Making Amorphous API

Making Amorphous API
Ann Newman
Seventh Street Development Group
PO Box 526, Lafayette, IN 47902
765-650-4462
ann.newman@seventhstreetdev.com
www.seventhstreetdev.com
PPXRD May 15, 2012 Fort Myers, FL
©2012 Seventh Street Development Group
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Amorphous
Amorphous can be produced in a variety of situations
Intentional
Vapor
condensation
Precipitation from
solution
-solvent evaporation
-freeze drying
-spray drying
Unintentional
-wet granulation
-drying
-polymer film coating
Amorphous
Supercooling
of liquid
Disruption of
crystalline lattice
Hancock and Zografi. J Pharm. Sci. 1997, 86, 1-12
Intentional
-grinding
Unintentional
-grinding
-desolvation
-compaction
Sample Generation
Adapted from Anderton. Amer. Pharm. Rev. 2007, 10, 34-40
3
Methods
Rotary
evaporation
• Small scale
Spray drying
– Solvent methods
• Fast evaporation, rotary
evaporation, freeze-drying, spray
drying, rapid precipitation
– Thermal
• Melt
– Other
• Grinding, supercritical
fluid, ultra-rapid
freezing
– Automated screening
http://www.mybuchi.com/
Large scale
spray drying
Melt extrusion
• Plates
• Large scale
– Freeze-drying
– Spray drying
– Melt extrusion
http://www.niro.com/niro/cmsdoc.
nsf/WebDoc/ndkk5hvdwpPRODUCT
IONMINORSprayDryersize
http://www.leistritz.com/extrusion/en/04_p
4
roducts/pharmaextruder.html
Methods
• Most methods can be applied to both amorphous API
(AAPI) and amorphous solid dispersions (ASD)
• Not all methods are scaleable
Nagapudi et al. Current Bioactive Compounds. 2008, 4, 213-224
5
Methods
Need to match preparation method with properties of
compound
– Melt quench
• Heat stable compounds
– Grinding
• Physically stable compounds
– Precipitation or spray drying
• Organic solvent soluble compounds
• Fluid bed-spray onto support (Sporonox)
– Freeze-drying
• Water soluble compounds
6
Melt Quench
Amorphous can be made by melting crystalline
material and quenching quickly
– Place crystals in clean vial
– Heat sample to just above melting point (~10 C)
– Quench sample
• Place sample vial at reduced
temperature (ice bath, liquid
nitrogen, etc)
• Pour molten liquid into a
mortar containing liquid
nitrogen and grind into a
powder
Melt quench
Cryoground
Itraconazole
Engers et al. J Pharm Sci. 2010, 99, 3901-3922
7
Melt Quench
Amorphous can be produced using DSC cycling experiments
• Heat samples to just above melting temperature and then cool with
fastest cooling rate possible
• Can use open pans for anhydrous materials
– Use hermetically sealed pans with hydrates/solvates to maintain solvation
state
Lu and Zografi. J Pharm Sci 2000, 86, 1374-1378
8
Grinding
• Methods
– Mortar and pestle
– Ball mill (Wig-L-bug)
– Cryogrinder
• Disperses heat during grinding
9
Grinding
• Cimetidine
– Ground in cryogrinder 180 min
Lin et al. J Pharm Sci. 2009, 98, 2696-2708
10
Grinding
Not all materials will convert to
amorphous during grinding
• 23 compounds examined
• Cryoground for up to 3 hours
• 12 fully amorphous(52%)
• 3 partially amorphous (13%)
• 8 remained crystalline (35%)
• Grinding time to produce
amorphous
• Range of 1-5 hours
• Some samples remained
crystalline even after 5 hrs
Lin et al. J Pharm Sci. 2009, 98, 2696-2708
11
Drying
• Trehalose
– Three known forms: dihydrate, anhydrate, amorphous
– Form obtained upon drying dihydrate depends on particle size, rate,
drying conditions
Trehalose Dihydrate
Small particles
(<425 µm)
dehydration
amorphous
Large particles
(>425 µm)
dehydration
anhydrate
Taylor and York. J Pharm Sci, 1998, 87, 347-355
XRPD patterns of dihydrate dried under
(a) slow conditions (1 K/min) to form
anhydrate
(b) fast conditions (>50 K/min) to form
amorphous
Willart et al. J Phys Chem B. 2002, 106, 3365-3370
Precipitation
• Want kinetic conditions to trap metastable form
–
–
–
–
–
–
Fast cooling
Fast precipitation
High concentrations
Large differences in temperature
Reverse anti-solvent addition
Rapid removal of solvent (rotovap,
spray drying, etc)
– Etc
• Ostwald’s Rule of Stages
– Metastable form will crystallize first
– Need to trap amorphous metastable form before it dissolves and
crystallizes into the stable form
Ostwald. Z. Phys. Chem. 1897, 22, 289-330. Figure from Blagden et al. Crystal Growth Des. 2003, 3, 873-885.
