Solvent Influences on Metastable Polymorph Lifetimes:Real-Time Interconversions Using Energy DispersiveX-Ray Diffractometry

LUCIANA L. DEMATOS,1 ADRIAN C. WILLIAMS,2 STEVEN W. BOOTH,3 CATHERINE R. PETTS,3

DAVID J. TAYLOR,4 NICHOLAS BLAGDEN1

1School of Pharmacy, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK

2School of Pharmacy, PO Box 224, University of Reading, Reading, Berkshire, RG6 6AD, UK

3Merck Sharp and Dohme Ltd., Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK

4CLRC Daresbury Laboratory, Warrington, Cheshire, WA4 4AD, UK

Received 15 August 2006; revised 11 October 2006; accepted 31 October 2006

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20924

ABSTRACT: Solvent influences on the crystallization of polymorph and hydrate forms ofthe nootropic drug piracetam (2-oxo-pyrrolidineacetamide) were investigated fromwater, methanol, 2-propanol, isobutanol, and nitromethane. Crystal growth profiles ofpiracetam polymorphs were constructed using time-resolved diffraction snapshotscollected for each solvent system. Measurements were performed by in situ energydispersive X-ray diffraction recorded in Station 16.4 at the synchrotron radiation source(SRS) at Daresbury Laboratory, CCLRC UK. Crystallizations from methanol, 2-propanol, isobutanol, and nitromethane progressed in a similar fashion with the initialformation of form I which then converted relatively quickly to form II with form III beinggenerated upon further cooling. However, considerable differences were observed for thepolymorphs lifetime and both the rate and temperature of conversion using the differentsolvents. The thermodynamically unstable form I was kinetically favored in isobutanoland nitromethanewhere traces of this polymorphwere observed below 108C. In contrast,the transformation of form II and subsequent growth of form III were inhibited in2-propanol and nitromethane solutions. Aqueous solutions produced hydrate forms ofpiracetam which are different from the reported monohydrate; this crystallizationevolved through successive generation of transient structures which transformed uponexchange of intramolecular water between the liquid and crystalline phases. � 2007

Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1069–1078, 2007

Keywords: polymorph; hydrate; transformation; crystal growth; piracetam; in situcrystallization; solvent effects; energy dispersive X-ray diffraction; synchrotron

INTRODUCTION

Processing of active pharmaceutical ingredients(API’s) can pose major challenges to manufac-turers that are required by law to produce drugsof consistent quality. Pharmacologically impor-tant physical properties including solubility,density, thermodynamic stability, and dissolutionrate are directly associated with a drug’s crystalstructure,1–3 and can have consequent effects on

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We dedicate this paper to Professor David Grant. Not only atalented scientist, he was a man who gave freely of his timeand ideas to support and encourage others, includingourselves.L.L. DeMatos’s present address is Department of Chemical

and Process Engineering, University of Sheffield, Sheffield,South Yorkshire, S1 3JD, UK.Correspondence to: Adrian C. Williams (Telephone: 0118 378

6196; Fax: 0118 378 6632;E-mail: A.C.Williams@Reading.ac.uk)

Journal of Pharmaceutical Sciences, Vol. 96, 1069–1078 (2007)� 2007 Wiley-Liss, Inc. and the American Pharmacists Association

bioavailability. Therefore, control of the crystal-line form is paramount to pharmaceutical devel-opment. The ability of compounds to adopt morethan one crystal form, broadly termed polymorph-ism, provides opportunities to study such struc-ture-property relationships and is therefore thesubject of much academic and commercial inter-est.4–6 New product patent characterization reg-ulations require specification of crystalline formand purity.7 Hence, pharmaceutical formulatorsmust consider all factors which may influencethe crystallization or transformation of an APIduring all stages of manufacturing and storage.8,9

Polymorph screening has therefore become aformulation pre-requisite where the most thermo-dynamically stable form is usually preferred forcommercialization. The late discovery of newcrystal forms of API can lead to product market-ing delays, withdrawal (in the case of ritonavir) ordisputes of patent intellectual property.4,10,11

Typical methods for the preparation of poly-morphs include crystallization from differentsolvents, melts, or supercritical fluids, throughsublimation or by application of high-pressureconditions.12–15 A range of microscopic, thermal,spectroscopic, and diffraction analysis is thentraditionally performed to characterise the result-ing products.12–15 This is a lengthy process, areason why robotic high-throughput technologiesare increasingly being employed.16 It is importantto recognise that high throughput screeningapproaches lead to the identification of the ther-modynamically stable forms. However, withinprocess optimisation, the lifetimes of transientforms may be solvent and impurity sensitive andscreening approaches to probe this are limited dueto the problems associated with in situ diffractionstudies of crystallising solutions. In this paper, wepresent an approach to address this situation.

