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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:
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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