13
Precipitation
Can be used to make amorphous API
or dispersions
• Sodium indomethacin:
indomethacin amorphous mixtures
– API dissolved in anhydrous methanol
at 60 °C
– Solid completely dissolved
– Solvent removed with rotary
evaporator up to 63 °C
– Variety of concentrations produced
– Samples remained amorphous for 14
months at 4 °C
Tong and Zografi. J Pharm Sci. 2001, 90, 1991-2004
XRPD powder patterns of mixtures after
storage at 4 °C for 14 months
14
Freeze Drying
•
•
•
Used to make reconstituted solutions,
such as parenterals
– Solids are commonly amorphous
– Can also have excipients, such
mannitol
– Buffers can play a role
Freeze drying, or lyophilization, cycle is
divided in three phases:
– An initial freezing process
– A primary drying (sublimation) phase
– A secondary drying aimed at
eliminating the final traces of water
which remain due to absorption
Lab or large scale
Rey, L.; May, J.C. Freeze-drying/Lyophilization of
Pharmaceutical and Biological Products, 2nd Ed.;
Marcel Dekker: New York, 2004.
15
Freeze Drying
• Sulfadimidine
– Different solvents used
– 40% acetone resulted in amorphous material
http://www2.ul.ie/pdf/269374500.pdf
16
Supercritical Fluid
Supercritical fluids
• Gases/liquids at temperatures and pressures above their critical point
• At critical point, supercritical fluids possess properties of both liquid
and gas with density similar to liquids and flow properties similar to
gases
• Most pharma applications use supercritical carbon dioxide
Kakamanu and Bansal. Business Briefing: Labtech 2004, 1-4
Gas
Tc ( °C)
Pc (MPa)
H2O
374
22
Xe
16.6
5.9
SF6
45.5
3.8
N 2O
36.5
4.1
C2H4
9.1
5.1
CHF3
25.9
4.7
CO2
31.3
7.4
Pasquali et al. Adv Drug Delivery Rev, 2008, 60, 399-410
17
Supercritical Fluids
Different processes
• Uses supercritical fluids as a solvent
• RESS : rapid expansion of a
supercritical solution
• RESOLV : rapid expansion of a
supercritical solution into a
liquid solvent
• Uses supercritical fluids as an
antisolvent
• GAS: Gaseous antisolvent
• PCA: Particles by compressed
antisolvent
• SAS: Supercritical antisolvent
• ASES: Aerosol solvent
extraction system
• SEDS: Solution enhanced
dispersion by supercritical fluids
Drug Soln
Pressure Gage
Drug Pump
Nozzle
CO2 cooler
CO2 pump
Vessel
Heat
Circulator
CO2 tank
Back Pressure
Regulator
Jo et al. Controlled Release Society 29th Annual Meeting Proceedings 2002
Pasquali et al. Adv Drug Delivery Rev, 2008, 60, 399-410
18
Supercritical Fluid
Celecoxib
• Produced by RESS process
– Celecoxib dissolved in SCF CO2 (50°C,
29 MPa)
– Solution rapidly depressurized to
atmospheric pressure
• Sample a: atomization vessel maintained
at 20 °C
• Sample b: additional stream of liquid CO2
injected to trap particles at very low
temperature after nucleation
Sample b
– Sample b resulted in amorphous
material
• Amorphous “frozen” after particle
generation prevented crystallization
http://www.futurechemtech.com/data/New%20Solid%20State%20Morph
ology%20of%20Particles%20Prepared%20by%20a%20SCF%20Process.pdf
19
Amorphous Screening
Manual
• Solvent and nonsolvent methods should be included
Solvent methods
Nonsolvent methods
•
•
•
•
•
•
•
•
•
•
•
Evaporation
Cooling
Antisolvent addition
Lyophilization
Supercritical fluid
Etc
Parameters to investigate
Melt quench
Grinding
Desolvation
Compression
– Solvent, concentration, cooling
rates, evaporation rates,
addition rates, etc
20
Amorphous Screening
• Automated
– Can use plates to look at a variety of solvents
– For dispersions, can look at a variety of polymers, ratios,
solvents, etc