Solvent Effects on Crystallization

A thermodynamic perspective is commonlyemployed in order to explain and control poly-morph crystallization in solution whilst impor-tant kinetic factors can often be overlooked. Theimportant role played by kinetics in this processwas highlighted in 1887 by Ostwald in his Rule ofStages according to which ‘‘when leaving anunstable state, a system does not seek out themost stable state, rather the nearest metast-able state which can be reached with loss of freeenergy.’’17 Time constraints and other experi-mental limitations mean that usually only the end

products from solution crystallizations are char-acterized. Such an approach ignores the potenti-ally critical role played by transitional metastableforms. This oversight is a common drawback inpolymorph screening methods which fail toprovide well-resolved structural data that canaccurately depict transformations occurring inthese constantly changing systems. The stabi-lization of a particular crystal phase in solutionhas been associated with solvent–solute in-teractions.13,18,19 Hence the kinetics of crystalgrowth, the lifetimes of metastable forms andsubsequent crystal phase transformations willvary with solvent choice.20–23

Synchrotron X-ray radiation diffraction andscattering techniques have been used in the pastto study the influence of these kinetic processes.However, scattering from the liquid phase oftencreates difficulties when resolving crystal phasedevelopment from solutions containing less than25% w/v solids.24–27 Here we have employedsynchrotron energy dispersive X-ray diffracto-metry (EDXRD) to monitor the effects of solventon the crystallization of piracetamusing a recentlyreported custom-built crystallizer for in situmeasurements.25 This cell successfully enhancesX-ray sensitivity by concentrating the crystallinematerialwithin the solution in awell-defined zone,which is aligned with the X-ray beam.25 For ourwork we have enhanced the sample arrangementby adapting an insulated chamber and including adigital display overhead stirrer onto themotorizedxyz-stage. The chamber was equipped with aheating–cooling loop mechanism whose tempera-ture settings were controlled from outside theX-ray hutch.

Piracetam Solid-State Chemistry

Piracetam (2-oxo-pyrrolidineacetamide) has cog-nition enhancement properties and is consideredto be the pioneer nootropic drug.28,29 It wasselected as the model compound for this work onthe basis of its chemical and crystallographiccharacteristics. Despite having a relatively simplestructure, Figure 1, its various functional modesgenerate a wealth of molecular interactions withdifferent solvents which can lead to the formationof polymorphs. Five crystal structures of pirace-tam are reported in the literature, four poly-morphs and a monohydrate form. Form I, III, andIV are monoclinic whereas form II crystallizes inthe triclinic form.14,30–33 Other metastable formshave been shown in a thermo-microscopy study

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of crystallization from the melt, though theirdescriptions are unclear and they appear to beshort-lived phases.34 The principal crystal struc-tures of piracetam can be obtained by directrecrystallization from solvents, with the exceptionof form IV which was obtained by subjectingmethanolic solutions to very high pressures andwhich is unsustainable at normal ambient condi-tions.12,28–35 Form I has the highest melting point(1538C), followed by form II and III (142.5 and1428C, respectively). The polymorphs intercon-vert through enantiotropic transformations; formI is the most unstable and form III is the moststable at room temperature.34 The role of solventsin the kinetics of piracetam crystallization and inmediating polymorph interconversions is unclearand was investigated in this work.

EXPERIMENTAL

Materials

Piracetam purchased from Sigma Chemical Co.(Lot# 36H0946) and HPLC grade water, metha-nol, 2-propanol, isobutanol, and nitromethanefrom Fisher Scientific were used in the crystal-lization experiments.

Preparation of Solutions andCrystallization Protocol

Solutions were prepared by gradually addingpiracetam to solvent at a defined start tempera-ture (T0), which was set approximately 5–108Cbelow the liquid’s boiling point. This providedessentially saturated starting solutions (i.e. atequivalent thermodynamic activity) whilst avoid-ing supersaturation. Consequently, maximalweight fractions of solute were achieved toimprove detection of the crystallizing polymorphswhilst preventing induced nucleation by excesscrystal seeds.

