 Fluid Bed Granulation: Towards a Comprehensive gSOLIDS
Model
29
Robert C. Schardmüller, Markus Pieber, Gregor Toschkoff,
Simon Fraser, Bruno Chilian, Daniela Steigmiller, Alfred Fetscher,
Markus Maus, Michael Braun, Johannes G. Khinast
14 Intra-tablet Coating Uniformity of Various Pharmaceutical
Tablet Shapes
30
Axel Zeitler, Ben Freireich, Bill Ketterhagen, Rahul Kumar, Ke Su,
Carl Wassgren
15 Multivariate Analysis of Residence Time Measurements in
HME Gained by Imaging
31
Josefine Pott, Markus Thommes
16 Binary Mixtures of Pharmaceutical Excipients: Evaluation of
Flow Properties and Compaction Behaviour
32
Jaime Conceição
17 A QbD approach to optimise electrochemical sensors
Itsvan Kondor
III
33
ICPE 2014
Rapid enzyme based detection systems display
upcoming infections in chronic wounds
D. Schiffer1, A. Heinzle1, D. Luschnig1, B. Binder2, E. Sigl1, G. M. Guebitz1, 3
1
Austrian Centre of Industrial Biotechnology
2
Institute for Dermatology, Medical University of Graz
3
Institute for Environmental Biotechnology, University of Natural Resources and Life
Sciences, Tulln, Austria
Email for correspondence: doris.schiffer@acib.at, guebitz@boku.ac.at
Wound infection is a global problem that affects 5-10% of post-surgical wounds and
25% of chronic wounds and furthermore delays or prevents the healing process. The
diagnosis is currently based on the classical clinical signs of infection as redness
(rubor), heat (calor), swelling (tumor), pain (dolor) and impairment of function
(functiolaesa) or microbiological analyses which take several days.
It is known that infection is characterized by an excessive stimulation of neutrophil
granulocytes, resulting in the release of proteolytic enzymes like human neutrophil
elastase (HNE), myeloperoxidase (MPO), lysozyme (Lys) and also matrix
metalloproteinases (MMP) into the plasma.
The enzyme activities of HNE, Lys, MPO and MMPs were directly monitored in wound
fluid of affected patients via hydrolysis of chromogenic and fluorescent substrates or of
peptidoglycan (PG) respectively (1). MPO was measured via oxidation of guaiacol.
Infected wound fluids led to significant higher substrate conversion compared to noninfected wound fluids (2). The lysozyme present in infected wound fluids led to an
increased hydrolyses of PG, visible as decrease of turbidity compared to non-infected
fluids (3).
In addition, the gelatinolytic activity from both- matrix metalloproteinases (MMPs) and
bacterial proteases were investigated in different types of wounds for the development
of an enzyme-responsive detection method.
An electrochemical sensor for fast and simple detection of MPO activity as marker for
infection was investigated. The MPO-chlorination activity - the formation of
hypochlorous acid (HOCl) - in different wound fluids was used to differentiate between
infected and non-infected wounds.
To furthermore allow integration of sensors in typical bandage materials we successfully
immobilized enzyme substrates on collagen, modified collagen, polyamide, polyesters
and silica gel. These immobilized substrates were converted only by infected wound
fluids, thus allowing on-line monitoring of wounds due to different colour stages of the
bandage.
1.
Hasmann, G. M. Guebitz, and E. Wehrschuetz-Sigl, New Sensor Materials for the Detection of
Human Neutrophil Elastase and Cathepsin G Activity in Wound Fluid, Exp Dermatol. 2011 Jun;20(6):50813
2.
Hasmann, E. Wehrschuetz-Sigl, and G. M. Guebitz, Analysis of Myeloperoxidase in Wound
Fluids as Marker for Infection, Ann.Clin.Biochem., 2011; 00:1-10.
3.
Hasmann, E. Wehrschütz-Sigl, G. Kanzler, B. Binder, E. Hulla, and G. M. Guebitz, Novel
Peptidoglycan Based Diagnostic Devices for Detection of Wound Infection, Diag.Micr.Infec.Dis., 2011
Sept; 71 (1):12-23
1
ICPE 2014
The adhesion of composite microparticles in 3D
differentiated model solid media
N. Sarvašová*, F. Štěpánek
Department of Chemical Engineering, Institute of Chemical Technology, Prague, Technicka 5,
166 28 Prague 6, Czech Republic, Tel.: +420 220 443 048
*E-mail for correspondence: Nina.Sarvasova@vscht.cz
In every development of functional particles, there is an important part consisting of the study of
their behaviour in conditions simulating their end use. For such measurements, there are
several methods available, though only few of them can yield any results without damaging or
irreversibly changing the studied material. Magnetic Resonance Imaging (MRI) is a method
widely acknowledged as a suitable one for such purposes, as it is non-destructive, non-invasive
and provides the opportunity to observe the experiment in “real-time” arrangement. In this work,
MRI was used as a means to observe the behaviour, mainly adhesion, of selected
microparticles in 3D differentiated media.
As a part of this work, porous media with different pore sizes were created from
Polydimethylsiloxane (PDMS) using solid template method. Each of the porous layers was
placed within the flow cell connected to the peristaltic pump enabling the flow through the
system. Thus, such setting allowed for both, stationary and flow measurements in the MRI
scanner. Resulting scans were evaluated and processed using graphic software ImageJ.
Regarding the microparticles used in this work, two types of composite particles containing
magnetic nanoparticles were used, one with the size around 1.5 m and the other with the size
of approximately 100 m. Magnetic nanoparticles contained in composite microparticles
belonged to the crucial requirements for these experiments, since it acted as a contrast agent
thus allowing for particle observation in MRI scans. In addition, the loss of the particles after the
experiment was estimated indirectly using UV/VIS spectroscopy as the loss of Fe3+ in the
circulating solution.
In summary, 3D complex PDMS media were created with the porosity estimated using MRI.
These were successfully used in the flow experiments to study the adhesion of
SiO2/PNIPAM/Fe3O4 and Alginate/SiO2/Fe3O4 microparticles. In both cases, there was some
adhesion observed and it was also backed up with the concentration loss of Fe3+ ions in inlet
and outlet streams during the experiments.
2
ICPE 2014
An effective tool of particle targeting to a cancer cell
by the antibody-antigen interaction
V. Tokarova1, V. Kral2, F. Stepanek1,*
1
Institute of Chemical Technology Prague, Department of Chemical Engineering,
Technická 3, Prague 6, 166 28, Czech Republic
2
Laboratory of Structural Biology, Institute of Molecular Genetics, Academy of Sciences of the
Czech Republic,v.v.i. 166 37 Prague 6, Czech Republic
*Email for correspondence: frantisek.stepanek@vscht.cz; Tel.: +420 220 443 236
Carbonic anhydrase IX (CA IX) is a trans-membrane protein over-expressed in a wide variety of
tumor cells. CA IX protein regulates intracellular pH during periods of hypoxia and thus plays a
role in the regulation of cell proliferation, oncogenesis and tumor progression1. It is therefore a
promising diagnostic and therapeutic target for a variety of cancers due to its almost exclusive
expression in tumors and very limited expression in healthy tissues. This work is concerned with
the surface modification of fluorescent silica nanoparticles by a monoclonal antibody IgG-M75
and the specific binding of such particles to surfaces coated by the PG domain of CA IX 2. The
adhesion strength of antibody-bearing silica nanoparticles to antigen-bearing surfaces was
investigated under laminar flow conditions in a microfluidic cell and compared to the adhesion of
unmodified silica nanoparticles and nanoparticles coupled with a nonspecific antibody3.
Adhesion to HT-29 cancer cells (cell line derived from colorectal carcinoma) using flow
cytometry was also investigated and compared with the cell line NIH 3T3 (sarcoma cell line)
which does not displayed CA IX on its surface. The antibody-bearing particles presented in this
work appear to be a promising tool for the targeting toward tumor cells.
1. V. Kral, P. Mader, R. Collard, M. Fabry, M. Horejsi, P. Rezacova, M. Kozisek, J. Zavada, J.
Sedlacek, L. Rulisek and J. Brynda, Proteins, 2008, 71, 1275-1287.
2. V. Tokarova, A. Pittermannova, V. Kral, P. Rezacova and F. Stepanek, Nanoscale, 2013, 5,
11490-11498.
3. V. Tokarova, A. Pittermannova, J. Cech, P. Ulbrich and F. Stepanek, Soft Matter, 2012, 8, 10871095.
3
ICPE 2014
Effects of the Drying Temperature on the Final
Properties of Calcium Stearate Micro-Pellets
S. Schrank*,**,***, B. Kann****, M. Windbergs****, B. J. Glasser*****, A. Zimmer**, J.
Khinast*,***, E. Roblegg**,***
*Institute for Process and Particle Engineering, Graz University of Technology, Austria
**Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of
Graz, Austria
***Research Center Pharmaceutical Engineering GmbH, Graz, Austria
****Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University,
Germany
*****Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway NJ,
USA
Drying is one of the standard unit operations during the manufacturing of pharmaceutical
products. However, its potential to impact the final product performance is often disregarded.
Considering wet extrusion/spheronization processes the granulation liquid needs to be removed
in a final step that is drying. The drying process design was shown to affect the pellet matrix (1,
2) and the physicochemical properties of the drug (3). Consequently, the drying process may
play a key role in meeting certain quality criteria, including in-vitro dissolution characteristics.
The present study addresses the impact of different temperatures (i.e, 20, 30, 40, 50 and 60 °C)
during tray drying on the physicochemical properties of ibuprofen after wet
extrusion/spheronization with calcium stearate (CaSt). The dried pellets were evaluated with
respect to i) the solid state of ibuprofen via differential scanning calorimetry (DSC), infrared (IR)
spectroscopy and small and wide angle X-ray scattering (SWAXS), ii) the spatial ibuprofen
distribution via Raman mapping and iii) their in-vitro dissolution behavior.
The solid state of ibuprofen remained unaffected during drying at 20, 30 and 40 °C. Drying at 50
°C however, induced amorphous transitions of ibuprofen and caused CaSt to partially form a
different lamellar phase. Moreover, these phases interacted on a molecular level via hydrogen
bondings. Drying at 60 °C yielded solid state modification, which were however not that
pronounced, as crystalline ibuprofen was still present after drying. From the in-vitro release
studies improved dissolution of amorphous ibuprofen was not evident.
As drying at 20 °C yielded comparatively strong convective liquid flow, dissolved ibuprofen
particles were transported towards the pellet surface. Ibuprofen re-crystallized on the pellet
surface thereby, leaving a pellet core that was depleted from ibuprofen. Ibuprofen release form
the pellets occurred fast and the release rate was only a function of the ibuprofen solubility.
Drying at 50 and 60 °C yielded rather homogeneous ibuprofen profiles due to suppression of
API migration. When the pellets were dried at 30 and 40 °C, the overall API distribution was
homogeneous again. However, ibuprofen was arranged in elongated assemblies, which
suggests a different drying mechanism despite similar ibuprofen profiles. For all homogeneous
ibuprofen distributions the ibuprofen release was slowed, since diffusion through the porous
CaSt matrix became the rate-governing step.
These findings underline the severity of drying induced modifications and suggest the need for a
mechanistic understanding of the drying process to rationally design multi-particulate dosage
forms.
1.
S. Schrank et al., Ibuprofen-Loaded Calcium Stearate Pellets: Drying-Induced Variations in
Dosage Form Properties, AAPS PharmSciTech 2012, 13(2), 686-698.
2.
S. Schrank et al., Microstructure of Calcium Stearate Matrix Pellets: A Function of the Drying
Process, J. Pharm. Sci. 2013, 102(11), 3987-3997.
3.
S. Schrank et al., Impact of Drying on Solid State Modifications and Drug Distribution in
Ibuprofen-Loaded Calcium Stearate Pellets, Mol. Pharmaceutics 2014, 11(2), 599-609.
4
ICPE 2014
The development and use of a piezoelectric impact
probe for pellet flow evaluation in a Wurster coater
M. Luštrik*,**, R. Šibanc*, S. Srčič*, M. Perpar**, I. Žun**, R. Dreu*
*University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia
**University of Ljubljana, Faculty of Mechanical Engineering, Aškerčeva 6, 1000 Ljubljana
Email for correspondence: matevz.lustrik@ffa.uni-lj.si
Particle coating is a commonly used process in which a coating solution or suspension is
sprayed onto a bed of fluidized particles. The distribution of particles inside the draft tube of the
Wurster coating chamber plays an important role in the performance of the fluidized bed coater.
A piezoelectric pressure transducer probe was developed to enable measurement of the
number of particle impacts on the probe’s active area inside the draft tube of conventional (CW)
and swirl generator equipped (SW) coating chamber.