– Can use centrifugal vacuum concentrator system
(centrivap) with plate attachment
http://www.labconco.com/_scripts/editc25.asp?catid=87
http://www.labconco.com/_scripts/EditItem.asp?ItemID=920
21
Dispersion Screening
• Variables
– Different polymers
– Drug:polymer ratio
– Binary vs ternary mixtures
– Solvent
– Common preparation conditions
• Solvent (evaporation, freeze drying)
• Melt
• Manual and automated (plate) methods
available
22
Dispersion Screening
• Plates used initially
• Scaled up to melt press
and then melt extruder
• Included in-vivo testing
on five formulations
Shanbhag et al. Int. J. Pharm. 2008, 351, 209-218
23
Dispersion Screening
Dissolution
• Number in each cell is the
average value of % dissolved
after 1 hr incubation in SIF
• Color of cells indicates whether
% dissolved was
– <25% (orange)
– between 25 and 50 (yellow)
– > 50% (green)
• Top row: surfactant only
formulations
• Left column: polymer only
formulations
• 13 formulations that were
scaled up using melt press
identified by bold numbers
• Standard deviations generally
less than 5%
Shanbhag et al. Int. J. Pharm. 2008, 351, 209-218.
24
Dispersion Screening
• Oral bioavailability tested for five dispersions and compared to IV
– HPMCP/TPGS was closest to oral solution for absolute bioavailability
• Did not look at crystallinity or physical stability as part of selection
process
Shanbhag et al. Int. J. Pharm. 2008, 351, 209-218.
25
Large Scale Production
Thayer. C&E News, 2010, 88, 13-27
26
Spray Drying
• API is dissolved in solvent
• Sprayed into a drying chamber to
quickly remove solvent (~ 1 sec)
• Various nozzles are available for
atomization
– Pressure (hydraulic), pnuematic,
rotary, ultrasonic, two fluid, etc
http://en.wikipedia.org/wiki/File
:Spray_Dryer.gif
http://en.wikipedia.org/wiki/File:SDXFamily1.JPG
27
Spray Drying
Laboratory scale
Process Flow
• Atomization of the liquid stream
• Droplets of the feed interact with heated drying gas
– Vaporization of solvent resulting in solid
• Isolation and collection of solid
• Secondary drying if needed
Large scale
http://en.wikipedia.org/wiki
/File:Labspraydryer.svg
Dobry et al. J Pharm Innov. 2009, 4, 133-142
28
Spray Drying
•
•
•
•
API or API/polymer is dissolved in solvent
– Organic solvents typically used
• Due to low aqueous solubility of many APIs
• Water can be used if API is water soluble
– Nitrogen atmosphere used to provide inert
atmosphere when using organic solvents
• Air used when water is the solvent
Solution is atomized
– Pressure nozzles usually used for pharma
applications
• Due to simplicity, scalability, and ease of
droplet size tuning
Droplets contact hot drying gas
– Solvent evaporates, leaving particles entrained in
drying gas in drying chamber
Solid separated from gas stream
– Usually use cyclone separator
Dobry et al. J Pharm Innov. 2009, 4, 133-142
29
Spray Drying
• Processing parameters
–
–
–
–
–
–
–
–
–
Solvent
Solid concentration
Solution feed rate
Nozzle size
Atomization pressure
Inlet temperature
Drying gas temperature
Drying gas flow rate
Dryer outlet temperature
Dobry et al. J Pharm Innov. 2009, 4, 133-142
30
Spray Drying
Effect of processing parameters on manufacturing
Cal et al. J Pharm Sci. 2010, 99, 575-586
31
Spray Drying
• Need to optimize parameters for process
– Design of experiments (DOE), Quality by Design (QbD), etc
Dobry et al. J Pharm Innov. 2009, 4, 133-142
32
Spray Drying
Processing parameters will affect the properties
•
•
Hot/fast drying
– Droplet temperature is near or above the boiling point of the solvent when droplet skin forms