Energy Dispersive X-ray Diffractometry (EDXRD)

EDXRD was performed at the synchrotron radia-tion source (SRS) Station 16.4 of DaresburyLaboratory, UK. Data were collected continuouslyin the spectral limits of white light radiation(ranged from 20 to 70 keV). Three germaniumdetectors (named for distinction as top, middle,and bottom) were positioned at different angles sothat diffracted energies were easily recorded by atleast one detector at any time. A motorized xyz-stage was fixed to the diffraction table andmounted with an insulated block. The latter con-stituted the holder for the crystallizer cell whichincorporated a built-in slot (to allow passage ofX-rays) and a heating–cooling loop mechanismthat connected to the diffractometer control room.The heating–cooling mechanism allowed stepcooling of the solutions with temperature equili-bration attained within 20 s. A Heidolph RZR2000 overhead motor fitted with a 1/60 pitchedtwo bladed steel impeller set at approximately300 rpm provided stirring. Temperature wasmonitored using a thermal probe linked to adigital display located outside the X-ray hutchand was recorded on completion of each individualscan. Crystallization conditions (e.g. tempera-ture, agitation rate) have been previously opti-mized and validated for our custom-builtcrystalizer.25

Whilst scan collection times could be as low as10 ms, we successively collected data over 45 s asthis providedwell resolveddatawith good signal tonoise ratios. Starting temperatures (T0), initialconcentrations andmonitoring times of the experi-ments performed are detailed in Table 1. Theexperimental set-up used in Station 16.4 isdepicted by the scheme in Figure 2. Reproducibledata was obtained for triplicate crystallizationsfrom each solvent.

Manipulation of Energy DispersiveDiffraction Data

Final corrections of the three detectors calibration2-theta positions were performed using diffrac-tion measurements obtained at room temperaturefrom solid benzamide. This compound was used asan external standard since it has well-definedstrong reflections in the white beam diffractionregion.

Manipulating energy dispersive diffractionsoftware (MEDD) was created for converting theraw measured diffraction files.36 The program

Figure 1. Chemical structure of piracetam.

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re-organizes the series of 4000 channels scanssystematically converting the keV output intod-spacing units. It automatically generates stack-ed diffraction plots of relative intensity versusd-spacing and three-dimensional graphics canbe created directly from converted xyz-files withany ordinarymath-package. The diffractometer inStation 16.4 measured reflections in terms ofenergy, where data output is in keV; conversionof d-spacing measurements to Angstroms (A) isstraightforward. The X-ray flux energy distribu-tion obeys Bragg’s Law, which is re-written inenergy dispersive X-ray diffraction as:

Ehkl ¼hc

2dhkl sinðyÞ

This relationship converts the energy of thediffracted beam to the corresponding lattice spac-ing, and utilises the detector calibration para-meters for Station 16.4. For a white light source:Ehkl is the energy in keV relating to the diffraction

of lattice planes (hkl), h the Planck–Einsteinconstant (6.626� 10�34 J�s), c the speed of light(3� 108 ms�1), dhkl the lattice spacing of the dif-fracting planes of the material in A, and y is theangle of the detector relative to the incident beam.

RESULTS AND DISCUSSION

Crystallization In Situ Monitoring

Piracetam main characteristic reflections wereobserved within the middle detector d-spacingregion. For this reason, middle detector resultswere used for the characterisation and compar-ison of the different crystallising systems. Resultsfrom the top and bottom detectors were primarilyutilized to check for instrument or software arte-facts, for example, to confirm the veracity of un-reported reflections or transient peaks observedin a single middle detector diffraction frame.

Typical examples of piracetamcrystallization inmethanol (Fig. 3), 2-propanol (Fig. 4), isobutanol(Fig. 5), nitromethane (Fig. 6), and water (Fig. 7)are presented in three-dimensional sequences ofdiffraction frames collected over time. The crystal-lizer, machined from a single block of polyte-trafluoroethylene (PTFE), provided consistentdiffraction lines with a main reflection occurringat 6.38 A. This feature provided an additionalcheck for the protocol robustness as it exhibitedexcellent reproducibility throughout and thereforefunctioned as an internal standard. A rise in thebaseline (in the shape of a broad hump) wasanother feature observed in the patterns, varyingslightly in position and intensity depending on thesolvent used. This broad signal arises from theamorphous regions of PTFE and scattering fromthe liquid phase, thus shifted depending on solventchoice. One further notable feature in several ofthe diffractograms is variation in peak intensities.This is probably due to hydrodynamic-inducedpreferred orientation effects; as the crystallites