A mini piezo actuator of a cubic shape with a side length of 2.00 mm (PICMA PL022.31, PI
Ceramics GmbH, Germany) was employed as a sensory element in constructing the probe. The
piezo actuator was fixed to a 220 mm long telescopic tube holder with a diameter of 2.80 mm.
The actuator was connected to a custom-made charge-to-voltage converter, employing an FETinput operational amplifier. The voltage spikes were generated at particle strikes in the piezo
actuator’s active area. Output voltage was recorded using a data logger at 50,000 samples per
second within a 30 s interval for every probe position. In addition to the sensor element, the
positioning mechanism was constructed, enabling the vertical orientation of the sensor probe
and also precise horizontal and height positioning inside the draft tube (36 measuring points
across the draft tube diameter). The probe diameter was small enough to minimize the probeinduced disturbances of the solids flow inside the draft tube of the coating chamber. Pellets in
range of 800 µm to 900 µm were subjected to fluidization [1].
The particle number density profiles were obtained, employing the data gathered by positioning
the probe across the draft tube diameter at four different heights or levels (Fig. 1). The most
evident difference between both coating chambers is in the location of the peak density values
of particle strikes. In the case of the CW coater the region was located close to the tube centre,
whereas in the SW the number density of particle impacts was higher close to the wall of the
tube in comparison to the central area. The same trend was noted regardless of the gap size.
The difference in particle number density profiles for both process chambers can be understood
as a significant difference in the two-phase flow within the coater draft tube, which may be the
underlying cause for the already demonstrated difference in performance of both process
chambers such as coating uniformity, process yield and degree of agglomeration [2].
Figure 1. Comparison between the particle number density profiles at 130 m³/h and a 20 mm
draft tube gap in CW (A) and SW (B) coating chamber.
1. M Luštrik, R Šibanc et al. Characteristics of pellet flow in a Wurster coater draft tube utilizing
piezoelectric probe. Powder Technol 235 (2013) 640–651.
2. R Dreu, M Luštrik et al. Fluid-bed coater modifications and study of their influence on the coating
process of pellets. Drug Dev. Ind. Pharm. 38 (2012) 501–11.
5
ICPE 2014
Flow regimes inside the Wurster coater draft tube
M. Luštrik*,**, R. Šibanc*, S. Srčič*, M. Perpar**, I. Žun**, R. Dreu*
*University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia
**University of Ljubljana, Faculty of Mechanical Engineering, Aškerčeva 6, 1000 Ljubljana
Email for correspondence: matevz.lustrik@ffa.uni-lj.si
Coating based on fluidized bed technology (i.e. air suspension coating) is commonly used in the
pharmaceutical industry to coat small particles and tablets. An ultimate objective of the fluid-bed
coating process is to prepare coated particles, each with a controlled, even coating layer and
assurance of acceptable process yield. The particle flow in the region close to the nozzle plays
an important role in this objective.
Piezoelectric sensor based probe for determination of characteristic frequencies of particle
impacts inside the draft tube of conventional (CW) and swirl generator equipped (SW) coating
chamber was developed. Probe measuring positions were distributed along the draft tube
diameter at 4 different levels, just above the upper end of the draft tube, at 6, 12, and 18 cm
below the upper end.
By using the Fast Fourier transform (FFT) analysis of the recorded signal, characteristic
frequencies of particle impacts have been identified: 1–5 Hz, 5–6 Hz, and 12–14 Hz. The
occurrence of characteristic impact frequencies is dependent on the gap size and fluidizing
airflow rate in the case of the CW chamber, whereas in the case of the SW chamber no such
conclusion can be drawn. In the case of the characteristic 1–5 Hz frequency band, it has been
shown that the occurrence is most likely the consequence of particle bed height fluctuations in
the zone around the draft tube.
The difference in characteristic particle impact frequency areas within the draft tube (Fig.1) for
both process chambers can be understood as a significant difference in the two-phase flow
within the coater draft tube, which may be the underlying cause for the already demonstrated
difference in performance of both process chambers. More uniform coating layer and higher
process yield was achieved in all cases of coating particles in a SW coating chamber [1,2].
Figure 1. Characteristic particle impact frequency areas within the draft tube of the CW (I) and
SW (II) chamber at fluidizing airflow rates of 105 m³/h (A), 130 m³/h (B), 156 m³/h (C), and 10
mm gap (only half of the draft tube is depicted).
1. M Luštrik, R Šibanc et al. Characteristics of pellet flow in a Wurster coater draft tube utilizing
piezoelectric probe. Powder Technol 235 (2013) 640–651.
2. R Dreu, M Luštrik et al. Fluid-bed coater modifications and study of their influence on the coating
process of pellets. Drug Dev. Ind. Pharm. 38 (2012) 501–11.
6
ICPE 2014
Issues on protein drug formulation filtration
B. Werner, G. Winter
Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics,
Ludwig-Maximilians-University, Butenandtstr. 5, 81377 Munich, Germany
E-mail for correspondence: benjamin.werner@cup.uni-muenchen.de
Biopharmaceutical drugs are taking a growing share of the pharmaceutical market due to their
enormous ability to treat severe diseases like cancer [1]. However, biologics are extremely
complex molecules and the development of a stable formulation represents a challenge, since
the stability and efficacy of these biopharmaceutical products have to be ensured [1, 2].
In the production of the biologics filtration is frequently applied [1]. But this important unit
operation is also used frequently in the laboratory and clinical applications. Filtration is used for
particle reduction and retention of bacteria and viruses [1]. In parenteralia different types of
particles like drug particles including protein aggregates or excipients, silicone oil or glass can
be found [2, 3].
From a clinical standpoint particles present a health hazard, since the aggregates present an
immunogenicity risk [4]. Although severe immune responses are rare, serious consequences
like death might occur [2, 4]. Particles are further associated with the occurrence of pulmonary
granuloma or emboli [3]. Endangered by particles are especially patients with a reduced
immune system like neonates or intensive care patients [3, 5]. To guard patients from harmful
particles in-line filters can be employed during preparation or administration of the drug. Proven
health benefits like the reduction of the incidences for infection, thrombi or phlebitis present the
consequences of usage of in-line filters [3, 5]. For approximately 50 protein drugs a filter
recommendation already exists.
Taking the benefits of in-line filters into account we propose to consider filtering protein drugs
before the injection into the patient. However, some handling issues need to be addressed
before a general recommendation for filters can be given. We provide data dealing with filtration
of protein drug products. First, to ensure a smooth ejection of the liquid from the syringe it
needs to be evaluated, whether the attachment of a filter with a 0.2 µm pore size leads to an
elevated ejection force. Next, filter application shall reduce the particle burden of parenteralia.
Yet, it is possible that filters increase the particle count by shedding particles as Liu et al.
observed [6]. Although the particles derived from the filter facilitate the formation of protein
aggregates, this is not relevant, if the drug is filtered right before administration because of the
slow formation of the aggregates [6]. Since filtration of parenteralia shall reduce the particle
burden injected into the patient it is important to determine, whether all filters shed particles and
if so to what extent. To this end, different filters are rinsed with varying buffers. Another question
is, whether protein aggregates can be reduced effectively by filtration.
1.
Shukla AA, Hubbard B, Tressel T, Guhan S, Low D. Downstream processing of monoclonal
antibodies—Application of platform approaches. Journal of Chromatography B. 848 (1), 28-39 (2007).
2.
Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors
and analysis, Journal of pharmaceutical sciences 98 (9), 2909-2934 (2009).
3.
Doessegger L, Mahler HC, Szczesny P, Rockstroh H, Kallmeyer G, Langenkamp A, et al. The
potential clinical relevance of visible particles in parenteral drugs. Journal of pharmaceutical sciences 8,
2635-2644 (2012).
4.
Rosenberg A. Effects of protein aggregates: An immunologic perspective. AAPS J. 8 (3), E501E507 (2006).
5.
van Lingen RA, Baerts W, Marquering ACM, Ruijs G. The use of in-line intravenous filters in sick
newborn infants. Acta Paediatrica 93 (5), 658-662 (2004).
6.
Liu L, Randolph TW, Carpenter JF. Particles shed from syringe filters and their effects on
agitation-induced protein aggregation. Journal of pharmaceutical sciences. 2012;101(8):2952-9.
7
ICPE 2014
crystals
M. Egart1, B. Janković1, I. Ilić1, N. Lah2, S. Srčič1
1
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, Ljubljana, Slovenia
Email for correspondence: biljana.jankovic@ffa.uni-lj.si
2
Introduction: In particular, more than 90 % of small molecule drugs are delivered in crystalline
form (Variankaval et al., 2008). Therefore, a comprehensive understanding of mechanical
properties and their dependence from crystal structure is a critical step to overcome
manufacturing challenges associated with designing solid dosage forms. Nanoindentation is
able to make a link between the structures of molecular solids and their single crystal
mechanical properties and to use it to predict bulk mechanical properties (Varughese et al.,
2013; Janković et al., 2013; Roberts, 2011). The main goal of this research was to assess the
mechanical properties of different APIs (famotidine, nifedipine, olanzapine, piroxicam) at the
single crystal level and relate them to the characteristics of their crystal structures.
Materials and Methods: The mechanical properties of oriented single crystals were determined
using instrumented nanoindentation (continuous stiffness measurement) (Oliver and Pharr,
2004). Thermodynamically stable single crystals were prepared according to procedure
described in the literature. Solid states were identified by single crystal x-ray diffractometry. The
face indexing of individual crystal was performed using CrysAlis PRO software (Agilent
technologies).
Results and Discussion: Mechanical properties such as Young`s modulus (E) and indentation
hardness (H) were consistent with the molecular packing of the solid forms investigated with
respect to the crystal orientation. Mechanically interlocked structures were characteristic for
most forms what is resulting in isotropic mechanical properties. The presence of slip planes was
detected for famotidine B only and this implies to plastic behaviour. This was confirmed with
essentially lower indentation hardness in comparison to famotidine form A.
Conclusion: According to the results, the nanomechnical measurements can be used for
quantitative assessing of molecular crystals mechanical attributes. Young`s modulus and
indentation hardness can thus represent valuable and effective tool in preformulation studies as
only a small amount of material is needed for evaluation of materials` mechanical properties
with high precision.
References
1. S. Varughese, M. S. R. N. Kiran, U. Ramamurty, G. R. Desiraju, Nanoindentation in Crystal
Engineering: Quantifying Mechanical Properties of Molecular Crystals, Angew. Chem. Int. Ed. 52
(2013) 2701-2712.
2. R. J. Roberts, Particulate analysis – Mechanical Properties, in Solid state Characterization of
Pharmaceuticals, (Eds. R. A. Storey and I. Ymen), John Wiley & Sons, Southern Gate UK 2011, pp.
357-369.
3. N. Variankaval, A. S. Cote, M. F. Doherty, From Form to Function: Crystallization of Active
Pharmaceutical Ingredients, Amer. Inst. Chem. Eng. 54 (2008) 1682 -1688.
4. B. Janković, M. Škarabot, Z. Lavrič, I. Ilić, I. Muševič, S. Srčič, O. Planinšek, Consolidation trend
design based on Young`s modulus of clarithromycin single crystals, Int. J. Pharm. 454 (2013) 324332.
5. W. C. Oliver, G. M. Pharr, Measurement of hardness and elastic modulus by instrumented
indentation: Advances in understanding and refinements to methodology, J. Mater. Res. 19 (2004) 320.
8
ICPE 2014
Nanoemulsification: Initial Junction of Lipid and
Aqueous Phase in High Pressure Microsystems
J.H. Finke1,2, T. Gothsch1, S. Beinert1, C. Richter3, J.-W. Thies3, A. Dietzel3, S.
Büttgenbach3, C.C. Müller-Goymann2, A. Kwade1
1
Institut für Partikeltechnik, TU Braunschweig, Braunschweig, Germany
2
Institut für Pharmazeutische Technologie, TU Braunschweig, Braunschweig, Germany
3
Institut für Mikrotechnik, TU Braunschweig, Braunschweig, Germany
Email for correspondence: jan.finke@tu-bs.de
The use of nanoemulsions is well established for parenteral nutrition as well as for drug
formulations for, e.g., diazepam and propofol. For intravenous injections, patient safety requires
the absence of large particles able to block capillary vessels. High pressure homogenization is
most commonly applied in industry to produce such narrowly distributed droplets in the
submicron range. However, research – in modern potential drug carrier systems such as solid
lipid nanoparticles – and early stage formulation development of candidate substances require
devices capable of handling small educt batch sizes for formulation screening.
