The basics of solubility data
• Solubilitydataareusedtomakecrucialdecisionsfromtheearliest
stagesofdrugdiscoveryandthroughouttheentiredevelopment
process.
• Clearpoints
Thesolubilitycurveofasubstanceconsistsofaseriesof‘clearpoints’.
Aclearpointisthepointatwhichsuspendedsolidmaterialdisappears
fromasolution(transmissivityof100%).Forasolidwithincreasing
solubilityathighertemperatures,theclearpointisusuallymeasured
onheating,thereverseofthecoolingcommonlyemployedforthe
crystallizationofsuchsubstances.
• Cloudpoints
Themetastablelimitcurveconsistsofaseriesof‘cloudpoints’.
Thecloudpointreferstothepointatwhichsolidmaterialfirst
appearsinasolutionfromwhichcrystallizationisbeingcarriedout
(decreasingtransmissivity).Themostcommonmodeofcrystallization
fromsolutionemployscoolingtocreatesupersaturation,thecloud
pointrepresentingthepointonthe(falling)temperatureprofileat
whichcrystalnucleationisfirstobservable.Thedetectionofthecloud
pointisimportantbecauseitdefinesthewidthofthemetastable
zone,orthetemperaturecorrespondingtothecriticalsupersaturation
levelatwhichcrystalnucleationbegins.
• MSZW
Themetastablezonewidthisdefinedasthezonebetweenthe
solubilitycurveandthemetastablelimitcurveandprovidesessential
informationfordevelopingwell-controlledcrystallizationprocesses.
Efficient determination
of solubility data
• TheCrystal16™isthesmallest
scalecommercialcrystallizer
unitwithintegratedturbidity
measurementtodeterminecloud
andclearpoints.Itsoperating
softwareallowstemperature
programstobedefinedforthe
crystallizationexperiments.
Atemperatureprogramspecifiestemperatureprofile,samplerate,
andstirringspeedforeachexperiment.Heatingandcoolingrates
oftheslurriesmustbechosencarefullytodeterminetheMSZW.
Goodaccuracycanbeobtainedbyduplicatingmeasurementsand
repeatingtemperatureprofiles(seefigureabove).Technobis
CrystalClear™softwarecanassistinidentifyingcloudandclear
pointsandcanautomaticallyconstructandexportsolubility
curvesandMSZWdiagrams.
4 ApplicAtion note 4
The metastable zone width provides essential information for developing
well-controlled crystallization processes. The gathering of the underlying
solubility data traditionally relies on labor-intensive techniques, which is why these
data are often not available. With the Crystal16™ and optional CrystalClear™ software,
scientists have now one integrated package providing all the tools needed to easily determine
the metastable zone width. The Crystal16™ being the smallest commercial scale crystallizer,
only minimal amounts of sample are required.
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
Metastable zone width determination with Crystal16TM
• Identificationofcloudpoints
Inprincipleanabruptchangeintransmissivityiseasytodetect.
Nevertheless,cloudpointscanbedifficulttoidentifybecausethe
appearanceofthefirsttracesofsolidmaterialinacrystallization
processoftenoccursgradually.Thefirstvisualindicationofthe
onsetofcrystallizationisoftenaslightmilkinessinthesolution,
correspondingtotheformationofsmallcrystalnucleiinthesupersa-
turatedsolution.Themilkinessincreasesasthenumberandsizeof
nucleiincrease,andeventuallysmallcrystalsandparticlesofsolid
materialscanbeseensuspendedintheliquid.Mostusefully,the
cloudpointcorrespondstotheonsetofnucleation,whichisbest
identifiedasthepointatwhichthetransmissivityofthesolutionfirst
startstodecrease.ThispointisdetectedbytheCrystal16™turbidity
measurements.
• Identificationofclearpoints
Clearpointsaremoreeasilydetectedbecausethedisappearanceof
thesolidphaseoftenoccursmoreabruptly.Clearpointsareidentified
asthepointswheretransmissivityceasestochange.Thesepointsare
detectedbytheCrystal16™turbiditymeasurements.
Examples
• Accuratedetectionofcloudandclearpointsdependsonthesolution
cooling/heatingrate.Rapidtemperaturechangesmayresultinover
orunderestimatedvalues.Thegraph(seeFigureA)illustratesthe
impactofcoolingandheatingratesontheMSZWofiso-nicotinamide
inethanol.Asexpected,thesolubilitycurve(blue)islesssensitiveto
heatingrateswhereasthemetastablelimitcurve(red)shiftstolower
temperatureswithfastercooling.Asaruleofthumb,Technobis
recommendsusingaheatingrateof0.5°C/minandacoolingrateof
0.3°C/mintodeterminethesolubilitycurveandthemetastablelimit
curve,respectively.
• Whenlookingattherawdata(seeFigureB),noiseontransmission
curvesistypicallycausedbylargerparticlesor,insomecases,
agglomerates.Thetransmissionplotstotherightshowthedissolution
ofparticlesobtainedaftercoolingcrystallizationbyfastcooling
(5°C/min;leftplot,nonoise)andslowcooling(0.1°C/min;rightplot,
substantialnoise).Theyclearlydemonstratethatslowcoolingfavors
particlegrowth,thenoiseontherightplotbeingcausedbylarger
particles.TheseexperimentswereperformedonaCrystal16™usinga
concentrationof100mg/mlofiso-nicotinamideinethanol,stirredat
700rpm.Dissolutionwasstudiedbyheatingthesolutionatafixed
heatingrateto55°Candkeepingitatthattemperaturefor30
minutes,followedbycoolingatthesamerateto0°C.
40.1 0C/min1.0 0C/min
5.0 0C/min
200
180
160
140
120
100
80
60
40
20
8 10 12 14 16 18 20 22 24 26 28 30
Con
cent
ration
(m
g/m
l)
Temperature (0C)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Transmission [%] Transmission [%]
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
FigureA
Figure B
Warning: MSZW can be affected by solution history, the presence of impurities or tiny
amounts of seeds, mixing, etc. Characterizing these effects is important, certainly when
the MSZW data are used for scale-up.
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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