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The basics and challenges of co-crystallization• Withanincreaseinthesizeandcomplexityofthemoleculesthat
enterintodrugdevelopment,companiesfacealargernumberof
compoundsthatareeitherpoorlysoluble,difficulttocrystallizeor
problematicwithrespecttophysicochemicalpropertiesforsuccessful
development.Traditionalapproachessuchassaltformationmayno
longeroffersufficientopportunitiestoprovideasolutionandnew
strategiesareactivelybeingexplored.
• Crystalengineeringhasbeenidentifiedbypharmaceuticalscientists
asameansofimprovingandtailoringthephysicochemicalproperties
ofactivepharmaceuticalingredients(API).ThepropertiesofanAPI
maybemodifiedthroughsaltformationusingalimitednumber
ofavailablecounterions.Co-crystalsofferfurtherpotentialfor
changingtheAPIpropertiesbyusingamuchmoreextensive
rangeofco-crystallizingmolecules(co-builders).
• Aco-crystalisdefinedasacrystalthatisbuiltupoftwoormore
organiccompoundswhich,intheirpureform,aresolidatam-
bientconditions.Aco-crystalcanhaveimprovedproperties
suchaslongershelflife,improveddissolutionrateand
increasedbioavailability.
• TheabilityofanAPItoformaco-crystalisdependenton
arangeofvariables,includingthetypesofco-former,
theAPIco-formerratio,thesolvents,thetemperature,
thepressure,thecrystallizationtechnique,etc.Asystematic
explorationofthecombinationofrelevantvariablesincreases
thechanceofdiscoveringaco-crystalwiththedesired
properties.
• Traditionalexperimentalmethodstendtooverlookasignificant
numberofco-crystalsastherangeofexperimentalco-crystallization
conditionsisoftentoolimitedandthermodynamicinformationis
neglected.
Solubility as key to co-crystal screeningThisapplicationnotedescribesasystematicandeffectivemethodto
discovernewstableco-crystalformsbasedoneasy-to-measuresolubility
dataofthepurecomponents.Thekeytooptimizingtheprobabilityof
findingco-crystalsistodeterminesolubility,startingwiththesolubilities
ofthepurecomponents.
• Thegraphoverleaf(seeFigureA)showsasimplifiedphasediagram
ofa1:1ABco-crystalattwotemperaturesT1andT2inasolution.
• Typically,thesolubilityofacomponentdropswhenothercomponents
areaddedtothemixtureandthisshouldbeobservedwhensmall
amountsofco-builderBareaddedtothesolutionorwhensmall
amountsofAareaddedtoasolutioncontainingco-builderB.Tosimplifytherepresentation,weassumethatthesolubilityofthe
purecomponentsAandBandthesolubilityproductoftheco-crystal
A:Bareconstant;thisresultsinastraightverticalandhorizontalline
(black)forthesolubilityofthepurecomponentsAandBrespectively.
Thesolubilityproduct(xA•xB)*forastableco-crystalissmallerthan
theproductofthepurecomponentsolubilitiesxA*•xB*.
5 ApplicAtion note 5
Co-crystallization brings new opportunities for preformulation and
is a first step towards crystal engineering. Indeed, where traditional
approaches such as salt screening fail, co-crystallization often still manages
to solve the crystallization problems or improve a drug substance’s
physicochemical properties. The Crystal16™ offers a systematic and effective
method to discover new stable co-crystal forms based on easy-to-measure solubility
data of the pure components.
ApplicAtion notes
Crystal16 TM - 1
Polymorph and salt screening - 2
Solubility measurements - 3
Metastable zone width determination - 4
Co-crystallization studies - 5
Anti-solvents - 6
Fast track to return on investment - 7
Improve and accelerate your crystallization research
with the Crystal16™ parallel crystallizer, the ultimate
tool for solid-state research and process development.
Designed by scientists for scientists, the Crystal16™
is a user-friendly multi-reactor benchtop system with
intuitive software to perform medium-throughput
crystallization studies at a 1-ml scale. It offers
invaluable assistance throughout the various stages
of the drug development life cycle, from preclinical
screening to process optimization. Developed for
crystallization studies, the Crystal16™ has also been
successfully used in other application areas such as
polymer solubility studies and process chemistry.