The application of microsystems is able to solve these challenges with customized geometries
for high pressure homogenization [1,2]. These microsystems require only one passage and
pave the way to continuous processing. Nonetheless, the primary junction of the disperse lipid
phase and the continuous aqueous phase has not been implemented as a continuous high
pressure process, yet. Accordingly, pre-emulsions need to be processed in external devices,
baring the risk of product loss and contamination. The establishment of continuous primary
emulsification in microsystems applying low flow rates (µl/min) and low pressure drops (< 5 bar)
is frequently reported in the literature [3,4]. Such approaches are interesting with regard to
mircofluidics, but nevertheless inefficient for formulation screening and impossible to be
integrated in high pressure systems.
A new approach to initial phase junction and emulsification in high pressure microsystems is
presented. Different design principles derived from low flow rate microsystems were tested.
Failures of these under high pressure conditions are discussed. Newly layed-out designs for
microsystems, suitable for high pressure applications, are presented. These efficient designs
were able to bring together the immiscible phases and produce emulsion droplets as small as
330 nm at a pressure loss of < 300 bar. The throughput was between 0.5 and 1.7 g/s,
depending on the applied pressures. Lipid phase concentration was variable up to 35 % with
mean particle sizes of 2 to 4 µm in that case. The particle size was dependent on the total
pressure drop, the ratio between lipid and water pressure, and on the resulting lipid
concentration.
With the small particle sizes achieved in this study, the developed design approach opens the
perspective that the process steps of initial phase junction and high pressure homogenization
for producing nanoemulsions can be combined and realized by the passage through only one
microsystem.
1. Finke, J. H., Niemann, S., Richter, C., Gothsch, T., Büttgenbach, S., Kwade, A. & Müller-Goymann, C.
C.; Chemical Engineering Journal (in press)
2. Finke, J. H., Schur, J., Richter, C., Gothsch, T., Büttgenbach, S., Kwade, A., Müller-Goymann, C. C.;
Chemical Engineering Journal, 209, 2012, 126–137
3. Zhao, C.-X.; Advanced Drug Delivery Reviews, 65, 2013, 1420–1446
4. Vladisavljević, G.T., Khalid,N., Neves, M.O., Kuroiwa, T., Nakajima, M., Uemura, K., Ichikawa, S.,
Kobayashi, I.; Advanced Drug Delivery Reviews, 65, 2013, 1626–1663
9
ICPE 2014
Development of critical quality attributes control
strategies in a continuous high shear wet granulation
process
N. Nicolaï 1,2, T. De Beer 2, K.V. Gernaey 3 and I. Nopens 1
BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of
Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
2
Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical
Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000
Ghent, Belgium
3
Department of Chemical and Biochemical Engineering, Technical University of Denmark,
Building 229, 2800 Kgs. Lyngby, Denmark
Email for correspondence: niels.nicolai@UGent.be
1
Transition towards continuous production has gained serious attention from the pharmaceutical
industry as well as its regulatory authorities, mainly because of its economic, product related
and environmental benefits. Clearly, such manufacturing systems require a combination of
advanced process measurement tools, a thorough understanding of the process dynamics and
an effective yet robust control strategy allowing real-time release. Therefore, continuous
manufacturing in the pharmaceutical industry demands a well-advised plan of action.
In this study, the focus is on an innovative continuous from-powder-to-tablet production line
used for secondary manufacturing of pharmaceutical tablets, ConsiGmaTM. Recent advances in
both process analysers as well as the ongoing development of validated mechanistic models for
the granulation and drying sub-processes, have paved the way for closed-loop control of the
considered continuous wet granulation and drying line. Typically, this line comes with a
regulatory control layer capable of controlling nine univariate critical process parameters (e.g.
drying temperature, screw speed and air flow rate). However, critical quality attributes (e.g.
granule size distribution, granule shape, density and residual moisture content), i.e. the
variables directly related to the quality of the product itself, are not measured nor controlled in
real-time, hence nullifying most of the advantages of continuous processing. Therefore, the
purpose of current research is to extend the regulatory control layer of the system by adding
additional control loops which allow for direct control of product quality related properties.
A first step towards this objective was the identification of all control relevant product variables
and the selection of a suitable operating point in the accompanying design space.
Subsequently, the dynamic behaviour of the system around this operating point needs a
thorough investigation in order to develop suitable multiple-input multiple-output (MIMO) control
strategies (e.g. decentralised control and decoupled control) using computer-aided design tools.
The ultimate goal of this ongoing study is the development of a system-wide supervisory control
layer capable of controlling the different sub-processes as one integrated system. Eventually,
this could unlock the full potential of the considered continuous manufacturing line as well as
continuous production in the pharmaceutical industry as a whole.
10
ICPE 2014
Preparation and characterization of lipid
nanocarriers containing ceramides
L. Vidlářová1, P. Ulbrich1, F. Štěpánek1, J. Zbytovská1,2
1
Institute of Chemical Technology, Prague 6, Czech Republic
2
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
Email for correspondence: lucie.vidlarova@vscht.cz
Ceramides are the main components of stratum corneum, the physical and mechanical barrier
of the skin. [1] Alterations in ceramide composition were reported in many inflammatory skin
diseases such as atopic dermatitis, ichthyosis, psoriasis and others. One approach to the
treatment of such a disrupted skin is ceramide supplementation.[2] Due to their lipophilic
structure, ceramides seem to be suitable candidates for incorporation into colloidal
nanocarriers.
The aim of this study was to prepare two types of colloidal systems, liposomes and lipid
nanoparticles, containing commercially available ceramide VI. For the preparation of particles
we used two different techniques: the high pressure homogenization [3] and the phase inversion
temperature method. [4]
The compostion of the lipid systems was varied to follow the evoked changes in the particle
parameters (size, polydispersity index, zeta potential, incorporation capacity). Different amounts
of ceramide VI (2, 5 and 10%) were loaded into the colloidal nanoparticles. High performance
thin layer chromatography was used to confirm the amount of the incorporated ceramide VI.
Size and zeta potential of the particles were determined by dynamic light scattering. The
particles were visualized by transmission electron microscopy.
Our results suggest that colloidal nanoparticles are suitable drug delivery systems to
incorporate ceramide VI. Both, liposomes and lipid nanoparticles, have shown a spherical
shape, an average size below the 100 nm and a low polydispersity index. Very good stability
was obtained with the particles of 5% loaded ceramide VI.
The work was supported by Czech Science Foundation (Project GACR 13-23891S).
References:
[1] Menon, G.K., G.W. Cleary, and M.E. Lane, The structure and function of the stratum corneum.
International Journal of Pharmaceutics, 2012. 435(1): p. 3-9
[2] Elias, P.M., Lipid abnormalities and lipid-based repair strategies in atopic dermatitis. Biochimica et
Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2014. 1841(3): p. 323-330.
[3] Jenning, V., A. Lippacher, and S.H. Gohla, Medium scale production of solid lipid nanoparticles (SLN)
by high pressure homogenization. J Microencapsul, 2002. 19(1): p. 1-10.
[4] Heurtault, B., et al., A novel phase inversion-based process for the preparation of lipid nanocarriers.
Pharm Res, 2002. 19(6): p. 875-80.
11
ICPE 2014
Manufacturing of Poloxamer 188-stabilized Lipid
Nanoemulsions by Premix Membrane Emulsification
S. Gehrmann, H. Bunjes
Institut für Pharmazeutische Technologie, Technische Universität Braunschweig,
Mendelssohnstraße 1, 38106 Braunschweig, Germany
Email for correspondence: s.gehrmann@tu-braunschweig.de, heike.bunjes@tubraunschweig.de
An increasing number of new drug substances is poorly water soluble and thus difficult to
effectively administer to patients. A promising option for the administration of such substances
is loading them into lipophilic colloidal carrier particles. Lipid nanoparticles (LNP) such as
colloidal lipid emulsion droplets, are commonly prepared by high pressure homogenization,
which exposes the formulation to high shear forces. An interesting alternative for the processing
of LNP formulations containing shear-sensitive substances, e.g. proteins, may be premix
membrane emulsification (Premix ME), because of the comparatively low process pressure. In
this process, a coarse predispersed emulsion is extruded through the pores of a membrane,
yielding smaller emulsion droplets. The resulting particles are in the size range of that of the
pores with a narrow particle size distribution [1]. The process of premix ME was originally
developed for the preparation of emulsions with particle sizes in the micrometer range and was
later transferred to the manufacturing of lipid nanoparticles [2]. In particular for the latter case,
the complex influences of process parameters are not understood in detail yet.
In order to gain deeper process understanding of premix ME an instrumented small scale
membrane extruder was developed and was applied for the preparation of sodium lauryl
sulphate (SDS)-stabilized medium chain triglyceride (MCT) nanoemulsions [3].Since SDS is not
a suitable emulsifier for administration into the bloodstream, the use of the physiologically more
compatible emulsifier poloxamer 188 (Pol) was investigated in the present study. Pol is a nonionic block copolymer, which is more demanding during premix ME.
An influence of the membrane material (polycarbonate (PC), polyester (PE), polyvinylidenfluoride (PVDF), polysulfone (PS), polyethersulfone (PES), nylon; pore size: 200 nm), like it has
been observed with SDS, was also found with Pol, but the effect was more pronounced. While
the use of some membrane materials (PE, PES, nylon) led to the formation of colloidal
emulsions after 21 extrusion cycles, the use of others induced formulations containing particles
in the micrometer range. Therefore, further investigations were preformed with PE membranes.
The initially used emulsifier concentration was quite high (20% MCT, 15% Pol). To optimize the
physiological compatibility of the formulation, the content of Pol was reduced. It was possible to
prepare nanoemulsions with a lipid to Pol ratio of 4:1.5 by 21 cycles through a 200 nm PE
membrane with a flow rate of 1.4 ml/s and a resulting extrusion pressure of around 25 bar. The
emulsion obtained had a median particle size of 183 nm with a span of 0.6 according to laser
light diffraction with PIDS technology.
The emulsion premix was usually prepared with an Ultra-Turrax at 16.000 rpm for 1 min. The
premix used for the study with Pol had a larger particle size ( d50 = 14 µm) and broader size
distribution than the premix made with SDS (d50 = 3 µm). To evaluate whether the quality of the
premix has an influence on the particle size resulting after 21 extrusion cycles, the particle size
(d50 value) of the Pol-stabilized premix was varied between 3 and 40 µm with the help of
different dispersion times and speeds. The particle sizes of the emulsions obtained after premix
ME did not differ much (178-195 nm) without a clear correlation between premix and
nanoemulsion size. It thus appears that the quality of the premix is not a crucial parameter for
the emulsifying success of Pol-stabilized emulsions processed under these conditions.
1.
K. Suzuki, I. Shuto, Y. Hagura, Food Sci. Technol. Int. 1 (1996) 43-47.
2.
S. Joseph, H. Bunjes, J. Pharm. Sci. 101 (2012) 2479-2489.
3.
S. Gehrmann, H. Bunjes, Poster presentation, 9 PBP World Meeting, Lisbon 2014.
th
12
ICPE 2014
Targeted drug delivery through surface
functionalization of human serum albumin
nanoparticles
A. Rollett*, A. Heinzle**, T. Reiter**, A. Repic***, H. Stockinger***, G.M. Guebitz*,**
* Institute for Environmental Biotechnology, University of Natural Resources and Life Sciences,
Vienna, 3430 Tulln, Austria
** ACIB GmbH, 8010 Graz, Austria
*** Institute for Hygiene and Applied Immunology, Medical University of Vienna, 1090 Vienna,
Austria
Email for correspondence: Alexandra.rollett@boku.ac.at
Specific targeting of malignant cells can improve efficacy of drugs and prevent damage of
healthy cells and tissues. Therefore it is essential to modify the surface of drug delivery systems
such as nanoparticles to introduce receptor or ligand molecules which can be recognized by
target cells. Folic acid (FA) can be recognized by folate receptor beta (FRß) which is specifically
expressed by chronically activated macrophages playing a key role in rheumatoid arthritis 1. Also
antibodies (mAb) are often exploited to achieve targeting to malignant cells.
For targeted drug delivery it is essential to modify the surface of nanoparticles to introduce
receptor or ligand molecules. Various biomaterial are used for the preparation of drug delivery
particles. The advantage of protein particles is that they provide several functional groups on
the surface which can be easily used for surface modification.
Here we present different strategies for surface modification of protein nanoparticles. On the
one hand simple click-chemistry using chemical cross-linkers was performed to achieve a side
specific covalent linkage of folic acid on the particle surface 2,3. While in another approach we
established a new enzymatic method to produce an antibody-protein conjugate avoiding all kind
of toxic chemicals 4.
