Challenges in API Form Control Case Study Examples 2012/PDF...Challenges in API Form Control Case Study Examples Piotr (Peter) Karpinski, Ph.D., D.Sc. Salt & Polymorphism and Particle

Challenges in API Form Control Challenges in API Form Control Case Study ExamplesCase Study Examples

Piotr (Peter) Karpinski, Ph.D., D.Sc.Salt & Polymorphism and Particle EngineeringSalt & Polymorphism and Particle Engineering

Novartis Pharmaceuticals Corp., USANovartis Pharmaceuticals Corp., USA

CF@Bo1919--21 January 2012, Bologna, Italy21 January 2012, Bologna, Italy

Contents of Presentation

�� IntroductionIntroduction�� Abundance of forms of APIAbundance of forms of API

Pursuing the right / desired crystalline Pursuing the right / desired crystalline �� Pursuing the right / desired crystalline Pursuing the right / desired crystalline form in manufacturing of APIsform in manufacturing of APIs�� Case study examplesCase study examples

�� Conclusions and own opinionsConclusions and own opinions

Properties of APIs

� structure/stoichiometry structure/stoichiometry �� polymorphpolymorph

Examples of specific properties targeted Examples of specific properties targeted in API manufacturingin API manufacturing

�� solvate/hydratesolvate/hydrate�� chemical purity chemical purity levellevel�� residual solvent levelresidual solvent level�� crystal morphology crystal morphology �� degree of agglomerationdegree of agglomeration�� crystal size and crystal size distributioncrystal size and crystal size distribution

Monomorphic free acid (FA)Monomorphic free acid (FA)Monomorphic free base (FB)Monomorphic free base (FB)Monomorphic neutral form (NF) Monomorphic neutral form (NF) Salts of FA and FBSalts of FA and FB

Pharmaceuticals (APIs) offer many opportunities (and even more challenges)

CoCo--crystals of FA, FB, NF, or saltcrystals of FA, FB, NF, or saltHydrates of FA, FB, NF, salt, or coHydrates of FA, FB, NF, salt, or co--crystal crystal Solvates of FA, FB, NF, salt, or coSolvates of FA, FB, NF, salt, or co--crystalcrystalPolymorphs of the abovePolymorphs of the aboveAmorphous FA, FB, NF, salt, or coAmorphous FA, FB, NF, salt, or co--crystalcrystal

Pharmaceuticals are more difficult to crystallize than common bulk chemicals!

� abundance of possible API formsabundance of possible API forms

�� different stoichiometry possible different stoichiometry possible �� polymorphism and solvatomorphismpolymorphism and solvatomorphismpolymorphism and solvatomorphismpolymorphism and solvatomorphism�� larger moleculeslarger molecules�� flexible molecules flexible molecules �� structurally related impuritiesstructurally related impurities�� no specialized equipmentno specialized equipment

Batch Manufacture of API Salt

Salt Forming Salt Forming Agent Agent solutionsolution

FFFF solutionsolution

Seeding and slowly cooling suspension

Adding antisolvent and cooling to final temperature

filtrationfiltrationdryingdrying

crystalline product

Case Study Examples

�� APIAPI--11�� pursuing 1:1 pursuing 1:1 stoichiometrystoichiometry for a salt (for which also for a salt (for which also

1:1.5, and 1:2 ratios of 1:1.5, and 1:2 ratios of free free basebase::acidacid are possible)are possible)

�� APIAPI--22�� pursuing the most thermodynamically stable pursuing the most thermodynamically stable pursuing the most thermodynamically stable pursuing the most thermodynamically stable

polymorphpolymorph (two stable and one metastable (two stable and one metastable polymorphs are known)polymorphs are known)

�� APIAPI--33�� pursuing a stable pursuing a stable coco--crystal formcrystal form

�� APIAPI--44�� coping with 8 polymorphs and an overwhelming coping with 8 polymorphs and an overwhelming

solvent effectsolvent effect

�� StoichiometryStoichiometry is essential for those is essential for those ionizableionizable polyvalent polyvalent APIs that form salts, as well as for coAPIs that form salts, as well as for co--crystals, hydrates, crystals, hydrates, and solvates. and solvates.

