Application Note: Crystal16 and Co-Crystallization

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

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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

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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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