Surface modification was monitored by CLSM, LC-MS/MS and SDS-PAGE. Furthermore it was
demonstrated that folate based nanocapsules are able to target folate receptor positive
macrophages. ELISA and FACS were used to demonstrate the binding ability of conjugated
mAb to its antigen.
1.
Puig-Kröger, A. et al., Cancer Res., (2009), 69, 9395-9403
2.
Rollett A. et al., RSCAdv. (2013), 3:1460-1467
3.
Rollett A. et al., Int. J. Pharm., (2013), 458:1-8
4.
Rollett A. et al., Int. J. Pharm., (2012), 427:460-466
13
ICPE 2014
Solid-state Compatibility Screening of Excipients
Suitable for Development of Indapamide Sustained
Release Solid Dosage Formulation
1*
1
1
1
Antovska, Packa , Petruševski, Gjorgji , Stefanova, Bosilka , Ugarkovic, Sonja , Makreski, Petre
2
1
Research & Development, ALKALOID AD, Aleksandar Makedonski 12,
1000 Skopje, Republic of Macedonia, phone: + 389 3104 114, fax: + 389 2 3104 114
2
Institute of Chemistry, Faculty of Science, SS Cyril and Methodius University, Arhimedova 5,
1000 Skopje, Republic of Macedonia
*
Email for correspondence: pantovska@alkaloid.com.mk
Differential scanning calorimetry (DSC) [1] and Fourier transform infrared (FT-IR) spectroscopy
[2,3] were applied as screening analytical methods to access the solid-state compatibility of
indapamide (4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoyl-benzamide) with several
polymers aimed for development of 24 hours sustained release solid-dosage formulation. After the
initial research phase which was directed towards selection of suitable polymer matrices, based on
their solid-state compatibility with the studied pharmaceutical active ingredient, the second phase of
evaluation was intended for compatibility selection of other excipients required to complete a
sustained release formulation [4,5]. The preformulation studies have shown that PVP/PVAc might
be considered incompatible with indapamide, and the implementation of this polymer career should
be avoided in the case of the entitled development. The experimental data additionally have
revealed that sorbitol is incompatible with indapamide. The obtained results afforded deeper insight
in to the solid-state stability of the studied binary systems and pointed out directions for further
development of indapamide sustained release solid-dosage formulation.
1.
Martini A, Kume S, Crivellente M, Artico R. Use of subambient differential calorimetry to monitor the
frozen-state behavior of blends of excipients for freeze-drying. PDA J Pharm Sci Technol 1997;51:62–
67.
2.
Blanco M, Valdés D, Bayod M. S, Fernández-Mari F, Llorente I. Characterization and analysis of
polymorphs by near-infrared spectrometry. Anal Chim Acta 2004; 502:221–227.
3.
Rodionova O. Y, Houmøller L. P, Pomerantsev A. L, Geladi P, Burger J, Dorofeyev V. L, Arzamastsev
A. P. NIR spectrometry for counterfeit drug detection: A feasibility study. Anal Chim Acta
2005;549:151–158.
4.
Gombás A, Szabó-Revész P, Kata M, Regdon G, Erõs I. Quantitative determination of crystallinity of αlactose monohydrate by DSC. J Therm Anal Calorim 2002;68:503–510.
5.
Medeiros A. C. D, Correia L. P, Simões M. O. S, Macêdo R. O. Technological quality determination of
pharmaceutical disintegrant by DSC cooling and DCS photovisual. J Therm Anal Calorim 2007;88:311–
315.
14
ICPE 2014
Permeability studies of the TCM formulation
Si-Miao-San, its modifications and main compounds
Ch. Reisinger, N. Pourshekhani, B.L. Bian*, A.H. Brantner,
Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz,
Universitaetsplatz 4/I, 8010 Graz, Austria
*Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No.16
Nanxiaojie, Dongzhimennei Ave., Dongcheng District, 100700 Beijing, PR China
Email for correspondence: adelheid.brantner@uni-graz.at
Traditional prescriptions like Si-Miao-San (SMS) which are used in Traditional Chinese Medicine
(TCM) attract increasing attention in the Western world. They can provide excellent sources in
the search for new active compounds. The TCM formulations and its component herbs are
complex mixtures of countless different compounds, only some of which are responsible for the
pharmaceutical effect.
In order to have any effect on the human body, a sufficient quantity of the drug has to be
absorbed by the body. On the basis of permeability – an important factor in oral drug absorption
– in vitro models can provide information on the absorption of orally administered drugs.
The aim of the study was to examine the TCM formulation Si-Miao-San (SMS) [1] and its
modifications m1SMS [2] and m2SMS [3] as well as the main compounds of these formulations.
Parallel Artificial Membrane Permeability Analysis (PAMPA) was used to obtain their
permeability coefficients, thus assessing their permeability.
The pure compounds berberine, ecdysterone, jatrorrhizine, magnoflorine and palmatine as well
as the traditionally used water extracts of SMS, m1SMS and m2SMS were analysed by PAMPA
assays. Thereby PAMPA was applied in two variations [4, modified], using artificial membranes
composed of hexadecane (HDM) and of lecithine/dodecane (LM). All experiments were
conducted both in Phosphate Buffered Saline (PBS) and in Hank’s Balanced Salt Solution
(HBSS) containing 5% Dimethyl sulfoxide (DMSO), in order to make a statement about the
usability of HBSS which is usually applied in cell cultures. However, it could be shown that
HBSS was inadequate.
LM-PAMPA proved to be the more reliable and significant model. In comparison to the alkaloids
berberine, jatrorrhizine, magnoflorine and palmatine, the phytoecdysone ecdysterone showed
less permeability through the LM. Depending on whether the substances were analysed as pure
compounds or as part of the extracts their permeability varied.
For comparison, evaluation of the pure compounds’ assays was done spectrophotometrically, a
method that is less time consuming and requires less technical expenditure, as well as by
HPLC, an evaluation method that is more complex but more accurate. Generally, a good
correlation could be detected which suggests the spectrophotometrical measurements to be
adequate for the evaluation of the permeability of pure compounds.
1.
Pharmacopoeia Commission of People’s Republic of China (2010) The Pharmacopoeia of the
People’s Republic of China, English Ed., Chem. Ind. Press, Beijing, pp 1216-1217 "Simiao Wan".
2.
Liu K., Luo T., Zhang Z., Wang T., Kou J., Liu B., Huang F. (2011) Modified Si-Miao-San extract
inhibits inflammatory response and modulates insulin sensitivity in hepatocytes through an IKKβ/IRS1/Akt-dependent pathway. J Ethnopharmacol 136, 473–479.
3.
Lower-Nedza A. D., Kuess C., Zhao H., Bian B., Brantner A. H. (2013) In vitro anti-inflammatory
and antioxidant potentials of Si-Miao-San, its modifications and pure compounds. Nat Prod Commun 8,
1137-1141.
4.
Niazi S. K. (2007) Handbook of Preformulation. Chemical, Biological, and Botanical Drugs,
Informa Healthcare, New York, pp 141-195.
15
ICPE 2014
A Refined Model for the Filling Rate
of a Liquid Bridge
M. Wu,1 J.G. Khinast,1,2 and S. Radl 1
1
Institute of Process and Particle Engineering
Graz University of Technology, Graz, Austria,
2
Research Centre Pharmaceutical Engineering GmbH, Graz, Austria
Email for correspondence: radl@tugraz.at
Key Words: Volume of Fluid (VOF) Method, Direct Numerical Simulation (DNS), Liquid
Bridges, wet particles
Many industrial applications involve gas-liquid-solid flows, e.g. the flow of wet granular
matters. Although these processes have been used for more than decades, much less of the
fundamental physics is well understood till now. A significant amount of research has
recently focused on such a fundamental understanding of wet particulate systems [1,2].
However, the detailed modeling and simulation of the effects stemming from the limited
drainage rate of the liquid adhering to the surface of particles still poses significant
challenges.
Previous research in the area of wet granular flows mainly focused on forces connected to
liquid bridges, and there is much less theory concerned with the process of liquid transfer
upon collisions. For example, to study the liquid transfer upon bridge rupture, a solution of
the Navier-Stokes equation (i.e., direct numerical simulations, DNS), or a solution based on a
quasi-static approximation of the bridge shape has been used [1,2]. For this second stage of
liquid transfer (i.e., liquid bridge rupture), models are already available in literature [3].
Unfortunately, little is known about the initial fast filling process during which liquid drains into
the meniscus.
We study the liquid bridge and drainage process at the surface of two wet particles using (i) a
DNS based on the Volume of Fluid method, as well as (ii) a solution of the film height
equation. The latter approach neglects the fluid’s inertia, and is based on a fixed shape of the
velocity profile across the film height. By scanning a large parameter space using DNS, our
overall goal is building a dynamic model for the bridge volume during filling based on detailed
DNS data. Such a model assumes that the particles’ relative motion has no effect on the
filling rate. In this talk, we will present results of DNS of (i) two identical particles coated with
films having a different thickness (i.e.,  = 0.10 and  = 0.20), as well as (ii) two different
particles with different film thicknesses to supplement our previous work [4]. From these
simulations, we extract parameters for our dynamic bridge filling model, taking different liquid
film heights and particle diameters into account.
References
[1]
P. Darabi, T. Li, K. Pougatch, M. Salcudean, D. Grecov, Modeling the evolution and rupture of
stretching pendular liquid bridges, Chemical Engineering Science. 65 (2010) 4472–4483.
[2]
S. Dodds, M. Carvalho, S. Kumar, Stretching liquid bridges with moving contact lines: The role
of inertia, Physics of Fluids. 23 (2011) 092101.
[3]
D. Shi, J.J. McCarthy, Numerical simulation of liquid transfer between particles, Powder
Technology. 184 (2008) 64–75
[4]
Radl et al, On the Filling Rate of a Liquid Bridge Between Wet Particles AIChE Annual Meeting.
San Francisco am: 03.11.2013.
16
ICPE 2014
Mini-tablets: an option for multiple unit dosage forms
1. Priese*, 2. Funaro**, 3. Mondelli**, 4. Fabi**, 5. Zakhvatayeva**, 6. Wolf*
*Anhalt University of Applied Sciences, Strenzfelder Allee 28, 06406 Bernburg, Germany
**IMA S.p.A. - ACTIVE Division, via 1° Maggio 14-16, 40064 Ozzano dell'Emilia Bologna, Italy
Email for correspondence: florian.priese@gmail.com
An attractive alternative to pellets represent mini tablets (MT) with exceptional small
dimensions. MT are characterized by a diameter equal to, or smaller than, 2–3 mm (1) to
ensure the advantages of multiparticulate dosage forms such as low risk of dose dumping and
reproducible bioavailability. The production of MT using a compression technique poses some
advantages in comparison to the production of pellets via extrusion and spheronization or
coating of pellets via fluidized bed technique, as solvents (e.g. water) are avoided and reduced
process times and higher production yields are obtained.
The aim of the investigation was to compare the release kinetics of mini tablets and pellets
coated with a release controlling ethylcellulose film (Surelease®, EC) by different manufacturing
technologies:
1. Inert pellets (Cellets® 200) were coated in a first step with the model drug sodium benzoate
(SB) and in a second step with EC. Talcum was added as anti-sticking agent.
2. The coated pellets were compressed into mini-tablets type 1 (MT1) and normal tablets.
3. Mini-tablets type 2 (MT2) were produced via direct compression of the model drug and
excipients and subsequently coated with the ethylcellulose film via fluidized bed coating.
Rotary press Pressima (IMA, Italy) was used for direct compression of MT1/2 and normal
tablets. The fluidized bed coating process was performed in a pilot fluidized bed coater Ghibli
Lab (batch range 3-6 l, IMA, Italy) equipped with central partition and bottom spray. The SB
content was measured by UV spectroscopy (Spekol 1300, Analytik Jena, Germany).
Both compression processes of MT1/2 as well as coated pellets into normal tablets were
successful. The compression of polymer coated pellets into MT1 does not pose any advantages
in comparison to compression into normal tablets.
The EC coating of MT2 was accompanied by agglomeration due to greater contact area of the
MT2 in comparison to pellets. This problem was overcome by increase of process air rate and
reduction of spray rate. The dissolution of the EC coated MT2 (direct compression) was very
slow in comparison to EC coated SB pellets with less polymer amount (Figure 1). There are
some specific conditions at the coating of mini tablets. Furthermore, the homogeneous covering
of the sharp edges of the MT2 is a critical point. If the EC coating layer is comparable thin, the
film will erupt preferentially at the edges in contact with water. In order to avoid burst effects it is
essential to exceed a critical thickness of the EC film at the edges of the MT2.