�� StoichiometryStoichiometry defines chemical purity of such APIs.defines chemical purity of such APIs.�� Also, stoichiometry defines properties of such APIs in a Also, stoichiometry defines properties of such APIs in a

Pursuing Right Stoichiometry

�� Also, stoichiometry defines properties of such APIs in a Also, stoichiometry defines properties of such APIs in a similar fashion as polymorphism does.similar fashion as polymorphism does.

�� Whenever different Whenever different stoichiometricstoichiometric ratios of API are possible, ratios of API are possible, only only stoichiometricallystoichiometrically pure phases must be targeted.pure phases must be targeted.

�� Pursuing the right stoichiometry for salts / coPursuing the right stoichiometry for salts / co--crystals may crystals may require careful control of the require careful control of the basebase::acidacid / / API:coAPI:co--crystalcrystalformerformer ratio throughout the course of the API manufacturing ratio throughout the course of the API manufacturing process, and may necessitate the use of nonstoichiometric process, and may necessitate the use of nonstoichiometric amount (excess) of salt forming agent / coamount (excess) of salt forming agent / co--crystal former crystal former

Background:

�� TheThe onlyonly knownknown anhydrousanhydrous monohydrochloridemonohydrochloride saltsalt ofofAPIAPI--11,, nonhygroscopicnonhygroscopic andand meltingmelting atat 215215 °°C,C, isisscheduledscheduled forfor manufacturemanufacture ofof aa 3030--kgkg batchbatch

Case Study: Pursuing Salt Stoichiometry

scheduledscheduled forfor manufacturemanufacture ofof aa 3030--kgkg batchbatch�� InIn oneone ofof thethe lastlast--stagestage scalescale--upup trials,trials, somethingsomething wentwent

wrong,wrong, andand differentdifferent productproduct morphologymorphology isis obtainedobtained......

usualusual �� differentdifferent ��

ImmediateImmediate objectiveobjective::

�� DetermineDetermine aa rootroot causecause ofof thethe productproductdifferencedifference..


�� DevelopDevelop aa robustrobust processprocess forformanufacturemanufacture ofof thethe targetedtargetedanhydrousanhydrous monomono--HClHCl saltsalt..

�� DevelopDevelop aa remediateremediate processprocess inin casecasethethe aboveabove targettarget isis missedmissed..

BKM120-H050906

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BKM120-H050907

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Typical process Unexpected resultsTypical process Unexpected results


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Time, h

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2Turbidity

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0 1 2 3 4 5 6 7 8

Time, h

0

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4

Turbidity

1.5-HCl

1.34% at 60C3.77% at 120C

9.67% at 180C

77.77°C

40.19°C

155.74°C

208.84°C

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Sample: BKM120-H050904Size: 3.3808 mg

Comment: Investigation of white portion in the batch

TGA-DTAFile: L:...\BKM10_AA\BKM120-H050904.001Operator: AARun Date: 17-Jul-09 13:25Instrument: 2960 SDT V3.0F


TGA-DTA thermograms of HCl salts of API-1:• monomono--HCl HCl –– anhydrous (the target)anhydrous (the target)• sesqui-HCl - monohydrate• di-HCl - sesquihydrate

di-HCl

mono-HCl

77.77°C

0.1

75

0 50 100 150 200 250 300

Temperature (°C)Exo Up Universal V3.9A TA Instruments

0.1438% 150 C

214.78°C

231.70°C

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Temperature (°C)

Sample: AAA-Size: 7.5162 mg

Comment: 10 AAA FSC batch

TGA-DTAFile: L:...\ -AAA- .Operator: LWRun Date: 18-Feb-09 13:34Instrument: 2960 SDT V3.0F

