The challenges of polymorph and salt screening• Crystallizationprocessesandcrystalstructuresareoftencomplexand

unpredictable.Itisthereforenotunusualforcrystallizationexperi­

mentstoinvolveafairamountoftrialanderror.Testingalargediver­

sityofconditions(solvents,solventmixtures,concentration,cooling

profiles,ripeningtimes,etc.)requiresaflexibleexperimentalsetup.

• Inthepreclinicalstageofdevelopment,whenonlysmallamountsof

expensivecompoundareavailable,crystallizationscreeningfocuses

ontheselectionoftheoptimalcrystalformforfurtherdevelopment.

Experimentscanrangefromtargetedstudiestoidentifyastable

polymorph,tobringingaboutamoredrasticalterationofthe

physicochemicalpropertiesbycreatinganewsaltform.

• Inthelaterstagesofdrugdevelopmentwhenincreasedattentionis

giventoenhancingpatentprotection,morecomprehensiveprograms

areundertakeninordertopinpointasmanycrystalformsaspossible,

polymorphsaswellassalts.

• Regulatoryauthoritiesworldwiderequirepharmaceuticalcompanies

todemonstratethattheyhaveabsolutecontroloverthesubstance

(API)andallstagesofitsproductionprocess.Thisinturnrequires

companiestounderstandinterconversionsandtoproduceconsistent

quality(i.e.ensureconstantcompositionofchemicalaswellas

physicalpurity).Thesolidformsproducedshouldbestable,

notonlyduringproduction,butalsointheirformulationand

subsequentend­use.

Increased efficiency with Crystal16TM

• Automatingtheexecutionofcrystallizationexperiments

meansmoreexperimentscanbecarriedoutinthesame

timeframe,butalso,theresultsaremuchmorereproducible

andcontrollable,whichisessentialforgoodscience

andansweringtherequirementsputforwardbythe

regulatoryauthorities.

• Superiorflexibility

OneCrystal16™canrunupto16experimentsinparallel.

The1­mlscaleissufficientlysmallandthesmallestscale

compatiblewithcommerciallyavailablestandardanalytical

equipment.Thereactorvialsaregroupedinto4independently

temperature­controlledreactorblocksallowingdifferentcooling

profilestobeappliedtoeachblock.Ineachblock,crystallization

conditionssuchassolventsandsolventmixtures,compound

concentrations,acidsandbasesor,forsaltformation,ratios

ofAPI/saltformercanbevaried.Experimentscanbeplanned

efficientlyand,beingautomated,lefttorunovernightaswell,

reducingtheexperimentationtimeevenfurther.

2 ApplicAtion note 2

Crystallization processes and crystal structures are often complex

and unpredictable. Regulatory authorities worldwide, however,

increasingly require pharmaceutical companies to demonstrate absolute

control over their production processes. The Crystal16™ offers an invaluable

tool to automate the execution of crystallization experiments, improving

reproducibility while drastically increasing productivity and efficiency and

without compromising on flexibility.

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

Polymorph and salt screening

• Onlineanalysis

TheCrystal16™notonlyruns16crystallizationsinparallel,

italsoanalyzesthem.In­situturbiditymeasurementscanprovide

informationabouttheapparentsolubilityandthedissolutionrate

ofthevarioussaltsandpolymorphsobtained(seeApplicationNote

3).TheoptionalCrystalClear™softwarepackageallowstheuserto

graphicallyvisualizethedataandtogeneratereportsthatcanbe

exportedtoWord.

• Polymorphversussaltscreening

Theexecutionofsaltscreeningstudiesissimilartothatofpolymorph

screening.Itshouldbenoted,however,thatthekeytosaltscreening

isnotsolelytoidentifythesaltformers(formationofasaltcanoften

bepredictedbasedonpKadifferencesbetweentheAPIandtheacid

orbase),butalsotodeterminetheoptimumconditionsunderwhich

thesaltsarecrystallized.Theresultingsolidsarereadilyrecoveredby

solventevaporationand/oroff­linefiltration.

Examples

• Polymorphscreening

Atypicalpolymorphscreeningprojectof96experimentswould

berunusing,forexample,2differentconcentrationsoftheAPIin

8solventsand4solventmixtures,applying2differentcoolingprofiles

(e.g.afastandaslowcoolingrateof5°C/min.and0.1°C/min.

respectively)incombinationwith2ripeningtimes(shortripening

tocaptureunstableorkineticallystabilizedformsandlongripening

toallowmorestableformstoappear).UsingtheCrystal16™,

96experimentscouldberuninlessthan2weeksusingonlya

fewgramsofsample.

• Saltscreening

Forasaltscreeningstudy,insteadofusing,forinstance,12solvents

orsolventmixtures,thenumberofsolventscouldbereducedto,

forinstance,6butcombinedwith8differentcounterions(acidsor

bases).Givenacoolingprofileandripeningtimeandusing2different

concentrationsforeachsolvent,thetotalnumberofexperiments

wouldagainbe96.RunonaCrystal16™thesaltscreeningstudy

wouldbecompletedinapproximately2weeks.

TheCrystal16™isausefultooltogenerateandidentifynewcrystal

formsandtohelpsolveproblemsrelatedtopolymorphismandcrystal­

lization.Usingminimalamountsofmaterial,eachscreeningprojectis

carefullydesignedtomeetitsspecificobjectives.Tofullycharacterize

thesolidformsobtained,screeningexperimentsexecutedonthe

Crystal16™aretypicallyfollowedbyextensiveoff­lineanalyticalwork

usingx­raypowderdiffraction,spectroscopictechniques(Raman)and

thermalanalysis.

2ApplicAtion 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

1810 KSC Alkmaar

Please contact us for more information:

Info@crystallizationsystems.com

www.crystallizationsystems.com

are products and trademarks of

Technobis Crystallization Systems B.V.

Pyrietstraat 2

The Netherlands

Tel: +32 72 3020040

Crystal16™ and CrystalClear™

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