Accessing Phase-Pure and Stable Acetaminophen Polymorphs byThermal Gradient CrystallizationBasab Chattopadhyay,*,† Luc Jacobs,† Piyush Panini,† Ingo Salzmann,§ Roland Resel,#

and Yves Geerts*,†

†Laboratoire de Chimie des Polymeres, CP 206/01, Faculte des Sciences, Universite Libre de Bruxelles (ULB), Boulevard duTriomphe, 1050 Brussels, Belgium§Department of Physics, Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrook St. West, Montreal,Canada#Institute of Solid State Physics, Graz University of Technology, Petersgasse 16, 8010 Graz, Austria

*S Supporting Information

ABSTRACT: We employ a simple and reproducible method-ology based on thermal gradient crystallization to access formsI and II of acetaminophen. This methodology provides insightinto the role of heat flux in the control over polymorphism andphase transitions. We report the crystallization of differentpolymorphs of acetaminophen as a function of the thermalgradient parameters (magnitude of the gradient, samplevelocity) in a thin film geometry. The thin-film samples weredisplaced at well-defined velocities (1 ≤ v ≤ 75 μm/s) tocontrol both the direction and the rate of crystal growth. Wecarried out a detailed structural analysis combining polarizedoptical microscopy and X-ray diffraction (specular and grazing-incidence) to characterize the crystalline forms isolated by the thermal gradient technique. The resulting polymorphic forms havebeen found to exhibit high phase purity and remarkable stability over time.

Polymorphism can be defined as the intrinsic ability of asolid material to exist in more than one crystal form, which

may differ in molecular conformation and/or crystal packing.This phenomenon is linked to the unpredictability of crystalstructures from first-principles, as distinct polymorphs differonly in energies ≤10 kJ/mol.1 Polymorphism is generallyunderstood in terms of nucleation; i.e., once a nucleus of agiven phase has formed, growth continues in the same phasewithout subsequent phase transitions. In recent times, it hasgenerated an extensive body of research,2−4 which can bepartially attributed to the serious implications that poly-morphism has on industrial research and development. At afundamental level, polymorphism is critical to our under-standing of crystal nucleation and growth through synthonevolution and to structure−property correlation.5−8 It is ofgreat importance for numerous industrial sectors, e.g., pharma,food, fertilizers, explosives, pigments, and organic electronics,because polymorphism can have a dramatic impact on theproperties of organic semiconductors.9−11 In particular, differ-ent polymorphic forms of active pharmaceutical ingredients canexhibit very different physical properties including solubility,thermal stability, or even bioavailability. The preparation andcharacterization of different polymorphic forms of a drugmaterial represent an essential element in the pharmaceuticalindustry.12−14 In most cases, one of the polymorphic forms isabundantly available and can be easily accessed. However, the

access and stabilization of metastable forms are very challenging.

Such forms can potentially exhibit enhanced physical proper-

ties. In the case of pharmaceuticals, a metastable form can

provide enhanced drug delivery and bioavailability.15−18 This is

also true for acetaminophen (N-(4-hydroxyphenyl)acetamide),

(Figure 1a) commonly known as paracetamol, which is

available as both an antipyretic (fever depressant) and analgesic

(painkiller) over-the-counter drug.19

Received: November 28, 2017Revised: January 10, 2018Published: February 6, 2018

Figure 1. (a) Chemical structure of acetaminophen; (b) schematicrepresentation of the thermal gradient setup.

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Acetaminophen (PM) is known to exhibit three polymorphicforms: a monoclinic form I and orthorhombic forms II and III(Table 1S).20−24 While form I is the stable form andcorresponds to commercially available products, forms II andIII are considered metastable. Form I crystallizes in aherringbone structure which is not suitable for directcompression into tablets due to its lack of slipping planes. Incontrast, forms II and III have layered crystal structures, whichis highly desired in this context. Form II shows well-definedslipping planes and undergoes plastic deformation uponcompaction.25,26 Form III, often described as “elusive”, wasrecently characterized experimentally,23 and it has beenreported that the growth of form III is promoted by solidsubstrates,27 nanoconfinement,28 enforcing Ostwald’s rule ofstages,29 among others. However, reliably accessing metastablepolymorphic forms is still challenging, and existing approachesare mainly empirical rather than based on solid principles. Forexample, the use of molecular additives to alter thecrystallization kinetics and to access metastable forms ofacetaminophen has been reported in recent studies. Form II isobtained in high yield using a cocrystallization approach,30−32

and templating with polysaccharides was successfully used toaccess and stabilize form III.33