Exo Up Universal V3.9A TA Instruments

37.86°C

73.41°C

162.49°C

213.36°C

1.582% at 60C(0.1369mg)

5.112% at 120C(0.4422mg)

10.15% at 175C(0.8785mg)

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/ mg)

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Temperature (°C)

Sample: -di HCl

Size: 8.6509 mg

Comment: 0903-1

TGA-DTAFile: -RYU0903-1 start mat di HCl.001Operator: mdlcRun Date: 3-Aug-09 10:52Instrument: 2960 SDT V3.0F


concentration

Temp. (ºC)


Acidity1 eq. HCl 1.07 eq. HCl

FBconcentration

FB⋅HCl solubility

FB⋅2HCl solubility

A B


play

(A) FB + HCl � FB⋅HCl↓

(B) FB + 2HCl � FB⋅2HCl↓

(C) FB⋅2HCl+ FB � 2FB⋅HCl

C

SesquiSesqui-- andand didi--HClHCl saltssalts werewere discovereddiscovered andand characterizedcharacterized

HClHCl overchargeovercharge combinedcombined withwith lowerlower solubilitysolubility ofof didi--HClHCl saltsalt vsvs..monomono--HClHCl saltsalt werewere thethe rootroot causescauses ofof thethe changechange ofof thethe productproduct

TheThe originallyoriginally selectedselected anhydrousanhydrous monomono--HClHCl saltsalt hashas thethe bestbestphysicochemicalphysicochemical propertiesproperties profileprofile outout ofof thethe threethree HClHCl salts,salts, andandshouldshould remainremain thethe formform ofof choicechoice..


shouldshould remainremain thethe formform ofof choicechoice..

DiscoveryDiscovery ofof thethe potentialpotential forfor concomitantconcomitant formationformation ofof didi--HClHCl saltsaltinin thethe currentcurrent processprocess atat thethe lablab scale,scale, hashas preparedprepared usus toto preventpreventthisthis problemproblem fromfrom occurringoccurring unexpectedlyunexpectedly atat aa manufacturingmanufacturingscale,scale, byby implementingimplementing thethe followingfollowing countermeasurescountermeasures::

EnsuringEnsuring –– viavia properproper inin--processprocess controlcontrol ––̶̶ thatthat therethere isis nono excessexcess HClHCloverover thethe stoichiometricstoichiometric freefree basebase--toto--HClHCl ratioratio correspondingcorresponding toto 11::11

PayingPaying particularparticular attentionattention toto thethe qualityquality (phase(phase purity)purity) ofof thethe seedseedmaterialmaterial usedused..

�� Polymorphism Polymorphism and/or and/or solvatomorphismsolvatomorphism occur in 85% of APIsoccur in 85% of APIs. . �� As a rule, the most thermodynamically As a rule, the most thermodynamically stable polymorph stable polymorph of of

an API should be targeted.an API should be targeted.�� Pursuing right polymorph requires understanding of solubilityPursuing right polymorph requires understanding of solubility--

MSZW diagrams and careful control of various operational MSZW diagrams and careful control of various operational

Pursuing Right Polymorph

MSZW diagrams and careful control of various operational MSZW diagrams and careful control of various operational parameters throughout the course of the API manufacturing parameters throughout the course of the API manufacturing process, and may necessitate the use of pureprocess, and may necessitate the use of pure--phase seeds.phase seeds.

�� EnantiotropicEnantiotropic systems systems offer a particular challenge: offer a particular challenge:

BackgroundBackground::

�� TheThe onlyonly knownknown polymorphpolymorph ofof APIAPI--22isis FormForm A,A, meltingmelting atat 173173 °°CC andand

Case Study: Pursuing a Specific Polymorph

isis FormForm A,A, meltingmelting atat 173173 °°CC andandnonhygroscopicnonhygroscopic..

�� AA 1515--kgkg batchbatch ofof FormForm AA waswasmanufacturedmanufactured..