Table 1. Summary of Experimental Conditions for In Situ PiracetamCrystallizations

ExperimentalConditions

Start Temperature(T0)/8C

StartConcentration/gml�1

MonitoringTime/Min

Methanol 65 0.33 34.502-Propanol 75 0.12 34.50Isobutanol 90 0.11 52.50Nitromethane 95 0.24 34.50Water 90 3.20 56.25

Figure 2. Schematic representation of the protocoldeveloped at Station 16.4 of Daresbury Laboratory,CCLRC UK, to monitor crystallization in situ bysynchrotron energy dispersive X-ray diffraction.Scheme key: 1, temperature probe; 2, insulated crystal-lizer holder; 3, detectors; 4, heating unit; 5, cooling unit;6, stirrer set at 300 rpm; 7, teflon crystallizer; 8, crystalsdiffracting X-ray beam; 9, adjustable plunger; and 10,bottom view of stirrer showing 58 torsion of blade.

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grow and are stirred in the crystallizer, particlesmay orient as they are presented to the X-raybeam.

Assignment of measured peaks to the corre-sponding crystal phases was performed by com-parison with reflections calculated from the unitcell parameters of reported piracetam crystalstructures (Cambridge Structural Database). Thegoodness of fit between the measured diffractionmaxima and the calculated d-spacings was within0.01 A. The occurrence of piracetam crystal formsin the tested solvents is summarized in Table 2where respective identifying peaks and lifetimesare specified.

Crystallization in Methanol

First signs of crystallization in methanol weredetected during scan 10 (7.5 min) at approxi-mately 318C. Even though initial impressionswere that only form II (3.54, 3.79, 4.11, 4.72, and5.58 A) was formed in the suspension at thisstage, closer examination of the patterns revealedweaker diffractions characteristic of form I (3.49,4.28, 5.14, and 5.56 A). The transformation of thelatter phase occurred rapidly as the suspensionwas cooled another five degrees. Even thoughsome form I peaks appeared to remain in thefollowing patterns, these were actually shiftedand correspond to emerging peaks characteristicof forms II (5.58 A) and III (3.46 A). Firstdiffraction lines of form III (2.53, 2.56, 3.46, and4.17 A) arose around 278C (scan 12). Both forms IIand III were observed below 108C. Form IIremained the predominant polymorph in themixture during monitoring, slowing down thegrowth of form III in suspension.

In contrast, previous laboratory experimentswith piracetammethanolic solutions yielded crys-tals composed almost entirely of form III. These

Figure 3. Diffraction profile of in situ crystallizationof piracetam from methanol recorded by energy dis-persive X-ray diffraction.A highlights the growth of the(21�2) face of formIIat 2.47 Awitha concomitant loss ofthe (�1 1 1) face at 4.47 A and B shows that the (6 1 1)face at 3.00 A is lost before the growth of the (4 0 2) face at3.25 A.

Figure 4. Diffraction profile of in situ crystallizationof piracetam from 2-propanol recorded by energy dis-persive X-ray diffraction.

Figure 5. Diffraction profile of in situ crystallizationof piracetam from isobutanol recorded by energy dis-persive X-ray diffraction.

Figure 6. Diffraction profile of in situ crystallizationof piracetam from nitromethane recorded by energydispersive X-ray diffraction.

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crystallizations were performed with identicalsolution concentrations systematically cooled from65 to 35, 25, and 158C and subsequently leftstirring for 45 min. This anomaly could be due todifferences in the cooling rate, whichwas slower inthe Daresbury protocol. However, it could alsoshow the influence of kinetic effects over timeinducing conversion, even though form II is theinitial thermodynamically favored polymorph.

Crystallization in 2-Propanol

Form II was the predominant initial crystallizingphase at 358C with several typical diffractionlines (2.80, 3.00, 3.79, 4.11, 4.47, 4.72, and 5.58 A)resolving from the background noise. The smallfraction of form I crystals completely convertedinto form II as temperature was reduced to 208C,shown by the loss of form I peaks at 3.49 and4.28 A and the increased signal of form IIreflections from scan 16 onwards.