As part of our ongoing research objective to understand themechanisms of nucleation and crystal growth, we haveemployed the thermal gradient approach to control the growthof terthiophene and obtained single-crystalline films with anaverage domain size of 200 μm.34 Crystallization in a thermalgradient is a well-developed technique in the inorganicsemiconductor industry;35 it decouples nucleation from crystalgrowth, thereby, promoting unidirectional crystal growth.34,36

The role of the thermal flux in such a setup on the control ofpolymorphism is crucial and cannot be neglected. As observedfor terthiophene,34 a certain scope of formation of a metastableform by using this technique always remains. In this context, wesought to understand the role of heat flux in the control overpolymorphism and phase transitions by using acetaminophen(PM) as a model system. This is experimentally realized by atemperature gradient heating stage, as illustrated in Figure 1b,which mainly consists of two independent heating elementsseparated by a distance of 2.5 mm. One of the heating elementsis set to a certain temperature above the melting point (hotside), while the other is set to a temperature below thecrystallization temperature (cold side) of the material. Thestructural evolution is then followed, as thin films (for filmfabrication, see Materials & Sample Preparation in theSupporting Information, p S3) of PM are translated from thehot to the cold zone. In general, thin films are ideal model

systems for crystallization in a thermal gradient, as due to theabsence of convection, heat transport occurs only by diffusion.In the present study, we report on the crystallization of

polymorphs of acetaminophen as a function of thermal gradientparameters (magnitude of the gradient, sample velocity) in athin film geometry. The thin film samples were displaced at agiven velocity (1 ≤ v ≤ 75 μm/s) to control the direction andrate of crystal growth. A detailed structural analysis combiningpolarized optical microscopy (POM) and X-ray diffraction(specular and grazing-incidence) has been carried out tocharacterize the crystalline forms achieved by the thermalgradient technique. With respect to pharmaceuticals, meltcrystallization has distinct advantages over solution-basedprocesses, the most important being solvent independencyand high production rate per unit volume.37 Moreover, the useof a temperature gradient provides a controlled andreproducible pathway. It is useful not only for controllingpolymorphism but also crystal morphology.34 The thermal andstructural aspects of PM24 make it an ideal candidate to bestudied in a thermal gradient. There, crystallization occurs in anout-of-equilibrium condition providing possible routes to accessdifferent polymorphic forms.Powder diffraction data of the purchased powder (Support-

ing Information, section Materials and Sample Preparation, pS3) could be unambiguously indexed and related to themonoclinic phase I of acetaminophen (Figure 1S). The effect ofmelting on the bulk powder was studied by collectingdiffraction data of the sample cooled to room temperature(RT) after melting. Diffraction results were consistent withdifferential scanning calorimetry (DSC) (Figure 2S): the bulkpowder melts at a temperature of 170 °C and upon cooling toRT, a glassy phase is formed, which, if annealed to 70 °C, formsphase II that melts at 154 °C. This observation is consistentwith the reported thermotropic behavior of acetaminophen.24

The diffraction pattern of the material obtained by annealingthe glassy phase to 100 °C for 10 min coincides with form II.This observation was confirmed by a Pawley fitting of therecorded diffractogram, which resulted in a good matchbetween the experimental and calculated profiles with agree-ment factors Rwp = 13.99, Chi2 = 4.4 (Figure 3S). However, thecrystallization of the glassy phase can also occur at atemperature of 60 °C resulting in traces of form III in thediffraction pattern. The formation of form III between confinedglass plates is well-documented in the literature.24 It can beattributed to the presence of the solid substrate which facilitatesstabilization of the unstable phase III. The role of the substratein crystallization of molecular functional materials has beenreviewed recently in detail,9 and its effect has also been

Figure 2. POM images of (a) form III as obtained from melt without thermal gradient; (b) form I obtained in the thermal gradient from the melt, asthe sample was translated from the 180 to 70 °C range by a translation velocity of 10 μm/s, and (c) form II obtained in the thermal gradient setupafter seeding at 70 °C; same translation velocity as in (b).