�� InIn preparationpreparation toto thethe nextnext batch,batch, ininlaboratorylaboratory scalescale--upup trials,trials, aa newnewFormForm BB isis discovereddiscovered..

ImmediateImmediate objectiveobjective::

�� PerformPerform fullfull physicochemicalphysicochemical characterizationcharacterizationofof thethe newlynewly discovereddiscovered FormForm BB..


ofof thethe newlynewly discovereddiscovered FormForm BB..�� Determine,Determine, whichwhich formform AA oror BB isis moremore stablestable..�� IfIf FormForm BB isis aa moremore stablestable form,form, developdevelop

aa reliablereliable processprocess toto produceproduce FormForm BB..


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35302520151052-Theta (deg)

35302520151052-Theta (deg)

158 .46°C 173.44°C

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t Flo

w (m

W)

40 60 80 100 120 140 160 180 200 220Temperature (°C)

Sample: THF 25C 48hrsSize: 0.0000 mg

Comment: equil THF 48hrs

DSCFile: L:...\ \ EQUIL THF 48HR.001Operator: tsgRun Date: 12-May-09 17:50Instrument: DSC Q1000 V9.9 Build 303


Form BForm A

�� InIn thethe competitivecompetitive slurryingslurrying equilibrationequilibrationexperiments,experiments, aa spontaneousspontaneous conversionconversion ofof thetheoriginaloriginal FormForm AA materialmaterial toto FormForm BB waswasobservedobserved inin solventssolvents inin whichwhich thethe APIAPI hashas


observedobserved inin solventssolvents inin whichwhich thethe APIAPI hashasnoticeablenoticeable solubilitysolubility..

�� AA competitivecompetitive slurryingslurrying experimentexperiment withwith aa 11::11mixturemixture ofof FormForm AA andand BB waswas performedperformed ininMTBE,MTBE, aa lowlow--solubilitysolubility solventsolvent forfor APIAPI--22.. AAcompletecomplete conversionconversion AA �� BB stillstill occurredoccurred inin

�� KineticallyKinetically slowslow processes,processes, suchsuch asas slowslowcrystallizationcrystallization fromfrom allall solventssolvents investigatedinvestigatedandand slurryingslurrying equilibrationsequilibrations inin certaincertainsolventssolvents producedproduced FormForm BB..

�� ToTo thethe contrary,contrary, kineticallykinetically fastfast processes,processes,


�� ToTo thethe contrary,contrary, kineticallykinetically fastfast processes,processes,withwith fastfast supersaturationsupersaturation rate,rate, suchsuch asasantisolventantisolvent addition,addition, producedproduced FormForm AA..

�� FormForm BB hashas aa slowerslower formationformation kineticskinetics andand‘‘catalyzescatalyzes’’ thethe conversionconversion ofof FormForm AA toto BB..Therefore,Therefore, FormForm BB isis moremore stablestable andand shouldshouldbebe targetedtargeted forfor futurefuture developmentdevelopment..


P21/c Density: 1.360 P-1 Density: 1.374

LED243-3114-43_01.raw

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ETOAc-slurry_01.raw

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Form A Form B


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Run History for API-2: Turbidity and Temperature v s. Time

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Form A

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Material in (g) Operation (g) Material out

A5 (Form A) 4 AddA5 (Form B) 0.004 Add

acetone 18.96 Add, StirHeat to 35 °C

↓Stir for 2 h

PSCPSC↓

Cool to 0 °C over 3 hStir for 1 h at 0°C

↓Filter

acetone 3.2 Wash 20 Acetone

↓

Dry the wet cake at 60°C overnight 3.8 A5 (Form B)

2.364 Acetone loss to vacuum

Total input 26.164 26.164 Total output

AlthoughAlthough coco--crystalscrystals cancan bebe easilyeasily obtainedobtained viaviagrinding,grinding, theythey maymay notnot bebe easilyeasily (co(co--)crystallized)crystallizedfromfrom solutionsolution