Diffraction from form III crystals (3.46, 4.17,and 5.07 A) was seen from approximately 168C(scan 20).

Figure 7. Diffraction profile of in situ crystallizationof piracetam from water recorded by energy dispersiveX-ray diffraction.

Table 2. Summary of Polymorph Lifetimes and Predominant Identifying d-Spacingsfor Crystallization of Piracetam From Various Solvents

Polymorph Methanol 2-Propanol Isobutanol Nitromethane

d-spacing(A):Form I Scan: 10–12 Scan: 10–15 Scan: 9–70 Scan: 5–45

2.853.49 3.49 3.49 3.49

3.83 3.833.90 3.9

4.28 4.28 4.28 4.285.14 5.14 5.145.56 5.56

5.97Form II Scan: 10–45 Scan: 10 to 45 Scan: 14–70 Scan: 12–45

2.80 2.803.00 3.00 3.00 3.003.25 3.253.543.79 3.79 3.794.11 4.11 4.114.47 4.47 4.474.72 4.72 4.72 4.725.58 5.58 5.58

Form III Scan: 12–45 Scan: 10–45 Scan: 16–702.532.563.464.17

3.464.175.07

3.46

5.98

Not observed duringmonitoring time

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Crystallization in Isobutanol

Kinetic solvent effects clearly favored form Istability in this system, which remained insuspension at temperatures lower than 108 C.This unexpectedly long lifetime of form I could befollowed particularly well through the evolution ofthe 5.14 A reflection, which is unique to thispolymorph, arising at the start of crystallizationaround 428C (scan 9). After a dramatic drop inintensity (scan 19) upon growth of forms II andIII, traces of form I appeared to remain in solutionwith growth staying virtually unchanged duringthe experiment.

Crystallization in Nitromethane

Form I crystallized early in nitromethane around508C (scan 5) but conversion rates were slow inthis solvent. Similarly to the isobutanol system,transformation occurred by gradual dissolution ofform I followed by crystallization of form II. Thisconversion process could be followed particularlywell by the initial evolution of form I peaks at2.85, 3.49, and 3.83 A whose intensities droppeddramatically prior to formation of form II around208C (scan 13 onwards). A phase equilibriumstage where diffraction patterns remained rela-tively unchanged followed until the solution wascooled below 108C and form II diffractions (4.11,4.47, 4.72, and 5.58 A) steadily increased (scan27 onwards).

Previous laboratory recrystallizations of pira-cetam from nitromethane showed changes in thecrystal habit of samples recovered at differenttemperatures. Needle-like crystals were obtainedat higher temperatures whereas rapid cooling ofthe solutions from 85 to 258C yielded mixtures ofneedle and of prismatic shaped crystals. Thesesame experiments also produced polymorphicmixtures of forms II and III when solutions wereleft stirring for 45 min at room temperature. Thismorphology modification and generation of poly-morphic mixtures could possibly explain theequilibrium stage described earlier. It is interest-ing that, in the EDXRD studies, form III was notobserved at temperatures as low as 88C (Fig. 6).Thismay again be attributed to kinetic differencesbetween the laboratory and in situ EDXRDexperimental protocols.

Crystallization in Water

The diffraction profile obtained from crystalliza-tion of aqueous piracetam solutions showed

patterns that could not be simply attributed toany of the reported polymorphic structures ofpiracetam, including the known monohydrate.Crystals first diffracted at 468C (scan 11) andthe following patterns depicted a chaotic periodwherein several peaks emerge and disappearfrom one diffraction frame to another. This struc-tural re-arrangement settled temporarily duringscans 15 to 24 where a new crystal phaseappeared with characteristic reflections at 3.20,3.58, 4.10, 5.41, 5.60, and 6.50 A.

Another transformation occurred wherein sev-eral of the above peaks were lost, others under-went dramatic changes in intensity and a newreflection emerged at 4.62 A. Rapid development ofthe two major surviving peaks at 3.58 and 5.60 Awas subsequently observed until a third transfor-mation occurred (scan 65). During this process asignificant diffraction increase at 2.80 A occurredwhilst the intensity of other major peaks waslargely reduced. This was a short-term event anddiffraction patterns returned to the previousconfiguration with a small peak arising at 2.67 A.