Figure 1 – Comparison of dissolution profiles of MT2 and coated pellets with different polymer coating levels
(PCL), black lines – MT2, blue line – coated pellets)
1.
Lennartz, P., Mielck, J.B., 1998. Minitabletting: improving the compactability of paracetamol
powder mixtures. Int. J. Pharm. 173, 75–85.
17
ICPE 2014
Estimation of particle concentration in a Wurster
coater draft tube via optical transmittance
R. Šibanc, R. Dreu
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia
Email for correspondence: rok.sibanc@ffa.uni-lj.si
Wurster coater is commonly used for coating of pharmaceutical pellets, with purpose of
adhering active ingredient on neutral pellets or to achieve protection or controlled release of the
active.
One of the key parameters for the coating process is the amount of particles in the draft tube,
where the coating occurs. Particle concentration affects the yield of the process, amount of
agglomerates formed during the coating and has a big impact on the inter-particle coating
thickness variation.
The aim of our research was to evaluate the local concentration of particles in the draft tube by
online measurements of optical transmittance. Beer-Lambert law describes the dependence of
the amount of transmitted light based on the concentration of particles in measured volume.
Higher amount of particles results in lower transmittance.
Experiments were performed on a GPCP-1 Wurster coater (Glatt GmbH, Germany) using a 20
mm beam diameter red laser as light source (RLE650-8-3-20, Roithner Lasertehnik GmbH,
Austria) and 10x10 mm2 photodiode (SLSD-71N500, Advanced Photonix, Canada) as a
detector. A glass draft tube was used in the measurements performed at the top side of the
draft tube, where pellets exit after being coated and are vertically transported along the tube.
The effects of the fluidizing air flow rate, the gap size between the draft tube and distribution
plate, the size and total mass of the particles in the apparatus were analyzed.
It was found that particle load (tested 500g, 1000g and 1500g) as well as particle size (tested
600 – 710 µm, 900 – 1000 µm and 1120 – 1250 µm) have large effect on local transmittance.
Inlet air velocity has medium effect and the effect of gap on transmittance is even lesser.
Figure 1. Transmittance of different sized pellets at different gap sizes at air flow rate of 105
m3/h and bed load of 1000 g.
These measurements provided good explanation of coating experiments outcomes and are also
very valuable in validation of numerical simulations of fluid bed equipment.
18
ICPE 2014
Development of a Drug Abuse-Alcohol-Resistant
Formulation Produced via Hot-Melt Extrusion
N. Jedinger*, J. Khinast*,**, E. Roblegg*,***
*** Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University
of Graz, Austria
Drug tampering often occurs through chewing or crushing to subsequently snort the drug or to
dissolve it in water or ethanol for intravenous injection to achieve euphoric and mind-altering
effects. To counteract these practices, two approaches exist, which can be classified into
abuse-deterrent formulations and abuse-resistant formulations1. Abuse-deterrent formulations
are designed to prevent facile release of the drug due to chemical manipulation. On the
contrary, abuse-resistant formulations use physical barriers and mechanical properties to hinder
alteration of the dosage form. Another challenge in the development of safe drug products is the
risk of alcohol-induced dose dumping. Here, the concomitant intake of alcoholic beverages
together with controlled-release oral dosage forms can have dangerous effects since alcohol
may alter the release rate controlling mechanism of the formulation, which can result in an
immediate and uncontrolled drug release2. Most studies performed yet, either deal with abuseresistance or alcohol-induced dose dumping. However, studies related to the development of
robust multiple unit dosage forms that withstand both the impact of alcohol and the manipulation
of the dosage form, are lacking.
This study focused on the development of pharmaceutical retarded pellets, designed to resist
deletion with commonly used household devices due to their (visco)elastic character. The
pellets were prepared via hot-melt extrusion using cornstarch as thermoplastic matrix-polymer
and water as plasticizing additive. Furthermore, antipyrine was incorporated as model drug and
the in-vitro drug release behavior was examined. Additionally, the obtained pellets were
characterized regarding their deformation/tensile strength. The results showed that they did not
crush but deformed and recovered after 2 minutes. Drug release studies revealed that the
pellets swelled during dissolution testing to a great extent and remained intact in the dissolution
media for 24 h. However, the drug was entirely released after 2 h. Next, the pellets were coated
with Aquacoat ARC® (Alcohol Resistant Coating) in a fluidized bed coater to firstly, modify
(retard) the drug release rate and secondly, to obtain a dosage form resistant to alcohol. The
dissolution studies demonstrated that a coating level of 20% led to a decreased drug release
rate. For the alcohol-induced dose dumping studies, dissolution testing was additionally
conducted in alcoholic media with ethanol concentrations of 20% (equivalent to mixed drinks)
and 40% (equivalent to hard liquor). To compare the drug release profiles in alcoholic media
with the corresponding profiles in non-alcoholic media the f2 similarity factor was used. An f2
value in the range of 50-100 indicates that the dissolution profiles are similar and hence,
resistance of the formulation in alcoholic media is achieved. In both alcoholic media no dose
dumping effect occurred and the estimated f2 values were well above 50 (i.e., 83 and 64 for
20% and 40% alcoholic media).
Thus, it can be concluded, that the (visco)elastic properties of hot-melt extruded corn starchbased pellets represents a promising physical barrier for the preparation of abuse-resistant solid
oral dosage forms. Moreover, the coating of the pellets led to a retarded drug release rate and
and revealed resistance in 20% and 40% alcoholic media.
1.
L.R. Webster, B. Bath, R.A. Medve, Opioid formulations in development designed to curtail
abuse: who is the target? Expert Opin. Investig. Drugs, 2009.
2.
N. Jedinger, J. Khinast, E. Roblegg, The design of controlled-release formulations resistant to
alcohol-induced dose dumping – A review, Eur. J. Pharm. Biopharm., 2014 DOI:
10.1016/j.ejpb.2014.02.008
19
ICPE 2014
The role of surface hydrophilicity/hydrophobicity of
nano-TiO2 in buccal uptake behaviour
B. J. Teubl*, G. Leitinger**, E. Fröhlich***, E. Roblegg*,
*University of Graz, Institute of Pharmaceutical Sciences, Department of
Pharmaceutical Technology, Austria
**Institute of Cell Biology, Histology and Embryology, Medical University of Graz,
Austria
***Center for Medical Research, Medical University of Graz, Austria,
The development of engineered nanomaterials (ENM) and their commercialization for
application in (consumer) products, medical and diagnostic devices and/or pharmaceutical drug
delivery vehicles presents an enormous challenge for the scientific, regulatory, industrial and
public field. Titanium dioxide (TiO2) nanoparticles, for example, are manufactured worldwide in
large quantities and TiO2 pigments (< 2.5 µm) account for 70% of the total production volume. In
nanoparticle uptake behaviour, the surface properties have been identified to play a major role.
TiO2 particles are often coated with organic or inorganic materials to enhance the compatibility
with lipophilic components of cosmetic applications, thus, changing their surface hydrophilicity/
hydrophobicity. As a consequence, the biological reactivity, the penetration depth and the
intracellular particle distribution are expected to change. This study was conducted to
investigate biological interactions of hydrophilic and hydrophobic TiO2 particles with the buccal
mucosa, a potential site of NPs uptake [1,2].
The results of particle size and zeta potential measurements demonstrated no significant
variances between hydrophilic and hydrophobic TiO2 particles. In general, a high aggregation
tendency was observed for both materials in biological media (i.e., PBS, DMEM and saliva),
presumably due to the high concentration of ions, resulting in a decreased electrical doublelayer repulsive energy between the particles. The determination of the Rose Bengal constant
demonstrated, that NM 103 exhibited a slightly hydrophobic surface (0.09 ml/mg), while the
surface of NM 104 was hydrophilic (0.04 ml/mg). TEM images of the buccal mucosa showed
that NM 103 and NM 104 particles were found in the superficial epithelium and in the basal
lamina/ connective tissue. Intracellular localization studies of nano-TiO2 conducted with LSM
revealed that NM 103 particles were colocalized with lysosomes. By contrast, NM 104 particles
were not detected in these organelles. The evaluation of reactive oxygen species (ROS)
demonstrated that NM 103 caused ROS production to a slight extent, while the ROS content of
NM 104 was in the range of the positive control, which indicates intracellular generation of
oxidative stress.
The investigated nano-TiO2 particles were able to penetrate into the buccal mucosa
independent on the degree of the surface hydrophilicity/hydrophobicity. Since hydrophobic
NM 103 particles were found in lysosomes, it is likely that they are taken up via endosomal
mechanisms. NM 104 particles are freely distributed in the cytoplasm and have the potential to
generate ROS. Our results clearly demonstrate the importance of the surface hydrophilicity/
hydrophobicity of nano-TiO2 regarding particle/cell interactions.
1.
Teubl B.J. et al., In-Vitro Permeability of Neutral Polystyrene Particles via Buccal Mucosa, Small,
9: 457-466 (2013)
2.
Teubl B.J. et al., The buccal mucosa as a route for TiO2 nanoparticle-uptake. Nanotoxicology,
2014, submitted
3.
Roblegg E. et al., Evaluation of a physiological in vitro system to study the transport of
nanoparticles through the buccal mucosa, Nanotoxicology, 6: 399-413 (2012)
20
ICPE 2014
Development of Lipophilic Hot-Melt Extruded
Alcohol-Resistant Pellets Containing Nicomorphine
N. Jedinger*, S. Mohr*, J. Khinast*,**, E. Roblegg*,***
*** Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University
of Graz, Austria
Over the last years, regulatory authorities have been increasingly concerned with alcoholinduced dose dumping of controlled-release oral dosage forms, since alcohol may alter (i.e.,
increase) the release-rate of the formulation1. Thus, authorities recommend that in-vitro drug
release studies of controlled-release dosage forms containing opioid and non-opioid drugs with
narrow therapeutic index should be conducted in alcoholic media using the f2 similarity factor to
compare the drug release profiles in alcoholic media with the corresponding profiles in nonalcoholic media. An f2 value in the range of 50-100 indicates that the dissolution profiles are
similar. Previously we demonstrated that CaSt can be used as a novel and versatile matrix
carrier in hot-melt extrusion2. Due to its hydrophobic nature, CaSt is insoluble in water and
ethanol, and thus, constitutes a promising matrix system for alcohol-resistant formulations. The
objective of our current study was to determine the impact of alcohol on the drug release
behaviour of hot-melt extruded pellets composed of 20% nicomorphine HCl (NM) as opioid
analgesic and vegetable calcium stearate (CaSt) as the matrix carrier.
In a first step, a HPLC-method for NM, which is a pro-drug (3,6-dinicotinoylmorphine) that
degrades (time- and pH-dependent) into its metabolites (i.e., 3-mononicotinoylmorphine, 6mononicotinoylmorphine, morphine), was established. For the dose dumping studies,
dissolution tests were conducted in 0.1 N HCl with 40% ethanol, equivalent to hard liquor.
Furthermore, the solubility of NM in dissolution media with and without alcohol was evaluated.
The findings of the solubility studies indicate that the solubility of NM is clearly dependent on the
dissolution media used. The solubility of the drug increased in 40% alcoholic media,
demonstrating a two-fold increase compared to physiological media. Drug release studies of the
CaSt/NM pellets revealed that NM was entirely released after 2 h (95.65%). Thus, retardation
compounds (i.e., Carbopol®, potato starch) were incorporated in concentrations of 10% to
modify the drug release rate. The addition of Carbopol® and potato starch significantly
decreased the drug liberation after 2 h (i.e., 10.95% and 8.27%, respectively). However, in
alcoholic media the drug release rate of Carbopol® pellets increased and the calculated f2 value
was below 50 (11.09). On the contrary, the potato starch pellets did not show dose dumping in
alcoholic media (f2 value = 72.64). This is due to the insolubility of the matrix carrier, as well as
the retarding additive in alcoholic media, which “protects” the highly ethanol-soluble drug during
the dose dumping studies.
Thus, it can be concluded, that lipophilic pellets composed of NM and CaSt were successfully
prepared via hot-melt extrusion. Moreover, the incorporation of potato starch into the
formulation led to a retarded drug release and showed resistance to alcohol-induced dose
dumping even in 40% alcoholic media.
1. N. Jedinger, J. Khinast, E. Roblegg, The design of controlled-release formulations resistant to alcoholinduced dose dumping – A review, Eur. J. Pharm. Biopharm., 2014 DOI: 10.1016/j.ejpb.2014.02.008
2. E. Roblegg, E. Jäger, A. Hodzic, G. Koscher, S. Mohr, A. Zimmer, J. Khinast, Development of
sustained-release lipophilic calcium stearate pellets via hot melt extrusion, Eur. J. Pharm. Biopharm.,
2011, 79:635-45.