LowLow throughputthroughput duedue toto lowlow solubilitysolubility (too(too dilutedilutesolution,solution, largelarge coco --crystallizationcrystallization equipment)equipment)

Potential Issues in Manufacture of Co-crystals

solution,solution, largelarge coco --crystallizationcrystallization equipment)equipment)

LowLow yieldyield

ComplexComplex processprocess

VariableVariable stoichiometrystoichiometry

PolymorphismPolymorphism

BatchBatch--toto--batchbatch variabilityvariability

OtherOther scalescale--upup issuesissues26

Case Study:Co-crystal form and manufacturability options

BackgroundBackground ::

�� APIAPI--3 is neutral and amorphous3 is neutral and amorphous�� At a small lab scale, APIAt a small lab scale, API--3 was easily 3 was easily

coco --crystallized with glycine (1:1)crystallized with glycine (1:1)coco --crystallized with glycine (1:1)crystallized with glycine (1:1)�� The monoglycine coThe monoglycine co--crystal melts around crystal melts around

150 ºC and based on initial characterization 150 ºC and based on initial characterization seems to have acceptable propertiesseems to have acceptable properties

27

BackgroundBackground (continued):(continued):

�� TheThe initialinitial coco--crystallizationcrystallization processprocess isis farfar fromfrombeingbeing acceptableacceptable::


((......)) TheThe startingstarting materials,materials, ii..ee..,, APIAPI--33 andand glycine,glycine, inin 11::11molarmolar ratio,ratio, werewere refluxedrefluxed inin ethanolethanol atat 9090 ºCºC forfor oneonehourhour.. TheThe resultingresulting gummygummy pastepaste waswas stirredstirred ininhexanehexane forfor 55 hourshours toto getget thethe powderpowder.. ((......))

28

Task:Task:

�� Further characterize the coFurther characterize the co--crystalcrystal�� Ensure fixed stoichiometryEnsure fixed stoichiometry�� Develop a scalable processDevelop a scalable process


�� Develop a scalable processDevelop a scalable process�� ULIMATELY: Ensure API supply for toxicology ULIMATELY: Ensure API supply for toxicology

and early clinical studiesand early clinical studies

29

New process developmentNew process development ::

�� CharacterizationCharacterization ofof differentdifferent smallsmall--scalescale laboratorylaboratorybatchesbatches revealedrevealed inconsistentinconsistent APIAPI33--toto--glycineglycine ratioratio

�� 11::22 (API(API--33::glycine)glycine) coco --crystalcrystal hashas beenbeen discovereddiscovered


�� 11::22 (API(API--33::glycine)glycine) coco --crystalcrystal hashas beenbeen discovereddiscovered

�� 11::22 (API(API--33::glycine)glycine) coco--crystalcrystal hashas appearedappeared toto havehavebetterbetter propertiesproperties thanthan originallyoriginally foundfound 11::11 coco--crystalcrystal

�� MoreMore robustrobust processprocess proposedproposed::

““dissolvedissolve APIAPI--33 andand glycineglycine ((11::22 molarmolar ratio)ratio) inin ethanolethanol--waterwater atat roomroom temperature,temperature, andand addadd isopropylisopropyl acetateacetate totocrystallizecrystallize 11::22 coco--crystalscrystals””

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nts)

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Polymorph B (di-glycine)

Forms of glycine coForms of glycine co--crystal of APIcrystal of API--33

31Case Study:

Co-crystal form and manufacturability options

0

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3 10 20 30

Monoglycine cocrystal

Hydrate (di-glycine)

Polymorph A (di-glycine)

diglycine co-crystal was selected for further development

Polymorphs of diglycine coPolymorphs of diglycine co--crystal of APIcrystal of API--33

Polymorph A Polymorph A (TGA(TGA--DTA)DTA) Polymorph B Polymorph B (DSC) (DSC)


32

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Adsorption/Desorption IsothermAdsorption1 Desorption1