– Vapor pressure in particle keeps it inflated when it dries producing hollow sphere morphology
Cold/slow drying
– Droplet temperature is below the boiling point of the solvent when droplet skin forms
– Causes particle to collapse into a “raisin” morphology
High speed images of pressurenozzle atomization and droplets
suspended on thermocouples
subjected to various drying
conditions, shoing images for
individual droplet drying
experiments when a film forming
polymer is used in an acetone
solution
Dobry et al. J Pharm Innov. 2009, 4, 133-142
33
Secondary Drying
• May need to remove solvent from spray dried
material
– Common for large scale batches
• Secondary drying (tray drying, fluid bed drying, etc)
can be used
Tray drying
Fluid bed drying
34
Processing
• Spray dried material can be used in a variety
of granulation processes similar to API
– Blending, compression, capsule filling
• Depending on stability of material, may need
to reduce exposure to water or RH conditions
– Water can plasticize amorphous materials, lower
Tg, and possibly lead to crystallization
– May need RH controlled processing labs
35
Case Study
Intelence
• Etravirine:HPMC dispersion
– Approved in Jan 2008 for HIV treatment
• Prepared by spray drying
• Dispersion formulated into tablets
– Microcrystalline cellulose, colloidal silicon
dioxide, croscarmellose sodium, magnesium
stearat, lactose monohydrate
– Tablet can also be placed in water and stirred
until it becomes cloudy
• Needs to be taken with food
– AUC decreased 51% under fasted conditions
http://www.intelence-info.com/about-intelence/about-intelence ;
http://www.natap.org/2008/Pharm/Pharm_07.htm
36
Melt Extrusion
• API and polymer are heated to melting
• Extruder consists of at least one rotation screw inside a stationary
cylindrical barrel (extrusion channel)
– An end plate die connected to the end of the barrel determines the shape
of the extruded product
• Most commercial extruders have a modular design
– Provides a choice of screws or interchangeable sections which alter
configuration of feed, transition, and metering zones
Extrusion channel
Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117
37
Melt Extrusion
• Process flow:
–
–
–
–
Feeding of the extruder
Conveying of mass and entry into the die
Flow through the die
Exit from the die and downstream processing
Single screw extruder
Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117
38
Melt Extrusion
Extrusion channel contains three parts
• Feed section
– Material fed from hopper
into extruder
• Transition or compression section
– A solid plug mixed,
compressed, melted,
Extrusion channel
plasticized
Single screw extruder
• Metering section
– Homogeneous plastic melt is extruded at a
uniform delivery rate
Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117
39
Melt Extrusion
Co-rotating twin-screw
Twin screw extruder
•
•
•
•
•
Counter-rotating twin-screw
Two agitator assemblies mounted on parallel shafts
– Can rotate in the same direction or opposite directions
– Agitators are self wiping to eliminate stagnation areas in
the mixing chamber and ensure narrow residence time
Short residence time
• About 2 min
Minimum inventory
• Continuous operation and low
volume of mixing chamber reduces
amounts needed
Verstaility
• Operating parameters can be
changed easily and continuously to
change mixing or extrusion rate
• Diameter of 16-18 mm and a length of
• Variety of die plates to alter
4-10X the diameter
extrudate diameter
• Throughput: 0.5-3 kg/h