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reported for acetaminophen.27 A representative POM image ofa film sandwiched between glass plates and cooled from themelt without the thermal gradient is shown in Figure 2a. Thecorresponding specular diffraction pattern of the sample isshown in Figure 3a and is dominated by the (202) reflection

characteristic of form III. This finding is corroborated by in-plane grazing-incidence X-ray diffraction (GIXD) data whichcould be uniquely indexed to form III (Figure 4S). Note thatthe glassy phase forms after the melt is cooled to RT andconverts to form III after aging for 24 h or by annealing thesample at 60 °C for 15 min. In the thermal gradient setup, thebulk powder (confined within two glass slides) is kept on thehot zone heated to Tmelt = 180 °C. The cold zone was kept at atemperature of 70 °C, and the sample was translated from thehot to the cold zone at different speeds viz. 1, 5, 10, 25, 50, and75 μm/s. Two different pathways of gradient crystallizationwere adapted for the study: (i) Crystallization was directlysought from the melt, and (ii) crystallization was accomplishedusing nuclei of form II, which is the only form that exists above70 °C. Representative POM images of films processed in thegradient with translation velocity of 10 μm/s are shown inFigure 2b,c. For (i), formation of form I was observed after thetranslation on the gradient. POM images show essentiallyidentical morphologies irrespective of the translation speed(Figure 6s). As seen from Figure 3a, all peaks in the diffractionpattern are in fact characteristic of the monoclinic form I.However, at lower gradient velocities of 1, 5, and 10 μm/s,most intense reflections are due to the (011) and (022)crystallographic planes. In contrast, at higher translationvelocities, other planes are observed, while the intensity of

the (011) and its higher order reflections are absent. Traces ofother forms of PM in the corresponding samples were ruled outby GIXD performed at the synchrotron radiation source BESSYII (HZB, Berlin, Germany). These data are shown in Figure 4a,and all peaks could be uniquely related to form I (see simulateddata below the reciprocal space map). As discussed earlier, inthe absence of a temperature gradient, only form III is obtainedwhen the confined melt is allowed to cool down without theinfluence of a gradient. Therefore, these data demonstrate thatemploying the thermal gradient enables access to themonoclinic form I, even from the melt. For (ii), “seeding”was performed by the following protocol: the samples werecrystallized from melt and heated to 70 °C to induce form II.This form was then used as a seed in the crystallizationexperiments employing the thermal gradient (Figure 5b showsthe crystallization using the seed of form II). Using seeds ofform II, the films were translated in the gradient leading tolarge and highly oriented domains of PM, as apparent in Figure2c (see Figure 7S for POM images of form II). Note that this issimilar to the case of terthiophene and other compoundsprocessed in a thermal gradient, as reported before.34 For thesefilms, X-ray diffraction reveals the formation of films of pureorthorhombic form II (Figure 3b). All the diffraction peakscould be uniquely assigned to form II without any traces ofform I or III. Corresponding synchrotron GIXD data shown inFigure 4b corroborates this observation. Moreover, the films ofform II that were prepared using the thermal gradient are stableon a long time scale beyond 12 months. Figure 6 juxtaposesspecular diffraction patterns collected for the same sampleimmediately after preparation and after 16 months (storedunder ambient conditions).The formation of different polymorphs can be related to

details of the crystallization conditions. One such parameter,the effective cooling rate (C) was varied, as the sample istranslated from the hot to the cold zone from 0.025 to 1.875°C/s (refer to Supporting Information, section Determinationof Gradient, p S3) (Figure 5S). Without gradient the coolingrate was varied from 0.02 to 0.5 °C/s. Under all coolingprofiles, a glassy phase was obtained which, when aged orheated to 60 °C, converts to form III. As the melt of PM istranslated across the gradient, it always results in form I. If weconsider the case where PM is cooled from the melt withoutthe effect of the gradient, it always crystallizes into a glassyphase, irrespective of the cooling rate. Form I of PM isgenerally accessed from solution-based approaches, the controlof thermotropic behavior being globally weak. Through the useof the thermal gradient, form I can be systematically obtainedfrom the melt.The formation of form I in the absence of seeds can be a

direct consequence of the presence of a favorable poly-amorphous phase,38 as it has been observed that crystallizationof a particular PM polymorph is preceded by the formation ofamorphous intermediates. The preordering of these inter-mediate forms then determines the final crystal structures. Thiswould also explain that we do not observe any phase mixing.Theoretical studies also revealed that nucleation is facilitated bythe presence of intermediate metastable phases.39 In particular,simulations of urea nucleation from melt showed the presenceof two coexisting polymorphic forms during the emergence ofthe crystal phase from the melt.40 However, we do not rule outother possible mechanisms where growth is dominated by thefastest growing form as demonstrated for ROY polymorphs.41

Although a detailed correlation between gradient parameters

Figure 3. (a) Specular diffraction patterns of PM cooled directly frommelt (bottom curve) and processed with different translation speeds inthe gradient setup (see text). (b) Specular diffraction patterns of thesamples of PM processed in the thermal gradient after seeding at 70°C. The indexed reflections corresponding to different forms of PMare shown.