Polymorph APolymorph A

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Adsorption/Desorption IsothermAdsorption1 Desorption1

Polymorph BPolymorph B


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Samp RH (%)Data Collection Started: 3/7/2011, 10:36 AM

Sample Name: LIK066-BYB 3216-119-21 acidSample Lot: 3216-119-21 /05.1

File Name: LIK066-4.IshOperator: LFeng

Instrument: VTI-SAS/N: ProTA

Critical RH for Critical RH for Polymorph A to Polymorph A to form hydrateform hydrate

Both samples became deliquescent at higher humidity Both samples became deliquescent at higher humidity and then solidify into monoglycine coand then solidify into monoglycine co--crystalcrystal

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Samp RH (%)Data Collection Started: 3/3/2011, 04:17 PMSample Name: LIK066-BYB polymorph B

Sample Lot: 1051001File Name: LIK066-3.Ish

Operator: LFengInstrument: VTI-SA

S/N: ProTA

33

Before equilibration

After equilibration

Condition

A+B A in acetone @ r.t. or 50 °°°°C, 24 h

A+B Mostly A in acetonitrile @ r.t., 24 h


A+B A in acetonitrile @ 50 °°°°C, 24 h

A A in ethanol @ r.t., 48 h

B A + B in ethanol @ r.t., 48 h

Competitive slurry equilibration study indicates Competitive slurry equilibration study indicates that polymorph A is thermodynamically more stablethat polymorph A is thermodynamically more stable

34

•• Two anhydrous polymorphs A and B, and one hydrate have been Two anhydrous polymorphs A and B, and one hydrate have been identified. The hydrate is unstable below 50% relative humidity. identified. The hydrate is unstable below 50% relative humidity.

•• Both anhydrous polymorphs are moderately hygroscopic below Both anhydrous polymorphs are moderately hygroscopic below 50% RH, and eventually deliquesce. Both polymorphs are needle50% RH, and eventually deliquesce. Both polymorphs are needle--shaped crystalline materials with comparable intrinsic dissolution shaped crystalline materials with comparable intrinsic dissolution rates in aqueous media.rates in aqueous media.


rates in aqueous media.rates in aqueous media.•• Both anhydrous polymorphs dissociate in water and convert into Both anhydrous polymorphs dissociate in water and convert into

amorphous free form, which results in the same solubility at amorphous free form, which results in the same solubility at equilibrium. equilibrium.

•• Polymorph B converted to polymorph A in the mixed polymorph Polymorph B converted to polymorph A in the mixed polymorph equilibration experiments at room temperature and at 50 equilibration experiments at room temperature and at 50 ooCC, , indicating that indicating that polymorph A is thermodynamically more stablepolymorph A is thermodynamically more stableof the two. of the two.

35

Polymorph selection of diglycine co-crystal of API-3

PropertyProperty Polymorph APolymorph A Polymorph BPolymorph B

Stability stable below 50% RHstable below 50% RH stablestable


Hygroscopicity slight below 50% RHslight below 50% RHhigh for RH>75%high for RH>75%

slight up to 75% RHslight up to 75% RH

Thermodynamic stability more stablemore stable less stableless stable

Ease of API manufacture easier and more robusteasier and more robust more complex, less more complex, less robustrobust

Ease of DP manufacture requires humidity requires humidity control

�� In competitive In competitive slurryingslurrying equilibration, equilibration, mixture of polymorphs is placed in a mixture of polymorphs is placed in a solvent in which all forms have certain solvent in which all forms have certain solubility. Eventually, in hours or days, the solubility. Eventually, in hours or days, the

Solvent Effect Solvent Effect in Polymorphism

solubility. Eventually, in hours or days, the solubility. Eventually, in hours or days, the suspension is composed of a single most suspension is composed of a single most thermodynamically stable polymorphthermodynamically stable polymorph

�� The result of The result of competitive competitive slurryingslurryingequilibration should not depend on a equilibration should not depend on a solvent choice, as long as each polymorph solvent choice, as long as each polymorph of the mixture has a nonof the mixture has a non--zero solubility in a zero solubility in a given solventgiven solvent

BackgroundBackground: :

The first pilot plant batch was produced and The first pilot plant batch was produced and designated as polymorph A.designated as polymorph A.In about 3 weeks, the XRPD pattern of the material In about 3 weeks, the XRPD pattern of the material

produced has changed to a new pattern (A produced has changed to a new pattern (A �� B).B).