21
ICPE 2014
PAT in High-Shear Granulation Processes using
In-line Particle Size Measurements
C. Hüttner, G. Kutz, S. Dietrich*
Pharmaceutical Engineering, Hochschule Ostwestfalen-Lippe, University of Applied Sciences,
Georg-Weerth-Straße 20, 32756 Detmold, Germany, Tel.: +49 5231 45800 26,
Fax: +49 5231 45800 60, e-mail: gerd.kutz@hs-owl.de
* Parsum, Gesellschaft für Partikel-, Strömungs- und Umweltmesstechnik mbH, Reichenhainer
Straße 34-36, 09125 Chemnitz, Germany, Tel.: +49 371 267586 90, Fax: +49 371 267586 90,
Email for correspondence: die@parsum.de
The intention of pharmaceutical manufacturers to create more robust and controlled processes
in production and development increased since FDA advised the implementation of PAT-Tools
instead of process validation [1]. By applying PAT-Tools, e.g. real time control of critical process
parameters, the results of the manufacturing processes will always be in accordance with the
defined specifications as long as the process can be controlled statistically. This approach is
called “Quality by Design”. In-line particle measurements are well established in different
pharmaceutical production processes [2]. In high-shear granulation processes particle size
measurements could be used to control particle growth as well as for endpoint detection. This
work covers two case studies exploring the technical capabilities to characterise wet granulation
processes in high-shear mixers with different dimensions using an unique in-line particle
measurement probe.
In the first case study the influence of basic parameter settings has been investigated to find
optimal adjustment to the measurement conditions of a high shear granulation process in a
P/VAC 10-60 (Diosna Dierks & Söhne GmbH, Osnabrück, Germany) high-shear mixer with a 60
L bowl. In detail the horizontal and vertical position of the probe, the influence of dispersing
parameters and basic software parameters to adjust the dynamical properties of the
measurement system to the process dynamic have been investigated.
A second case study was performed in order to investigate the sensitivity of the in-line particle
measurement probe to show the influence of different formulations also during a high-shear
granulation process in a P1-6 (Diosna Dierks & Söhne GmbH, Osnabrück, Germany) highshear mixer with a 4 L bowl. In both studies an in-line particle probe IPP 70-S (Parsum GmbH,
Chemnitz) was used. The measurement principle is based on the established technique of
Spatial Filter Velocimetry [3]. Data collection and evaluation were performed with specific
software. To overcome the tendency of the wet material to stick at the probe and to hold the
optics clean it was necessary to use the inline disperser D23.
It could be shown during both studies that it is possible to monitor the complete particle size
distribution over the whole granulation process with the selected IPP 70-S probe. An optimal set
of measurement parameters for this highly dynamic granulation process could be found. It
allows to clearly characterize the process steps dry mixing, spraying and granulation by particle
size values x10,3; x50,3 and x90,3.
The impact of different auxiliary substances on the granulation characteristics has been studied.
A strong influence of the different formulations on the resulting particle size distribution could be
detected in real time.
[1] Guidance for Industry: PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance, http://www.fda.gov/downloads/Drugs/Guidances/ucm070305.pdf
(29. Apr. 2014, 10 am)
[2] Burggraeve, A., Van Den Kerkhof, T., Hellings, M., Remon, J. P., Vervaet, C., De Beer, T., Batch
statistical process control of a fluid bed granulation process using in-line spatial filter velocimetry and
product temperature measurements, Eur J Pharm Sci. 2011 Apr 18; 42(5):584-92.
[3] Petrak, D. et al., In-line particle sizing for real time process control by fibre-optical spatial filtering
technique (SFT). Advanced Powder Technology, Vol. 22, Issues 2, Pages 203-208 (2011)
22
ICPE 2014
Diafiltration in a manufacturing process of liposome
embedded DNAzymes
K. Marquardta, S. Kerkera, A. Eichera, Z. Kovacsb,
M. Ebrahimia, T. Schmidtsa, P. Czermaka, F. Runkela
a
Institute of Bioprocess Engineering and Pharmaceutical Technology –
University of Applied Sciences Mittelhessen
b
Department of Food Engineering - Corvinus University of Budapest
Email for correspondence: kay.marquardt@kmub.thm.de
This study focuses on the integration of a filtration process for the reduction of unprotected
fractions of deoxyribozymes (DNAzyme) in the outer phase of liposomes after their formation. A
diafiltration first separates the DNAzyme in the outer phase from the liposome embedded
DNAzyme. Secondly, the recovered DNAzyme is concentrated in an ultrafiltation step in order to
reuse it in the manufacturing process.
DNAzymes are a new kind of synthetic agents which are able to address potential pathogen
gene expressions by post-transcriptional regulation. The DNAzyme’s structure is based on
deoxyribonucleotides with a length of approximately 34 nucleotides and a molecular weight of
approximately 11 kDa [1]. Variation of the nucleotide sequence can treat different pathogen
gene expression patterns resulting in a high amount of potential therapeutical approaches [2]
like in the therapy of asthma bronchiale, breast cancer or viral diseases.
Deoxyribonucleotides are prone to enzymatic hydrolysis and especially exposed to endo and
exogenous degrading enzymes during therapeutical application on biological matrices [3].
Modification at the phosphate backbone or at the termini can prolong the half life. Additionally,
DNAzyme can be protected by an encapsulation into liposomes. Liposomes are able to enclose
deoxyribonucleotide molecules, like DNAzymes, into the aqueous inner phase. A lipid bilayer
separates the inner phase from an aqueous outer phase, resulting in a protection of the
DNAzymes from degrading enzymes on the application site. In the manufacturing process of
liposome embedded DNAzymes a high encapsulation rate is beneficial. DNAzymes that are not
entirely encapsulated during liposome formation remain partly unprotected in the outer phase. A
potential degradation of the molecules can reduce the overall activity of the valuable active
pharmaceutical ingredient (API).
In the manufacturing process of this study, nanoscaled liposomes were prepared with
encapsulated DNAzyme. The unprotected DNAzyme in the outer phase was removed from the
liposomes through diafiltration in a stirred ultrafiltration cell. Subsequently, this collected
DNAzyme was concentrated with a tangential flow filtration. The filtration processes were
monitored in regards to the following aspects: 1. Integrity of the liposomes and the DNAzyme.
2. Recovery of the liposomes and the DNAzyme
The data of the study were analyzed by different techniques like dynamic light scattering (DLS),
anionic exchange high-performance liquid chromatography (AEX-HPLC) and fluorescence
labelling of the liposomes (fluorimeter). The experimental results were compared to simulated
data for an improved understanding of the process. Apart from the selection of the appropriate
material and membrane pore size for the diafiltration and the concentration step, the
identification of the optimum operation conditions regarding product stability is essential for an
efficient process.
1.
Breaker, R.R.; Joyce, G.F. (1994): A DNA enzyme that cleaves RNA. In: Chem. Biol. 1 (4),
S. 223–229.
2.
Santoro, S.W.; Joyce, G.F. (1997): A general purpose RNA-cleaving DNA enzyme. In: Proc. Natl.
Acad. Sci. U.S.A. 94 (9), S. 4262–4266.
3.
Tan, M.L., Choong, P.F. & Dass, C.R. (2009): DNAzyme delivery systems: getting past first base.
In: Expert Opin Drug Deliv 6, S. 127-138.
23
ICPE 2014
Surface coverage of surface modified glass beads
as model carriers in dry powder inhalers influences
the FPF
S. Zellnitz*, H. Schroettner**, N. A. Urbanetz*
*Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13/III, 8010 Graz, Austria
** Austrian Centre for Electron Microscopy and Nanoanalysis, Graz Technical University,
Steyrergasse 17, 8010 Graz, Austria
Email for correspondence: sarah.zellnitz@tugraz.at
Dry powder inhalers (DPIs) are medical devices used to treat asthma and other chronically
obstructive lung diseases. Active pharmaceutical ingredient (API) particles that are administered
via DPIs have to be in the size of 1-5 µm to be able to reach the deep lung [1]. As particles of
this size are rather cohesive and possess poor flow properties, carrier based formulations have
been invented, where the micron sized API particles are attached to larger carrier particles to
create a good flowing formulation. The formulation has to be stable during handling, transport
and dosing but during inhalation the API must separate again from the carrier so that the API
particles can reach their target site, the deep lung. Thus, interparticle interactions play a key
role in this kind of formulations. As the surface properties of the carrier largely affect interparticle
interactions [2], the model carriers used in this work are surface modified glass beads
(SiLibeads® Glass Beads Type S, Sigmund Linder GmbH, Warmensteinach, Germany). By
mechanical surface modification in a ball mill (Ball Mill S2, Retsch, Haan, Germany) glass beads
with different shades of roughness have been generated using quartz and tungsten carbide
powders as grinding materials and different grinding times [3]. By chemical surface treatment
with different silanes (3,3,3-Trifluoropropyltrimethoxysilane (FPTS) and Triphenylchlorosilane
(TPCS)), glass beads with hydrophobic surfaces have been generated.
The aim of this work was to investigate the relationship between surface coverage and fine
particle fraction (FPF) of carrier based formulations consisting of untreated and modified glass
beads and spray dried salbutamol sulphate as model API. Therefore adhesive mixtures were
prepared of untreated and surface modified glass beads with 100%, 50% and 25% surface
coverage of spray dried salbutamol sulphate (USP25 quality, Selectchemie Zuerich,
Switzerland).
This study showed that when trying to load the carriers with a certain amount of salbutamol
sulphate (calculated surface coverage) the resulting actual surface coverage is always lower as
a certain amount of API sticks to the mixing vessel and is lost for surface coverage. Even more
API can be lost during transport and capsule filling, so the true surface coverage of glass beads
used to test the performance of the formulations in NGI experiments can even be lower.
Compared to untreated glass beads the actual and the true surface coverage that can be
reached is higher for modified glass beads. This can be explained by the introduction of active
sites on the glass beads surface during the surface modifying procedures. So, when studying
the influence of surface coverage on the FPF, the true surface coverage has to be taken into
account as due to the carrier material used and the distribution of active sites on the carrier
surface, the true surface coverage can differ notably from the targeted or calculated surface
coverage. Considering the true surface coverage results showed that increased surface
coverage lead to increased FPF. However the influence of surface coverage on FPF is less
pronounced than the choice of the carrier particles. Compared to untreated and chemically
modified glass beads physically modified glass beads show an increased FPF.
1.
G. Pilcer, et al., Adv. Drug Deliv. Rev. 64 (2012) 233–56.
2.
P. Young et al., J. Aerosol. Sci. 39 (2008) 82–93.
3.
S. Zellnitz, et. al., Int. J. Pharm. 447 (2013) 132–8.
24
ICPE 2014
Characterization and synthesis of alginate
microparticles using microfluidics device
A.Pittermannová1,2, N. Bremond2, F. Štěpánek1
1
ICT Prague, 5 Technická, 166 28, Prague 6, Czech Republic,
Telephone: 00420220443236
2
ESPCI, 10 rue Vauquelin, 75231 Paris, France
Email for correspondence: Frantisek.Stepanek@vscht.cz
Recent research in the drug delivery systems has resulted in the first templates of alginate
composite microparticles, which are able to release active component encapsulated in the
particles. These composite alginate microparticles were prepared by the Ink-jet method with a
smallest achievable size around 40 µm.1 For further use of these particles in the medicine, their
adhesion properties in the living tissues will be a necessary step to investigate. It is therefore
desirable to decrease the particle size of the alginate microparticles to be not larger than size of
the red blood cell, which is approximately 6 µm.
Microfluidic technique is one of the possible ways how to produce such small microparticles. At
the beginning we count into two main microfluidic strategies to produce alginate
microparticles.2,3 The first possibility is to synthesize particles right on the chip using flow
focusing device where the continuous phase is 1-undecanol with Ca2+ ions and disperse phase
is aqueous solution of alginate. Flow focusing regime is producing w/o emulsion and gelation of
particles is started due to diffusion of Ca2+ ions from continuous phase to droplets. Second way
is to synthesize particles in a two-step process. In the first step, w/o emulsion of droplets with
required sized were prepared on membrane chip by step emulsification where the disperse
phase is 1% of alginate solution and continuous phase is mineral oil with surfactant. Emulsion is
collect and gelation is established outside of the chip by introducing calcium ions. These two
methods were compared and evaluated.
1. Hanuš J., Ullrich M., Dohnal J., Singh M., Štěpánek F., “Remotely controlled diffusion from
magnetic liposome microgels”, Langmuir 29, 4381-4387 (2013).