Improve and accelerate
your crystallization research
Co-crystallization studies
Thesolubilitylineofastableco-crystalwillintersecttherectangular
envelopeofthepurecomponentsolubilitiesxA*(T1)andxB*(T1)
belowitsupperrightpoint(indicatedinred)withcomposition
(xA*(T1),xB*(T1)).
• Inprinciple,attemperatureT1withcorrespondingcomponent
solubilitiesxA*(T1)andxB*(T1),asolutionwithoverallcomposition
(xA*(T1),xB*(T1))willgenerallybewell-positionedtoobtainco-crystals.
Forco-crystalscreeningthisprinciplehastheimportantconsequence
thatasolutionwithcomposition(xA*(T1),xB*(T1))willhaveasatura-
tiontemperatureT2(oftheco-crystallinephase)abovethepurecom-
ponentsaturationtemperatureT1.Thesesaturationtemperaturesare
experimentallyeasilyaccessible.
ExampleTheCrystal16™canbeusedtodesignaco-crystalscreeningprogram
bymeasuringtheclearpointsofaseriesofco-buildersandtheAPI.
Thepossibilityforco-crystallizationcanbecheckedbymeasuring
thesaturationtemperatureofthemixtures,basedontheindividual
components’solubilities.Asanexample,theco-crystallizationof
carbamazepine(CBZ)withiso-nicotinamide(INA)wasstudiedona
Crystal16™,usingthefollowingapproach:
• Inafirstexperiment,differentconcentrationsofthepurecomponents
wereslurriedinethanolandfromthemeasuredsolubilitycurvesthe
solubilityoftheindividualcomponentsCBZ(XCBZ)andINA(XINA)
werereadat10,15,20and25°C.
• Inthenextexperiment,mixturesofCBZandINAwereprepared
basedonthesolubilitydataofthepurecomponents.Theprepared
slurriesweredissolvedandrecrystallizedafterwhichthesaturation
temperature(clearpoint)wasdetermineduponheatingat0.3°C/min.
ThesaturationtemperaturesTSofthemixturesofCBZandINAare
listedinthetable(seeFigureB)andareallsignificantlyhigherthan
thepurecomponentsaturationtemperatures(e.g.42°Cversus25
°C),indicatingthatamorestableandthereforelesssolubleco-crystal
phasewasrecrystallized.TheconclusionisthatCBZandINAmost
likelycanformco-crystals.NotethatalargeexcessofINA(atleasta
factor6basedonmolarratio)isneededtosuccessfullyco-crystallize,
thesolubilityofINAbeingmuchhigherthanthatofCBZ.
• Thisexampleillustratesthatasystematicscreeningmethodcanbe
appliedtoinvestigateseveralcombinationsofAPI,co-buildersand
solvents,optimizingtheprobabilityofdiscoveringco-crystalline
materials.Matchingsolutionwithco-crystalstoichiometryshouldbe
setaside,andco-crystalscreeningshouldbedesignedbasedoneasily
accessiblepurecomponentsolubilities.
5
T[0C]
10152025
XCBZ
[mmol/mol]
2.93.74.65.7
XINA
[mmol/mol]
21.825.229.033.3
molar ratioCBZ:INA
0.120.130.130.14
TS [0C]
26.834.236.942.0
Note: to maximize the probability of co-crystal formation,
not only is it important to choose the appropriate compo nent
ratio, it is also important to choose an appropriate solvent as
both components should be sufficiently soluble and competition
between co-crystallization and solvation of the API should
be minimal.
ApplicAtion notes
Crystal16 TM - 1
Polymorph and salt screening - 2
Solubility measurements - 3
Metastable zone width determination - 4
Co-crystallization studies - 5
Anti-solvents - 6
Fast track to return on investment - 7
XB*(T2)
XB*(T1)
XA*(T1) XA*(T2)XA
XB
(XA*(T1), XB*(T1))
(XA.XB)*
T2>T1
FigureA
FigureB
1810 KSC Alkmaar
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