CASE STUDY:Which polymorph to develop?

produced has changed to a new pattern (A produced has changed to a new pattern (A �� B).B).In a comprehensive polymorph screening, six new In a comprehensive polymorph screening, six new

modifications were identified (C, D, E, F, G, and H).modifications were identified (C, D, E, F, G, and H).

TaskTask: :

Determine, which form, out of eight known, should Determine, which form, out of eight known, should be selected for further development.be selected for further development.

Path ForwardPath Forward: :

Produce multigram quantities of the new forms Produce multigram quantities of the new forms (C to H)(C to H)


(C to H)(C to H)Fully characterize all formsFully characterize all formsDetermine relative stability of the formsDetermine relative stability of the formsSelect the most stable form, preferably based on Select the most stable form, preferably based on

competitive slurry equilibration study.competitive slurry equilibration study.

Interim findingsInterim findings: :

All eight distinct crystalline forms A to H, seem to exhibit All eight distinct crystalline forms A to H, seem to exhibit identical infrared spectra, indicating identical hydrogen identical infrared spectra, indicating identical hydrogen bonding patterns and close similarities in conformations. bonding patterns and close similarities in conformations. For this highly flexible molecule, polymorphic differences For this highly flexible molecule, polymorphic differences


For this highly flexible molecule, polymorphic differences For this highly flexible molecule, polymorphic differences are most likely due to varying packing arrangements and, are most likely due to varying packing arrangements and, perhaps, small conformational differences that are perhaps, small conformational differences that are undetected by infrared spectroscopy. undetected by infrared spectroscopy.

Modifications D and E are unstable: they spontaneously Modifications D and E are unstable: they spontaneously convert to modifications F and C, respectively, in around convert to modifications F and C, respectively, in around two months, at room temperature.two months, at room temperature.

G

H

Amorphous

CASE STUDY:Unusual solvent-directed polymorphic transformations

All forms are not solvates or hydrates

2-theta-scale

Lin

(Cou

nts)

A

B

C

Form HForm HForm CForm C

Form BForm B

Ethanol

Acetone

CASE STUDY:Results of competitive slurry equilibration

Form GForm G

Form BForm B

MeC

N

1004.7

1004.8

1004.9

1005.0

Pea

k po

siti

on (

cm-1

)

form H

B HEthanol

CASE STUDY:In situ Raman monitoring (1)

1004.2

1004.3

1004.4

1004.5

1004.6

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form A

Time (mins.)

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1003.4

1003.6

1003.8Form G

Pea

k po

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B GAcetonitrile

CASE STUDY:In situ Raman monitoring (2)

1002.0

1002.2

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1003.0

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Form B

AllAll formsforms areare microcrystallinemicrocrystallineandand nono suitablesuitable singlesingle crystalcrystalofof anyany polymorphpolymorph isis availableavailable


Form AForm A

Form BForm B Form GForm G

Two mechanisms can account for polymorphic Two mechanisms can account for polymorphic transformations in solution: transformations in solution:

(I) interconversion, accomplished by partial (I) interconversion, accomplished by partial dissolution of the solid particles and subsequent dissolution of the solid particles and subsequent


dissolution of the solid particles and subsequent dissolution of the solid particles and subsequent nucleation and precipitation of the new form, nucleation and precipitation of the new form, (II) interconversion occurring without dissolution (II) interconversion occurring without dissolution of the solid particles (solid state transformation).of the solid particles (solid state transformation).