2. Hong Zhang et all., “Microfluidic Production of Biopolymer Microcapsules with Controlled
Morphology”, J. Am. Chem. Soc. 128, 12205-12210 (2006).
3. Ai Mey Chuaha et all., “Preparation of uniformly sized alginate microspheres using the novel
combined methods of microchannel emulsification and external gelation”, Colloids and Surfaces
A: Physocochem. Eng. Aspects 351, 9-17 (2009).
25
ICPE 2014
Feedback Control Loop for a Continuous
Crystallization Process: Tuning Crystal Size Distributions
M.O. Besenhard1,2, C. Ho3, P. Neugebauer3, R.J. Eder3,J.G. Khinast3
1 Research Center Pharmaceutical Engineering (RCPE) GmbH, 8010 Graz, Austria
2 Siemens AG, Corporate Technology, Graz, 8054 Graz, Austria
3 Graz University of Technology, Institute for Process and Particle Engineering, 8010 Graz, Austria
Email for correspondence: maximilian.besenhard@rcpe.at
Continuous crystallization remains a complex challenge in pharmaceutical engineering. By
using tubular reactors it is possible to overcome obstacles like heterogeneous concentration
profiles, a slow response to changes of the outer parameters and inaccurate or fluctuating
levels of super saturation.
Based on our previous work on tubular crystallizers, seeded[1] and self seeded [2], their
application is discussed in detail. Pipe plugging, sedimentation, breakage, mixing and the
advantage and obstacles of segmented flow will be discussed in detail. By virtue of a
mathematical process model, it was possible to quantify the sensitivity of product crystals’
quality attributes to varying process conditions and to choose the optimal reactor settings [3].
Due to the implementation of an online crystal size distribution (CSD) measurement it was
possible to realize a feedback control loop to maintain and tune the CSD. Since the impact of,
e.g. the flow rates, on the product CSD is known from previous studies and the mathematical
process model a control algorithm could be implemented easily. Both, the flow rate of the feed
solution or the seed suspension (feeding of seed crystals) are suitable control variables not
least because they can be changed conveniently. Figure 1 outlines this concept.
Figure 1: Schematic drawing of the feedback control loop
To our knowledge, this is the first time that the CSDs can be tuned as rapidly and accurately
during a crystallization process (batch or continuous).
References
[1]
R.J.Eder, S. Radl, E. Schmitt, S. Innerhofer, M. Maier, H. Gruber-Wölfler and J. G. Khinast,
“Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active
Pharmaceutical Ingredients,” Cryst. Growth & Design, vol. 10, no. 5, pp. 2247–2257, May 2010.
[2]
R.J. Eder, S. Schrank, M. Besenhard, E. Roblegg, H. Gruber-Woelfler and J. G. Khinast,
“Continuous Sonocrystallization of Acetylsalicylic Acid (ASA): Control of Crystal Size,” Cryst.
Growth Des., vol. 12, no. 10, pp. 4733–4738, Oct. 2012.
[3]
M. Besenhard, A. Hodzic, R. Hohl, R. Eder and J.G. Khinast, “Modeling a seeded cont. crystallizer
for the production of active pharm. ingredients,” Cryst. Res. & Tech., vol. 49, Feb. 2014.
26
ICPE 2014
The influence of residual water on the reconstitution
behavior of lyophilized human fibrinogen
V. Wahl * **, S. Leitgeb *, P. Laggner ***,J. Khinast * **
* Research Center Pharmaceutical Engineering, Graz, Austria
*** Bruker AXS GmbH, Graz, Austria
Email for correspondence: verena.wahl@rcpe.at
Major advances in biotechnology and biochemical understanding led to increasing numbers of
protein-based drugs approved for human use or under investigation for clinical safety and
efficacy on the market over the last years. Besides the advantages for new therapeutic
approaches the complexity of protein molecules opens increased challenges for formulators.
Protein formulations are problematic to handle due to their fragile nature e.g. maintenance of
native structure, stability during shipping and long term storage. The most common method for
preparing solid protein pharmaceuticals and therefore to enhance product shelf life is freeze
drying. Thus, the solid state stability of freeze dried protein formulations is of particular interest.
Among other parameters, the water content of lyophilized protein formulations can have a
tremendous impact on protein stability as it often determines the chemical and physical stability
of the solid state of protein powders (1,2). Whereas several studies about the influence of
relative humidity (RH) on the stability of lyophilized protein powders are available, nothing has
been reported in the context of powder characteristics and dissolution behavior in dependence
of water content in protein powders.
In this work we focused on the reconstitution behavior of freeze-dried protein powders using
human fibrinogen as model protein. The influence of powder properties on reconstitution
behavior was evaluated critically by analyzing the optimal water content for a rapid and
complete dissolution and hence, subsequent processing of the pharmaceutical product. In order
to quantify the effect of varying humidity levels on powder characteristics we equilibrated 6
batches of freeze dried protein powder under controlled conditions for two weeks over saturated
salt solutions in humidity chambers. Using different salts we were able to produce protein bulk
powder with moisture contents between 6 and 21 %. The water content was determined by Karl
Fisher titration. Furthermore particle size and shape were investigated via dynamic image
analysis. Additionally, the specific and inner surface was analyzed by BET and SAXS (small
angle X-ray spectroscopy). To examine the dissolution behavior a USP 4 flow through cell and
UV spectrophotometry was used. It can be noted that freeze dried fibrinogen powders which
were stored at lower relative humidities (<52% RH) display smaller, irregular shaped particles
and higher surface areas. Additionally, the solid state protein was determined as amorphous.
Therefore, the dissolution is faster compared to powders stored at higher relative humidities
(>70% RH). These powders crystallize during storage and particles tend to aggregate, which
decreases the surface area. Thus, the dissolution medium is hindered to reach the powder bed
and a slower dissolution kinetic can be observed. A correlation between the inner surface of
powder samples and the dissolution behavior was identified. The results prove that the
identification of the ideal water content for subsequent process steps is very useful in the
development of solid state protein formulations to improve the processing performance.
1.
Costantino HR, Langer R, Klibanov a M. Solid-phase aggregation of proteins under
pharmaceutically relevant conditions. J Pharm Sci [Internet]. 1994 Dec;83(12):1662–9. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/7891292
2.
Hageman MJ. The role of moisture in protein stability. Drug Dev Ind Pharm. 1988;14(14):2047–70.
27
ICPE 2014
Novel Strategy for Downstream Process
Development along QbD Principles
A. Meitz*, P. Sagmeister**, T. Langemann*/***, C. Herwig**
* RCPE GmbH, Graz; ** Technische Universiät Wien, *** BIRD-C GmbH, Wien
Email for correspondence: christoph.herwig@tuwien.ac.at
Downstream process (DSP) development of pharmaceutical products involving multiple process
steps presents a challenge for manufacturing companies in reducing design cycles, costs and
improving quality. For science and risk based DSP development along Quality by Design (QbD)
principles a high number of critical process parameters that are spread across multiple unit
operations have to be analyzed and optimized to gain thorough process understanding. Current
state of the art DSP development starts process characterization with employing risk
assessments to identify the most critical parameters which are then analyzed for each unit
operation separately, as exemplified in several contributions [1-3]. However, the regulatory
authorities underline that interactions of parameters need to be considered within the QbD
approach [4], which in our understanding also includes interactions across unit operations. The
sequential unit operations form an integrated process, whereby a change in one unit operation
can possibly show and procreate an effect in subsequent unit operations. Thus, interaction
effects of parameters across unit operations are possible and need to be considered within
process development.
Here, we present a new risk based method for process development across unit operations that
takes the risk of parameter interaction across unit operations into account. A novel interaction
matrix is introduced to the QbD workflow. Considering the integrated process rather than single
unit-operations, this interaction matrix provides risk-based rationales for the choice of the type
of experimental design and presents the key element of the method to deal with a multitude of
process parameters within downstream process development. Subsequently, design of
experiments (DoE) across unit operations are conducted that have the power to reveal hidden
interdependencies and gain a more comprehensive view on the whole process when compared
to DoEs performed for each unit operation separately.
The power of the presented method is shown for early protein isolation steps of a recombinant
human growth factor (rhGF) inclusion body (IB) process. The concentration of Triton X-100
during IB purification was shown to interact with the g-number of the following centrifugation
step. While the g-number alone has no significant effect on IB purity - the interaction of Triton X100 with higher g-numbers showed a 10 percent increase of purity when investigated across
process steps. The presented risk-based method allows to i) deal with a high number of process
parameters that are possibly critical , ii) achieve a holistic view on the process, iii) efficiently
design statistical experimental plans across process steps iv) reveal interdependencies across
unit operations. The overall goal is the development of a method that is capable to build a
knowledge space across multiple process steps, thereby giving the opportunity to define a
design space and control space in the course of process development
1.
Bade, P.D., S.P. Kotu, and A.S. Rathore, Optimization of a refolding step for a therapeutic fusion
protein in the quality by design (QbD) paradigm. J Sep Sci, 2012. 35(22): p. 3160-9.
2.
Bhambure, R. and A.S. Rathore, Chromatography process development in the quality by design
paradigm I: Establishing a high-throughput process development platform as a tool for estimating
"characterization space" for an ion exchange chromatography step. Biotechnol Prog, 2013. 29(2):
p. 403-14.
3.
Rathore, A.S., et al., Case study and application of process analytical technology (PAT) towards
bioprocessing: Use of tryptophan fluorescence as at-line tool for making pooling decisions for
process chromatography. Biotechnol Prog, 2009. 25(5): p. 1433-9.
4.
ICH. Guidance for Industry: Q11 (step 5) Development and Manufacture of Drug Substances.
2012
28
ICPE 2014
Fluid Bed Granulation: Towards a Comprehensive
gSOLIDS Model
R.C. Schardmüller1, M. Pieber1, G. Toschkoff1, S. Fraser1, B. Chilian2, D. Steigmiller2, A.
Fetscher2, M. Maus2, M. Braun2, J. G. Khinast3,*
1
Research Center Pharmaceutical Engineering GmbH, Graz, Austria
Boehringer Ingelheim Pharma GmbH & Co. KG, Process Development Solids, Biberach, Germany
3
*Email for correspondence: khinast@tugraz.at
2
Although fluidised bed granulation (FBG) is a widely-used unit operation, its practical application
is often guided by empirical methods and operator experience rather than by systematic and
scientifically-based strategies. Employed in various branches of industry, granulation in general
- and fluid bed granulation in particular - remained more of “an art than a science” [1].
The development of realistic mathematical models interlinked with in-line process
measurements can yield powerful tools for a knowledge-based control of process and product
quality for all particulate processes [2]. The complex interplay of many different variables and
processes during fluid-bed granulation poses a significant challenge in developing such models.
The associated effects may be grouped into one of three categories [3]: wetting and nucleation,
consolidation and growth, as well as breakage and attrition. Every realistic model for a fluid bed
granulator must incorporate these three effetcs. In addition, the model needs to account for all
process-relevant parameters.
Figure 1: Schematic of the process modelling approach (“flowsheeting”) using the custom FBG unit.
In our work, we develop a model of the fluid bed granulator based on a basic model provided in
the process simulation software gSOLIDS 3.1 (Process Systems Enterprise Ltd., London, UK).
The basic model already contains agglomeration, drying, and elutriation of particles as separate
phenomena. To make it suitable for batch processes, the extended model additionally takes into
account the breakage of granulates, as well as the continuous introduction of spray. For
breakage, different commonly used models are compared with respect to their applicability. The
spray introduction is based on a new user-defined phenomenon for the wetting of particles. In
addition, we also explored the possibility of introducing a liquid binder component as a part of
an additional solid phase. We present results for the different approaches for wetting and for a
selection of combinations of agglomeration and breakage kernels. The results are further
compared to in-line measurements of particle size and moisture from industrial fluid bed
processes of different scales.
References
[1]
[2]
[3]
J. D. Litster, Powder Technol. 130, 35 (2003).
I. T. Cameron, F. Y. Wang, C. D. Immanuel, and F. Stepanek, Chem. Eng. Sci. 60, 3723 (2005).
S. M. Iveson, J. D. Litster, K. Hapgood, and B. J. Ennis, Powder Technol. 117, 3 (2001).
29
ICPE 2014
Intra-tablet Coating Uniformity of Various
Pharmaceutical Tablet Shapes
B. Freireich1, B. Ketterhagen2, R. Kumar3, K. Su4, C. Wassgren3, J. A. Zeitler4
1
The Dow Chemical Company,Midland, MI 48667, USA
2
Pfizer Global Research and Development, Groton, CT 06340, USA
3
School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, USA
4
Department of Chemical Engineering and Biotechnology, University of Cambridge,
Cambridge CB2 3RA, UK
Email for correspondence: jaz22@cam.ac.uk
We present recent computational and experimental work investigating intra-tablet coating
variability. Prior analytical work has shown that tablets having a preferential orientation when
passing through the spray zone approach an asymptotic coating variability limit, with larger
degrees of preferred orientation resulting in larger intra-tablet coating variability [1,2]. Discrete
element method computer simulations predict this effect and produce coating patterns
consistent with experimental measurements of coating thickness made using terahertz imaging
(Figure 1). Comparisons with Monte Carlo predictions based on tablet orientation distributions
demonstrate that tablet obscuration due to neighboring tablets also significantly affects coating
uniformity.