The transformation trends observed in thisprocess could indicate changes in the molecularcomposition of the crystal form rather thansuccessive lattice re-arrangements of a structureof equal constitution. Major peaks in the patternremained throughout, only experiencing intensitychanges upon temporarily loss or gain of addi-tional peaks. This could be a reflection ofmolecularwater exchange between liquid and crystallinephases. The mechanistic paths intrinsic to thesetransformations are currently being examined.

Crystal Morphology Influence onDiffraction Profile

Crystal morphology was dramatically affected bysolvent selection. Crystallizations from isobutanolproduced small needle-like crystals whereas 2-propanol and methanol yielded larger prismaticcrystals. A mixture of both was recovered fromnitromethane.

Table 2 summarizes the diffraction variationsobserved for each polymorph in the differentsolvents. These differences are due to dissimila-rities in the growth rates of crystal faces andresulting crystal morphologies which are inducedby solvent interactions.Depending onhowcrystalsgrow in solution, the orientation of their dynamicflow will also change, consequently detection ofsome crystal faces will be favored in relation toothers.25 This effect was particularly clear with

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the crystallization from isobutanol as the dynamicorientation adopted by the needle shaped crystalsduring stirring dramatically favored diffraction ofthe elongated crystal faces which diffract moreintensely.

By the same principle, it was also possible toindependently follow the evolution of one crystalphase during crystallization. Though these struc-tural mechanisms are currently being scrutinized,the stages in crystal phase development that canbe monitored by this method are exemplified inFigure 3. Events A and B mark changes in form IIevolution during growth in methanol. Unlikeform III, whose peak intensities remained rela-tively unchanged during most of the process,form II diffractions varied significantly. Duringsequence A, diffraction of the (2 1�2) face at 2.47 Aincreased as the 4.47 A peak corresponding to the(�1 1 1) face reduced. Similarly in sequenceB, the(4 0 2) reflection at 3.25 A was preceded by themarked signal decrease of the (6 1 1) face at 3.00 A.

Summary of Crystal Phase Transformations

Form I became unstable and transformed intoforms II and III on cooling in all solvents exceptnitromethane where form III did not appear evenwhen the temperature fell to 88C. Polymorphconversion occurred rapidly in methanol and 2-propanol but was more gradual in nitromethaneand isobutanol reaching an equilibrium state withthe other polymorphs in solution. Figure 8 sum-marizes the interconversions and co-existenceof piracetam polymorphs from these differentsolvents. Crystal phase transformation pathwaysvaried, with some conversions happening bydirect structural re-arrangement, others throughdissolution followed by recrystallization and inthe case of hydrates via multiple short-livedintermediate states.

Unlikemodifications from themelt, polymorphsoften coexisted in solution for extended period oftimes. Although temperature was continuouslyreduced, interconversion generally progressedgradually. The growth rivalry observed here andelsewhere12 between forms II and III during crys-tallization could be explained by the polymorphsenergetic and structural similarities. Even thoughprevious experiments demonstrated that the lat-ter form is normally favored over time, conversionrates differed depending on the solvent of choice.

Solution-mediated transformations of pirace-tam conform to Ostwald’s Rule of Stages occurring

in the expected stability order from form I to II toIII as temperature was decreased.

CONCLUSION

The incremental heating/cooling loop mechanismallowed a wider monitoring temperature intervalwhich could be controlled from outside the X-rayhutch. This in situ technique is a powerful tool tomonitor structural mechanisms of phase trans-formations and can be effectively used as a rapidmethod for polymorph screening providing excel-lently resolved diffraction data. Additionally, thetechnique can be valuable informing crystalliza-tion solvent selection. Piracetam crystallizationwas strongly affected by solvent effects producinga variety of phases that crystallized in eitherprismatic or needle habits via different pathwaysand at variable growth rates.

ACKNOWLEDGMENTS

This work was financed by Bradford UniversitySchool of Life Sciences and Merck Sharp &

Figure 8. Schematic representation of piracetamcrystallization profiles from methanol, 2-propanol, iso-butanol, and nitromethane showing polymorph evolu-tion during cooling of solutions. Key: T0, initialtemperature of solution; I, form I crystals; II, form IIcrystals, and III, form III crystals.

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Dohme. The authors thank Dr. Colin Seaton forhis help with the creation of MEDD software, andAlfie Nield and Barry Hammond for the supportgiven in the development and set-up of the stagefor Station 16.4.

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