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and phase formation lies beyond the scope of the present work,it is evident from representative POM images and diffraction

data that the domain size and plane-orientation of the filmscrystallized in the gradient are directly affected. Crystallizationin a thermal gradient from the melt can be correlated with thediffusive nature of solidification in metals. The solidification inPM can be considered to be interface controlled, where theprocess is governed almost entirely by the kinetics of moleculardiffusion at the interface.42 In directional solidification the mostimportant factors controlling growth are the direction of thethermal gradient and the nature of crystal orientation.43 Crystalanisotropy has been shown to govern the direction of crystalgrowth as well as the shape of the growth fronts.43 Thismanifests itself in the difference in the growth fronts of forms Iand II, as shown in Figure 5. While directly crystallizing fromthe melt, the growth front exhibits a branched sea-weed typemorphology, with form I being the resulting phase (on the basisof our diffraction data). In contrast, in cases where form II iscrystallized via preseeding, a planar morphology is obtainedinstead. In this respect, the role of the crystal packing and theequilibrium crystal habit needs to be considered. In both formsI and II, PM molecules pack in a two-dimensional layeredstructure via N−H···O and O−H···O hydrogen bonds: in I thelayers adopt a zigzag herringbone packing, while in II the layersare planar (Figure 8S) dominated by van der Waals interactionbetween adjacent layers. In the crystal habit, (011) facets inform I and (200) facets in form II are parallel to the substrate,which is consistent with the specular diffraction pattern shownin Figure 3 (see also Figure 9S), while all other crystal facesalong the gradient direction can be correlated to the GIXDpattern in Figure 4 (Figure 9S). We hypothesize that in form II,the presence of the “seed” and, in particular, the planar natureof its crystal packing facilitates the formation of planar growthfronts resulting in large and highly oriented domains of PM,whereas the zigzag packing in form I leads to branched sea-

Figure 4. GIXD data for PM samples crystallized with the gradient with translation speed of 10 μm/s; qxy and qz denote the in-plane and out-of planecomponents of the scattering vector; data are scaled logarithmically; colors correspond to diffraction intensities from blue (lowest) to red (highest).(a) GIXD of form I obtained from the melt (top) and the corresponding simulated diffraction pattern together with Debye−Scherrer rings. (b)Form II prepared after seeding at 70 °C.

Figure 5. Nature of growth fronts for PM samples crystallized in thegradient with translation speed of 10 μm/s: (a) form I as obtainedfrom the melt, (b) form II prepared after seeding at 70 °C. Brightnessand sharpness of the images have been edited to increase the contrastof the growth fronts.

Figure 6. Comparison of specular diffraction data of a pristine PMform II film (thermal gradient, translation speed 5 μm/s) and thesame film aged for 16 months, as compared to the corresponding bulkpattern.

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weed type growth front due to the presence of randomlyoriented small crystalline domains.44

To summarize, we have employed a methodology based ontemperature gradient crystallization to access forms I and II ofacetaminophen as a function of gradient parameters. Wedemonstrated that crystallization in a thermal gradient offers afascinating alternative pathway toward reproducibly accessingpolymorphic phases. The resulting polymorphic forms havebeen found to exhibit high phase purity and remarkable stabilityover time. Differences in the growth front of differentpolymorphs could be attributed to the nature of their crystalpacking and equilibrium crystal habit. Besides, we obtain anoverview of the growth mechanism of PM molecules from themelt. Future work will focus on further pharmaceuticalcompounds to exploit our practical approach for the isolationof polymorphs of improved materials properties. Furthermore,the thermal gradient crystallization technique will be employedto access unknown metastable states of various molecularmaterials like active pharmaceutical ingredients, organic semi-conductors, among others.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.cgd.7b01661.

Experimental, DSC, POM images, and XRD patterns(PDF)

■ AUTHOR INFORMATIONCorresponding Authors*E-mail: basab.chattopadhyay@ulb.ac.be (B.C).*E-mail: ygeerts@ulb.ac.be (Y.G).ORCIDBasab Chattopadhyay: 0000-0001-5106-1880Yves Geerts: 0000-0002-2660-5767NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSB.C. kindly acknowledges financial support from the FRS-FNRS (Belgian National Scientific Research Fund) for thePOLYGRAD Project 22333186. B.C. is a FRS-FNRS ResearchFellow. The authors thank the Helmholtz Zentrum Berlin(HZB) for the allocation of synchrotron beamtime andgratefully acknowledge experimental support from DanielTobbens (HZB).

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