The basics of solubility curves

• Solubilitydataareusedtomakecrucialdecisionsfromtheearliest

stagesofdrugdiscoveryandthroughouttheentiredevelopmentpro­

cess.Asolubilitycurveshowshowthesolubilityofasubstancevaries

withtemperature.Thesubstancesaretypicallyfreebasesorsalts,and

waterisbyfarthemostcommonsolvent.Thesolubilityofasubstance

inwaterdependsonseveralfactors.

• Thesolid­statecharacteristicsofdrugsareknowntoexertapoten­

tiallysignificantinfluenceonthesolubility.Polymorphsofadrug

substancecanhavedifferentmeasuredaqueoussolubilityanddissolu­

tionrates.Whensuchdifferencesaresignificant,theirbioavailability

differs,inwhichcaseitmaybedifficulttoformulateabioequivalent

drugproductusinganalternativepolymorph.Whensolubilityand

dissolutionrateoftherelevantpolymorphic

formsaresufficientlyhigh,regulatorycon­

cernswithrespecttobioavailabilityand

stabilityareminimal.Whendecidingwhich

polymorphtodevelopandregister,the

BiopharmaceuticsClassificationcriteria

ofhighsolubilityandrapiddissolution

shouldbeconsidered.

Efficient determination of solubility curves

• Experimentaldeterminationofsolubilitycurvestraditionallyrelies

onlabor­intensivetechniques,whichiswhydetailedsolubilitydata

areoftennotavailable.TheCrystal16™combinesautomationwith

integratedturbiditymeasurementtodeterminecloudandclearpoints

andisideallysuitedtoacquiresolubilitydataatanearlystageusing

onlyminimalamountsofsample.

• Thesolubilitycurveisathermodynamicpropertyofthesubstance­

solventsystem.Whenmeasuringthesolubilitycurveusingveryfast

heatingrates,itispossibletoovershoot,butatslowerratesthe

measuredclearpointshouldbeconstantirrespectiveofheating

rate.Aseriesofmeasurementswiththe

Crystal16™showthatheatingratesbelow

0.5°C/mingenerallyyieldconsistentclear

pointswhereasthesolubilitycurvecan

beeasilyovershotatheatingratesabove

5°C/min.

• UsingaCrystal16™with16vialsholding

4differentconcentrationsofadrug

substancein4differentsolventsand

applying2temperaturecycleswitha

heatingrateof0.5°C/minandacoolingrateof1°C/min,

4solubilitycurvescanbemeasuredinduplicateinhalfaday.

3 ApplicAtion note 3

Solubility data are used to make crucial decisions from the earliest

stages of drug discovery and throughout the entire development

process. The Crystal16™ and optional CrystalClear™ software provide

the ideal tools to efficiently gather and analyze solubility data at an early

stage, using only minimal amounts of sample. Discover why several pharmaceutical

companies have already chosen the Crystal16™ as their standard tool to determine

solubility of their drug compounds.

0

-10 0C 0 0C 10 0C 20 0C 30 0C 40 0C 50 0C 60 0C

10.00 min

1.00 min

0.10 min

0.01 min

60 0C 65 0C 70 0C 75 0C

Heat/Cool Rate (0C/min)

Concentration (mg/g)

Concentration (mg/g)

0

100

40

20

60

80

100

120

140

200

300

400

500

600

-10 0C 0 0C 10 0C 20 0C 30 0C 40 0C 50 0C 60 0C

Gravimetric

MethanolBlock A

Solvated

Anhydrous

iPropanolBlock C

EthanolBlock B

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

Solubilitymeasurements

Examples

• APIsolubility

SeveralpharmaceuticalcompanieshavechosentheCrystal16™as

theirstandardtooltodeterminesolubility.Thegraphtotheright

showsthesolubilitycurvesofanAPIinthreesolvents,determinedon

theCrystal16™using3ofthe4blocks.Ineachoftheblocks4HPLC

vialswithdifferentconcentrationsoftheAPIwereheatedto60°C

at0.3°C/min.Thedataresultingfromtheexperimentscarriedout

ontheCrystal16™(fulllines)agreedwellwiththedataobtained

usingagravimetricmethod(dashedlines).

• APIinterconversions

Atypicalexperimentwouldconsistof(i)preparinganarrayofslurries

ofvaryingconcentrationsofsolidin1mlofasolventorsolvent

mixture,(ii)heatingto75°Cat0.3°C/min,usingmagneticstirbars

toagitatetheslurry,determiningthedissolutiontemperature

byturbiditymeasurements(iii)followedbycoolingto0°Cat

1°C/mintoobservecrystallizationofthesample,againbymeasuring

turbidity.Intheexampleshownopposite,eachmeasurementcycle

wasrepeated3timestoincreaseconfidenceintheresults.Inthefirst

measurementcycle,crystallizationofthesubstanceduringthecooling

cycleresultedinahydrateratherthantheanticipatedanhydrous

form.Consequently,adifferentsolubilitycurvewasobtainedinthe

subsequentmeasurementcycles.Thesolvatedformappearstobethe

thermodynamicallystableformbelow15°C(i.e.lowestsolubility).

Thisexampleillustratesthat(pseudo)polymorphicchangescanbe

inducedandobservedbyrepeatedmeasurementsofthesolubility

curve.Thesechangesmayprovidecrucialinformationfortheultimate

crystallizationprocessdevelopmentordownstreamoperations.

Inaddition,duplicateortriplicatemeasurementswillincrease

confidenceintheresults.

21st century manufacturing

Theapplicationofprocessanalyticaltechnology(PAT)tocrystallization

processdesignhasalwaysbeenanareaofhighinterestforboth

thechemicaldevelopmentandmanufacturingarenas.Thisispartly

duetothegrowingemphasisonPATasatoolfor‘21stCentury

Manufacturing’asdescribed,forexample,intheguidelinedocument

‘PAT­AFrameworkforInnovativePharmaceuticalDevelopment,

Manufacturing,andQualityAssurance’issuedbytheFDAin2004.

Theuseofin­situturbiditymeasurementandautomatedmethods

todeterminesolubilitycurvessignificantlyreducesoperatorworkload

comparedtotraditionalmethods,whichshouldencouragetheuseof

solubilitydataintheearlystagesofcrystallizationprocessdevelopment.

3

0

-10 0C 0 0C 10 0C 20 0C 30 0C 40 0C 50 0C 60 0C

10.00 min

1.00 min

0.10 min

0.01 min

60 0C 65 0C 70 0C 75 0C

Heat/Cool Rate (0C/min)

Concentration (mg/g)

Concentration (mg/g)

0

100

40

20

60

80

100

120

140

200

300

400

500

600

-10 0C 0 0C 10 0C 20 0C 30 0C 40 0C 50 0C 60 0C

Gravimetric

MethanolBlock A

Solvated

Anhydrous

iPropanolBlock C

EthanolBlock B

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

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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