For APIFor API--4, mechanism (I) dominates; only 4, mechanism (I) dominates; only transformation Btransformation B��A is a solidA is a solid--state relaxation.state relaxation.

PuzzlePuzzle:

DueDue toto thethe overwhelmingoverwhelming solventsolvent effect,effect, thethe usualusualthermodynamicthermodynamic stabilitystability rankingranking ofof thethe polymorphs,polymorphs,deduceddeduced fromfrom thethe competitivecompetitive slurryslurry equilibrationequilibrationexperimentsexperiments withwith mixturesmixtures ofof polymorphs,polymorphs, appearedappeared


experimentsexperiments withwith mixturesmixtures ofof polymorphs,polymorphs, appearedappearedtoto bebe ofof limitedlimited benefitbenefit..TheThe solventsolvent seemsseems toto inhibitinhibit crystallizationcrystallization ofof certaincertainformsforms andand promotepromote crystallizationcrystallization ofof otherother form(s)form(s)..

Conclusions

�� In order to avoid lateIn order to avoid late--stage development stage development surprises, only thermodynamically most stable, surprises, only thermodynamically most stable, thoroughly characterized, biothoroughly characterized, bio--pharmaceutically pharmaceutically acceptable, and scalable API forms should be acceptable, and scalable API forms should be acceptable, and scalable API forms should be acceptable, and scalable API forms should be developed. developed.

All these imperatives necessitate a very All these imperatives necessitate a very significant research and development effort.significant research and development effort.

�� ScaleupScaleup of API crystallization process may of API crystallization process may result not only in different CSD and crystal result not only in different CSD and crystal properties but also in a properties but also in a different API form different API form -- due due to the fact that hydrodynamics, mixing, and to the fact that hydrodynamics, mixing, and

Conclusions - continued

crystallization kinetics scale up in a nonlinear crystallization kinetics scale up in a nonlinear and dissimilar fashion. and dissimilar fashion.

�� ScaleupScaleup itself should be considered in the itself should be considered in the context of the entire process: wellcontext of the entire process: well--designed designed experiments and thorough API characterization experiments and thorough API characterization at the bench scale enable success at the large at the bench scale enable success at the large scale. scale.

Conclusions - continued

�� Successful manufacture of the targeted form of API at Successful manufacture of the targeted form of API at a larger scale requires a thorough understanding of a larger scale requires a thorough understanding of API properties, inAPI properties, in--depth knowledge of crystallization,depth knowledge of crystallization,and downstreamand downstream processing unit processing unit operationsoperations, such as , such as filtration and drying, as well as significant scale up filtration and drying, as well as significant scale up filtration and drying, as well as significant scale up filtration and drying, as well as significant scale up efforts. efforts.

�� Automation, robotics, and parallel reactors employed Automation, robotics, and parallel reactors employed in the laboratory stage lead to a more robust in the laboratory stage lead to a more robust crystallization process and, ultimately, facilitate crystallization process and, ultimately, facilitate pursuing of API form. Similarly, deploying inpursuing of API form. Similarly, deploying in--line line technology (PAT) to monitor process performance at technology (PAT) to monitor process performance at various scales will improve robustness.various scales will improve robustness.

Acknowledgements

�� Dario and PolyCrystalLineDario and PolyCrystalLine

�� AudienceAudience�� AudienceAudience

�� Particle Engineers from NovartisParticle Engineers from Novartis--US:US:

Dimitris Papoutsakis, Jerzy Budz, Anthony Dimitris Papoutsakis, Jerzy Budz, Anthony DiJulio, Anju Mahesh, Lili Feng, Tanise DiJulio, Anju Mahesh, Lili Feng, Tanise ShattockShattock--Gordon, and Jianli YuGordon, and Jianli Yu

Documents

Challenges in API Form Control Case Study Examples 2012/PDF...Challenges in API Form Control Case Study Examples Piotr (Peter) Karpinski, Ph.D., D.Sc. Salt & Polymorphism and Particle