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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
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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
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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
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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
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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
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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
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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
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�� 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
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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 ��
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ImmediateImmediate objectiveobjective::
�� DetermineDetermine aa rootroot causecause ofof thethe
productproductdifferencedifference..
Case Study: Pursuing Salt Stoichiometry
�� DevelopDevelop aa robustrobust processprocess
forformanufacturemanufacture ofof thethe
targetedtargetedanhydrousanhydrous monomono--HClHCl saltsalt..
�� DevelopDevelop aa remediateremediate processprocess inin
casecasethethe aboveabove targettarget isis missedmissed..
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BKM120-H050906
20
30
40
50
60
70
80
90
100
T (
°C)
or T
urbi
dity
(%
)
4
6
8
10
12
14
16
Dosing V
olume (m
l)
Dosing volume
Tj
Tr
BKM120-H050907
30
40
50
60
70
80
90
100
T (
°C)
or T
urbi
dity
(%
)
4
6
8
10
12
14
16
Dosing V
olume (m
l)
Dosing volume
Tj
Tr
Typical process Unexpected resultsTypical process Unexpected
results
Case Study: Pursuing Salt Stoichiometry
0
10
20
0 1 2 3 4 5 6 7 8 9
Time, h
0
2Turbidity
0
10
20
0 1 2 3 4 5 6 7 8
Time, h
0
2
4
Turbidity
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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
0.2
0.3
0.4
0.5
Tem
pera
ture
Diff
eren
ce (
°C/m
g)
80
85
90
95
100
Wei
ght (
%)
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
Case Study: Pursuing Salt Stoichiometry
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
-0.15
-0.10
-0.05
0.00
0.05
0.10
Tem
pera
ture
Diff
eren
ce
(°C/m
g )
85
90
95
100
105
Wei
ght (%
)
0 50 100 150 200 250 300
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)
0.00
0.05
0.10
0.15
Tem
pera
ture
Diff
eren
ce ( °C
/ mg)
85
90
95
100
Wei
ght (
%)
0 50 100 150 200 250 300
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
Exo Up Universal V3.9A TA Instruments
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concentration
Temp. (ºC)
Case Study: Pursuing Salt Stoichiometry
Acidity1 eq. HCl 1.07 eq. HCl
FBconcentration
FB⋅HCl solubility
FB⋅2HCl solubility
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Case Study: Pursuing Salt Stoichiometry
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A B
Case Study: Pursuing Salt Stoichiometry
play
(A) FB + HCl � FB⋅HCl↓
(B) FB + 2HCl � FB⋅2HCl↓
(C) FB⋅2HCl+ FB � 2FB⋅HCl
C
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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..
Case Study: Pursuing Salt Stoichiometry
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..
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�� 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:
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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..
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ImmediateImmediate objectiveobjective::
�� PerformPerform fullfull physicochemicalphysicochemical
characterizationcharacterizationofof thethe newlynewly
discovereddiscovered FormForm BB..
Case Study: Pursuing a Specific Polymorph
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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Case Study: Pursuing a Specific Polymorph
50
100
150
200
250
300
350
400
450
50
100
150
200
250
300
35302520151052-Theta (deg)
35302520151052-Theta (deg)
158 .46°C 173.44°C
-20
-15
-10
-5
0
Hea
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
Exo Up Universal V3.9A TA Instruments
Form BForm A
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�� 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
Case Study: Pursuing a Specific Polymorph
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
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�� 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,
Case Study: Pursuing a Specific Polymorph
�� 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..
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Case Study: Pursuing a Specific Polymorph
P21/c Density: 1.360 P-1 Density: 1.374
LED243-3114-43_01.raw
35302520151052-Theta (deg)
50
100
150
200
250
300
350
400
450
ETOAc-slurry_01.raw
35302520151052-Theta (deg)
50
100
150
200
250
300
Form A Form B
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Case Study: Pursuing a Specific Polymorph
25
30
35
40
80
100
120
T, °° °°C
Tu
rbid
ity
Va
lue
, %
Run History for API-2: Turbidity and Temperature v s. Time
Tr
Form A
-5
0
5
10
15
20
0
20
40
60
0 1 2 3 4 5 6 7
T,
°° °°
Tu
rbid
ity
Va
lue
, %
Time, h
Turbidity
Form B
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Case Study: Pursuing a Specific Polymorph
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
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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
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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
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BackgroundBackground (continued):(continued):
�� TheThe initialinitial coco--crystallizationcrystallization
processprocess isis farfar fromfrombeingbeing
acceptableacceptable::
Case Study:Co-crystal form and manufacturability options
((......)) 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
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Task:Task:
�� Further characterize the coFurther characterize the
co--crystalcrystal�� Ensure fixed stoichiometryEnsure fixed
stoichiometry�� Develop a scalable processDevelop a scalable
process
Case Study:Co-crystal form and manufacturability options
�� 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
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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
Case Study:Co-crystal form and manufacturability options
�� 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””
30
-
Lin
(Cou
nts)
20
30
40
50
60
70
80
90
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
10
2-Theta - Scale
3 10 20 30
Monoglycine cocrystal
Hydrate (di-glycine)
Polymorph A (di-glycine)
diglycine co-crystal was selected for further development
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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)
Case Study:Co-crystal form and manufacturability options
32
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10.000
15.000
20.000
25.000
We
igh
t (%
ch
g)
Adsorption/Desorption IsothermAdsorption1 Desorption1
Polymorph APolymorph A
20.000
25.000
30.000
35.000
Weig
ht
(% c
hg)
Adsorption/Desorption IsothermAdsorption1 Desorption1
Polymorph BPolymorph B
Case Study:Co-crystal form and manufacturability options
-5.000
0.000
5.000
10.000
0 10 20 30 40 50 60 70 80 90 100
We
igh
t (%
ch
g)
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
-5.000
0.000
5.000
10.000
15.000
0 10 20 30 40 50 60 70 80 90 100
Weig
ht
(% c
hg)
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
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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
Case Study:Co-crystal form and manufacturability options
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
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•• 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.
Case Study:Co-crystal form and manufacturability options
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
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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
Case Study:Co-crystal form and manufacturability options
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
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�� 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)
CASE STUDY:Which polymorph to develop?
(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
CASE STUDY:Which polymorph to develop?
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
Time (mins.)
Pea
k po
siti
on (
cm
1004.10 500 1000 1500 2000 2500 3000 3500 4000
form A
Time (mins.)
1004.10 500 1000 1500 2000 2500 3000 3500 4000
-
1003.4
1003.6
1003.8Form G
Pea
k po
siti
on (
cm-1
)
B GAcetonitrile
CASE STUDY:In situ Raman monitoring (2)
1002.0
1002.2
1002.4
1002.6
1002.8
1003.0
1003.2
1003.4
0 200 400 600 800 1000Time (mins.)
Pea
k po
siti
on (
cm
Form B
-
AllAll formsforms areare microcrystallinemicrocrystallineandand
nono suitablesuitable singlesingle crystalcrystalofof anyany
polymorphpolymorph isis availableavailable
CASE STUDY:Unusual solvent-directed polymorphic
transformations
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
CASE STUDY:Unusual solvent-directed polymorphic
transformations
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
CASE STUDY:Unusual solvent-directed polymorphic
transformations
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