Throughput 0.5-3 kg /hr
Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117; Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926
40
Melt Extrusion
• Degradation by heat can be minimized
– Temperature control of barrels are independent
• Range of 30-250 °C
– Oxygen and moisture may be excluded
• Process monitoring and control of parameters
– Temperature in extruder, head, die
– Pressure in extruder and die
• Considerations
– Molecular weight of polymer
– Glass transition/melting temperature of
amorphous/semicrystalline polymer
– Sensitivity of the matrix or drug towards
heat and shear force
– Miscibility of drug and polymer
– Can use plasticizers to lower processing temperatures
Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117; Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926
41
Carriers
A variety of polymers and excipients have been used for HME
– Not a comprehensive list; wide range of temperatures
– In general, want polymer with low melt viscosities and high thermal conductivity
acrylates
HPC
cellulose derivatives
CAP
PEO
PEG
PVP
PVA
HPMCP
PVP/VA
HPMC
HPMCAS
Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926
42
Melt Extrusion
Examples of drug substances processed by HME
Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926
43
Processing
• A variety of high end
formulations can be made
– Implants, stents, transdermal
patches, ophthalmic inserts
• Dispersions can be
produced in various shapes
and sizes
Pelletizer used to chop rod shaped extrudates
into pellets or granules
– Pellets, films, etc
• Can also be formulated
– Capsules
– Tablets
Film assembly
Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926
44
Case Study
• Kaletra
– Ritonavir and lopinavir combination
product
– Oral soft gelatin capsule and solution
introduced in 2000
• Both refrigerated storage
– Improved melt extrusion-based
tablet formulation introduced in 2005
• amorphous dispersion produced
• based on melt extrusion technology
– copovidone (cross-linked PVP) used
• patients take fewer tablets (from 6 to 4)
• needs no refrigeration
• no food effect
http://www.thebody.com/confs/ias2005/pdfs/WeOa0206.pdf ; Breitenbach. Am J Drug Deliv. 2006, 4, 61-64
45
What Have We Learned
• Amorphous API and dispersions are metastable forms
– Need kinetic conditions to trap the amorphous material
• Various methods can be used
– Melt quench, grinding, precipitation, lyophlization, spray
drying, melt extrusion, etc
• Large scale production is limited
– Spray drying, melt extrusion, lyophilization, precipitation
• Spray drying and melt extrusion common for dispersions
• Amorphous materials can be formulated
– Reconsituted solutions, tablets, capsules
– May need to monitor environmental conditions
46
References
Spray drying
• Dobry et al. J Pharm Innov. 2009, 4,
133-142
• Cal at al. J Pharm Sci 2010, 99, 575586
• Sollohub et al. J Pharm Sci 2010, 99,
587-597
• Vehring Pharm Res. 2008, 25, 9991022
Hot melt
• Crowley et al. Drug Dev Ind Pharm
2007, 33, 909-926.
• Repka et al. Drug Dev Ind Pharm
2007, 33, 1043-1057
• Forster et al. IJP 2001, 226, 147-161
Grinding
• Lin, Wildfong et al. J Pharm Sci. 2009,
98, 2696-2708
Supercritical Fluid
• Rehman et al. Europ J Pharm Sci.
2004, 22, 1-17
• Pasquali et a. Adv Drug Delivery Rev.
2008, 399-410
Dispersions
• Padden et al. Amer Pharm Rev. 2011,
Jan-Feb, 66-73
• Dhirendra et al. Pak J Pharm Sci 2009,
22, 234-246
• Sharma et al. Asian J Pharm. 2007, 1,
9-19
• Dong et al. IJP, 2008, 355, 141-149
• Leuner and Dressman. J Pharm
Biopharm. 2000, 50, 47-60
47