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

This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium

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Amorphous

Amorphous can be produced in a variety of situations

Amorphous

Vapor condensation

Precipitation from solution

Supercooling of liquid

Disruption of crystalline lattice

Hancock and Zografi. J Pharm. Sci. 1997, 86, 1-12

Intentional -solvent evaporation -freeze drying -spray drying

Unintentional -wet granulation -drying -polymer film coating

Intentional -grinding

Unintentional -grinding -desolvation -compaction

Sample Generation

3 Adapted from Anderton. Amer. Pharm. Rev. 2007, 10, 34-40

http://www.niro.com/niro/cmsdoc.nsf/WebDoc/ndkk5hvdwpPRODUCTIONMINORSprayDryersize

Large scale spray drying

Methods

• Small scale – Solvent methods

• Fast evaporation, rotary evaporation, freeze-drying, spray drying, rapid precipitation

– Thermal • Melt

– Other • Grinding, supercritical

fluid, ultra-rapid freezing

– Automated screening • Plates

• Large scale – Freeze-drying – Spray drying – Melt extrusion

http://www.mybuchi.com/

4

Rotary evaporation

Spray drying

http://www.leistritz.com/extrusion/en/04_products/pharmaextruder.html

Melt extrusion

Methods

• Most methods can be applied to both amorphous API (AAPI) and amorphous solid dispersions (ASD)

• Not all methods are scaleable

5

Nagapudi et al. Current Bioactive Compounds. 2008, 4, 213-224

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

7

Itraconazole

Melt quench

Cryoground

Engers et al. J Pharm Sci. 2010, 99, 3901-3922

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

8

Lu and Zografi. J Pharm Sci 2000, 86, 1374-1378

Grinding

• Methods

– Mortar and pestle

– Ball mill (Wig-L-bug)

– Cryogrinder

• Disperses heat during grinding

9

Grinding

• Cimetidine

– Ground in cryogrinder 180 min

10 Lin et al. J Pharm Sci. 2009, 98, 2696-2708

Grinding

Not all materials will convert to amorphous during grinding

11

• 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

Drying

• Trehalose – Three known forms: dihydrate, anhydrate, amorphous – Form obtained upon drying dihydrate depends on particle size, rate,

drying conditions

Taylor and York. J Pharm Sci, 1998, 87, 347-355

Trehalose Dihydrate

Small particles (<425 µm)

Large particles (>425 µm)

dehydration

amorphous

dehydration

anhydrate

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

14

Tong and Zografi. J Pharm Sci. 2001, 90, 1991-2004 XRPD powder patterns of mixtures after storage at 4 °C for 14 months

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

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

16 http://www2.ul.ie/pdf/269374500.pdf

Supercritical Fluid

17

Kakamanu and Bansal. Business Briefing: Labtech 2004, 1-4

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

Gas Tc ( °C) Pc (MPa)

H2O 374 22

Xe 16.6 5.9

SF6 45.5 3.8

N2O 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

Supercritical Fluids

18

CO2 tank

CO2 pump

Drug Soln Drug Pump

CO2 cooler

Pressure Gage

Vessel Heat Circulator

Back Pressure Regulator

Nozzle

Jo et al. Controlled Release Society 29th Annual Meeting Proceedings 2002

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

Pasquali et al. Adv Drug Delivery Rev, 2008, 60, 399-410

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 resulted in amorphous material • Amorphous “frozen” after particle

generation prevented crystallization

19

http://www.futurechemtech.com/data/New%20Solid%20State%20Morphology%20of%20Particles%20Prepared%20by%20a%20SCF%20Process.pdf

Sample b

Amorphous Screening

Solvent methods • Evaporation

• Cooling

• Antisolvent addition

• Lyophilization

• Supercritical fluid

• Etc

• Parameters to investigate – Solvent, concentration, cooling

rates, evaporation rates, addition rates, etc

Nonsolvent methods

• Melt quench

• Grinding

• Desolvation

• Compression

20

Manual • Solvent and nonsolvent methods should be included

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

21

http://www.labconco.com/_scripts/EditItem.asp?ItemID=920 http://www.labconco.com/_scripts/editc25.asp?catid=87

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

26 Thayer. C&E News, 2010, 88, 13-27

Spray Drying

27 http://en.wikipedia.org/wiki/File:SDXFamily1.JPG

• 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

Spray Drying 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

28

Laboratory scale

Large scale

http://en.wikipedia.org/wiki/File:Labspraydryer.svg

Dobry et al. J Pharm Innov. 2009, 4, 133-142

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

29

Dobry et al. J Pharm Innov. 2009, 4, 133-142

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

30

Dobry et al. J Pharm Innov. 2009, 4, 133-142

Spray Drying

Effect of processing parameters on manufacturing

31

Cal et al. J Pharm Sci. 2010, 99, 575-586

Spray Drying • Need to optimize parameters for process

– Design of experiments (DOE), Quality by Design (QbD), etc

32 Dobry et al. J Pharm Innov. 2009, 4, 133-142

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

33 Dobry et al. J Pharm Innov. 2009, 4, 133-142

High speed images of pressure-nozzle 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

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

34

Tray drying Fluid bed drying

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

36

http://www.intelence-info.com/about-intelence/about-intelence ; http://www.natap.org/2008/Pharm/Pharm_07.htm

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

Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117 37

Extrusion channel

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

Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117

38

Single screw extruder

Melt Extrusion

Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117 39

Single screw extruder

Extrusion channel

Extrusion channel contains three parts • Feed section

– Material fed from hopper into extruder

• Transition or compression section – A solid plug mixed,

compressed, melted, plasticized

• Metering section – Homogeneous plastic melt is extruded at a

uniform delivery rate

Melt Extrusion

Twin screw extruder • 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

40 Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117; Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926

• 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

• Variety of die plates to alter extrudate diameter

• Throughput 0.5-3 kg /hr

• Diameter of 16-18 mm and a length of 4-10X the diameter • Throughput: 0.5-3 kg/h

Co-rotating twin-screw

Counter-rotating twin-screw

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

41 Breitenbach. Europ J Pharm Biopharm. 2002, 54, 107-117; Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926

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

42 Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926

acrylates

HPMCAS

HPMC

cellulose derivatives

PVP

PEG

PEO

HPC

PVA

PVP/VA HPMCP

CAP

Melt Extrusion

Examples of drug substances processed by HME

43 Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926

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 – Pellets, films, etc

• Can also be formulated – Capsules – Tablets

44

Pelletizer used to chop rod shaped extrudates into pellets or granules

Crowley et al. Drug Dev Ind Pharm. 2007, 33, 909-926

Film assembly

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, 575-

586 • Sollohub et al. J Pharm Sci 2010, 99,

587-597 • Vehring Pharm Res. 2008, 25, 999-

1022 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