DEM method
Figure 1: Experimental vs. theoretical intra-tablet coating thickness distribution at the example
of an almond shaped tablet.
1. Freireich, B., & Wassgren, C. (2010). Intra-particle coating variability: Analysis and Monte-Carlo
simulations. Chemical Engineering Science, 65(3), 1117–1124.
2. Freireich, B., Ketterhagen, W. R., & Wassgren, C. (2011). Intra-tablet coating variability for several
pharmaceutical
tablet
shapes.
Chemical
Engineering
Science,
66(12),
2535–2544.
doi:10.1016/j.ces.2011.02.052
30
ICPE 2014
Multivariate Analysis of Residence Time
Measurements in HME Gained by Imaging
J. Pott, M. Thommes
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University
Email for correspondence: Josefine.Pott@hhu.de
Hot melt extrusion is a widely used method in pharmaceutical industry. Analysis of the mean
residence time (MRT) broadens process understanding. This study aims to develop a new
analytical method for MRTs with low tracer concentrations. Photos of extrudates with a certain
amount of tracer (carbon black), representing the residence time, were taken. The photos were
analysed using multivariate data analysis (MVDA).
Extrusion of copovidone (Kollidon VA64, BASF) was conducted on a twin-screw extruder (Mikro
27 GL-28D, Leistritz) using a feed rate of 30 g/min and a screw speed of 100 rpm. Theophylline
monohydrate and carbon black were added in a binary mixture (50:50) as tracer substances.
Samples were taken every 30 s. The content of theophylline monohydrate was determined
offline by UV spectrometry (Lambda 2S, PerkinElmer). By the use of MATLAB® software
(Mathworks) photos were transformed into gray scale and its histogram was calculated. For
MVDA (SIMCA, Umetrics) the UV data were used to create a PLS (Partial Least Squares)
calibration model. Based on this, the grey histogram for each photo was predicted and
compared to the actual values.
The UV results and the predicted photo
results describe the same residence time
progression (Fig. 1) with a fast onset and a
tailed offset. From the low tracer
concentration of less than 300 ppm, a
negligible impact of the tracer to the
extrusion process is expected. A quantitative
assessment of the calibration model is given
by R2Y (cumulative sum of squares of all yvariables explained by the extracted
components) and Q2 (cumulative fraction of Fig. 1: UV ( ), predicted photos ( ) and fitted photos
the total variation of X and Y that can be (line) of carbon black in copovidone.
predicted by the current component). In this model two principle components were used,
resulting in a R2Y (cum) of 0.993 and a Q2 (cum) of 0.953. For further insights the predicted
photo results were fitted with the residence
time model according to Reitz et al. [1] (Eq.
1). Multivariate analysis provides much more
details than recent univariate studies [2], but Eq. 1: Residence time model of Reitz [1], initial tracer
still there are some issues regarding the concentration (c0), rate constant (k), average RT of the
tracer (tdead), width of the distribution curve (σ), area
photo technology, such as light reflections. under the
curve (AUC) and mixing volume (Vmix).
Also the black/white scale differentiation is
limited to distinct units from 0-255, which might lead to an inferior resolution. These aspects
might lead to the comparatively high signal-to-noise ratio. Another polymer (aPMMA) gave
similar results (data not shown).
The presented multivariate analysis of MRT analysis provided good results regarding the low
tracer concentration. However, the high signal-to-noise ratio will be the topic of further
investigations. The analysis of RGB instead of grey scale might lead to a better resolution and
therefore lower signal-to-noise ratio.
1. Reitz, E., Podhaisky, H., Ely, D., Thommes, M. Residence time modeling of hot melt extrusion
processes. Eur. J. Pharm. Biopharm. (2013), in press.
2. Pott, J., Polinard, O., Quodbach, J., Reitz, E. and Thommes, M. Residence time evaluation in hot
melt extrusion using image analysis, Poster at PBP (2014).
31
ICPE 2014
Binary Mixtures of Pharmaceutical Excipients:
Evaluation of Flow Properties and Compaction
Behaviour
J. Conceição, M. Estanqueiro, M. H. Amaral, J. P. Silva, J. M. Sousa Lobo
Research Centre for Pharmaceutical Sciences, Laboratory of Pharmaceutical Technology,
Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Portugal
Email for correspondence: jmgmconceicao@ff.up.pt
The physical properties of pharmaceutical powders are very important in the development of
solid dosage forms. Compaction, an essential manufacturing step in the manufacture of tablets,
includes compression (i.e., volume reduction and particle rearrangement), and consolidation
(i.e., interparticulate bond formation) (1).
The major objectives of this study were: (i) to evaluate the flow properties (angle of repose, flow
time, compressibility index (CI), Carr index (CrI) and Hausner ratio (HR)) of technological
excipients used in tablets manufacturing which behave differently during compaction, either
pure or in binary mixtures, and whose composition varied between 20% (w/w) and 80% (w/w) at
intervals of 20% (w/w) (2, 3); (ii) to measure energies and forces exerted during compaction of
these materials using a Dott Bonapace alternative machine (model CPR-6); (iii) to calculate the
plasticity index (PI) according to Stamm and Mathis; (iv) to register the force/time and
force/displacement compression profiles; (v) to determine the periods (consolidation time, dwell
time and contact time) of the force/time compression curves; (vi) to characterize the
manufactured uncoated tablets (evaluation of weight and hardness).
The raw materials used were microcrystalline cellulose (Avicel PH-200 (AV), FMC Corporation,
United States), an insoluble diluent with plastic behaviour, and dibasic calcium phosphate
dihydrate (Emcompress® (EMC), JRS Pharma, Germany), an insoluble diluent with
fragmentable behaviour.
Pure excipients and their binary mixtures presented similar CI and CrI (<16.7 %), HR (<1.25)
and angle of repose (39.3-44.4º) values. However, the flow time value determined with EMC
was about half of the value obtained with AV. Increasing the amount of EMC decreased the flow
time.
Uncoated tablets with acceptable physical properties were produced. But it was not possible to
prepare tablets with EMC keeping constant the volume of the compression chamber and the
upper punch displacement (conditions maintained constant during the experiments).
From the values of the force measured in the upper punch (Fs), it was possible to differentiate
the tested materials. In this way, as the amount of EMC increased, the value of Fs increased
also. And as Fs increased, the apparent net energy (ELA) also increased.
A consistent relationship between FS and the tablets hardness was not observed. All
compaction curves showed the same configuration. The values of PI were high (> 91.6 %) and
similar for all the tested materials. As the amount of EMC in the binary mixtures increased, PI
decreased. As far as the periods measured in the force/time compression curves are
concerned, it was observed that they decreased when the amount of EMC increased.
In this work, compressibility and compaction behaviour were studied. The outcomes
demonstrated that the binary mixtures and the pure excipients showed similar flow properties.
On the other hand, the tablets obtained with the plastic excipient had lower values of FS and
ELA, and higher values of PI and time periods of the force/time compression curves.
1.
Patel S, Kaushal AM, Bansal AK. Compression physics in the formulation development of tablets.
Crit Rev Ther Drug Carrier Syst. 2006;23(1):1-65.
th
2.
European Pharmacopoeia. 8 ed. Strasbourg: EDQM, Council of Europe; 2014.
3.
Carr RL. Evaluating flow properties of solids. Chem Eng. 1965;72:163-8.
32
ICPE 2014
A QbD approach to optimise electrochemical
sensors
I. Kondor1, C. Planchette1, A. Mercuri1, G. Scharrer1, H. Steiner2, G. Brenn2
1
Research Center Pharmaceutical Engineering, Graz, Austria,2 TU Graz, Institut für
Strömungslehre und Wärmeübertragung, Graz, Austria
Email for correspondence: itsvan.kondor@rcpe.at
Electrochemical sensors for gases have been widely used to measure various parameters such
as oxygen, carbon dioxide or glucose concentrations, etc. Using screen printing it is possible to
build up a suitable sandwich architecture where a reference electrode, a counter electrode and
a working electrode are obtained from different pastes. Typically such pastes contain microparticles ensuring the functionality of the layer, polymers playing the role of binder and solvents
allowing for drying. The performances of these sensors highly depend on the microstructure of
the resulting films which is by itself influenced by several material properties and process
parameters.
In this study, we propose a QbD (Quality by Design) approach to optimize the performances of
these sensors. More precisely, we are interested in the following Critical Quality Attributes
(CQA) of the final electrode: thickness, overall particle packing and homogeneity in terms of
particle packing. The Critical Material Attributes (CMA) and the Critical Process Parameters
(CPP) under investigation are respectively the solvent content of the organic matrix, the volume
fraction of particles, the particle size distribution, the drying temperature, and the velocity of the
drying air flow.
Our study is performed via numerical simulations: the liquid matrix is modelled as a binary
mixture of polymer and solvent; the particle phase is modelled by an advection equation using
Stokes drag law with hindrance function and the transport in the liquid phase is extended from
classical advection-diffusion equation using a convective term which takes into account for the
motion induced by the settling particles.
Our results show that the time dependent solvent and particle spatial distributions are well
represented for various drying conditions and paste compositions. It is found that process
parameters had no significant influence on the final layer thickness nor on particle packing. The
initial solvent content was identified to be the most influential parameter, while initial particle
volume fraction and particle size were found to be non-critical.
33
ICPE 2014
Author Index
Luštrik, Matevž 5, 6
A
M
Antovska, Packa 14
Beinert, Stefan 9
Besenhard, Maximilian 26
Braun, Michael 29
Büttgenbach, Stephanus 9
Makreski, Petre 14
Marquardt, Kay 23
Maus, Markus 29
Meitz, Andrea 28
Mondelli, Giusi 17
Müller-Goymann, Christel Charlotte 9
C
N
Chilian, Bruno 29
Conceição, Jaime 32
Neugebauer, Peter 26
Nicolaï, Niels 10
Nopens, Ingmar 10
B
D
P
Dietrich, Stefan 22
Dietzel, Andreas 9
Dreu, Rok 18
Eder, Raffael 26
Petrusevski, Gjorgji 14
Pieber, Markus 29
Pittermannova, Anna 25
Pott, Josefine 31
Priese, Florian 17
F
R
Fetscher, Alfred 29
Finke, Jan Henrik 9
Fraser, Simon 29
Freireich, Ben 30
Funaro, Caterina 17
Radl, Stefan 16
Reisinger, Christine 15
Reiter, Tamara 13
Repic, Anna 13
Richter, Claudia 9
Rollett, Alexandra 13
E
G
S
Gehrmann, Sandra 12
Glasser, Ben 4
Gothsch, Thomas 9
Guebitz, Georg M. 13
Jedinger, Nicole 19, 21
Sarvasova, Nina 2
Schardmüller, Robert C. 29
Schiffer, Doris 1
Schrank, Simone 4
Schroettner, Hartmuth 24
Šibanc, Rok 18
Srcic, Stane 8
Stefanova, Bosilka 14
Steigmiller, Daniela 29
Stockinger, Hannes 13
Su, Ke 30
K
T
Kann, Birthe 4
Ketterhagen, Bill 30
Khinast, Johannes 16, 26, 27
Khinast, Johannes G. 29
Kondor, Itsvan 33
Kumar, Rahul 30
Kutz, Gerd 22
Kwade, Arno 9
Teubl, Birgit 20
Thies, Jan-Wilhelm 9
Thommes, Markus 31
Tokarova, Viola 3
Toschkoff, Gregor 29
H
Heinzle, Andrea 13
Ho, Cheng-Da 26
Hüttner, Carina 22
J
U
Ugarkovic, Sonja 14
Urbanetz, Nora Anne 24
L
V
Laggner, Peter 27
Leitgeb, Stefan 27
Vidlarova, Lucie 11
35
ICPE 2014
W
Wahl, Verena 27
Wassgren, Carl 30
Werner, Benjamin 7
Windbergs, Maike 4
Winter, Gerhard 7
Wolf, Bertram 17
Wu, Mingqiu 16
Z
Zakhvatayeva, Anastasiya 17
Zeitler, Axel 30
Zellnitz, Sarah 24
36

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