Nucleation of Elusive Crystal Polymorphs at the Solution–Substrate

Article pubs.acs.org/crystal

Nucleation of Elusive Crystal Polymorphs at the Solution−Substrate Contact Line Sendhil K. Poornachary,*,† Jose V. Parambil,‡,§ Pui Shan Chow,† Reginald B. H. Tan,†,‡ and Jerry Y. Y. Heng*,§ †

Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833 ‡ Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576 § Surfaces and Particle Engineering Laboratory, Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, United Kingdom ABSTRACT: While metastable crystal forms are kinetically favored at higher supersaturation conditions, more stable polymorphs often crystallize under the control of competing kinetic processes such as solvent-mediated polymorphic transformation and/or preferential molecular self-assembling in solution. In such cases, alternative methodologies are required to facilitate nucleation and growth of a metastable polymorph. In this study, the metastable polymorphs of D-mannitol (δ form) and glycine (β form)  which are usually difficult to isolate by classical solution crystallization methods  were obtained by slow evaporation of aqueous solution microdroplets. The metastable forms preferentially nucleated at the “contact line” where the solution−air interface meets the glass substrate surface. In contrast, the thermodynamically stable polymorph of mannitol (β form) and kinetically stable polymorph of glycine (α form) crystallized within the solution drop. Upon nucleation at the contact line, δ mannitol grew out from the solution drop by entrapping the solution in the region between the dendrite-shaped crystals. Evaporation of the thin film of solution effectively removed the water around the crystals and consequently prevented any solution-mediated transformation to the stable form. On the other hand, β glycine crystals nucleated at the contact line partially transformed to the α form through solvent-mediated transformation. By analyzing the nucleation behavior of mannitol and glycine polymorphs under fast solvent evaporation conditions, we surmise that preferential nucleation of the metastable polymorphs from aqueous solution microdroplets is not controlled solely by the rate of supersaturation generation. Alternatively, development of higher supersaturation at the solution−substrate contact line via a Marangoni-driven convective solute transport in the solution drop could influence crystallization of the metastable polymorph.

1. INTRODUCTION Polymorphism, which refers to the ability of a molecule to crystallize into more than one crystal form, could considerably impact the functional performance of pharmaceutical products such as dissolution rate and bioavailability.1,2 Solid dosage forms of an active pharmaceutical ingredient (API) or an excipient are generally formulated with the thermodynamically stable form.3,4 Yet it is important to identify, isolate, and characterize metastable solid forms so as to avoid potential problems associated with undesired polymorphic transformations during the manufacturing process.5 Besides, a metastable polymorph is at times preferred over the stable form because of its improved material handling, dissolution, and formulability properties (for example, compaction and tabletting)6,7 or for reasons relating to intellectual property issues.1 Ostwald’s Rule of Stages8 proposes that a crystallizing system prefers to form the solid phase that involves the least change in free energy of the system rather than the lowest energy form. Accordingly, a supersaturated solution (or melt) will initially form a metastable polymorph, which then transforms stepwise to the © 2013 American Chemical Society

thermodynamically stable polymorph. Nevertheless, for a polymorphic system, compliance with the rule of stages will depend on the relative nucleation kinetics of the metastable versus stable polymorph at a given supersaturation.8,9 Conventionally, kinetically favored polymorphs may be obtained from solutions by quench cooling,10 antisolvent addition,11 or fast evaporative crystallization12 that generate higher levels of supersaturation. On the other hand, selectivity toward a metastable form can be influenced by the choice of solvent,13 modifying solution pH,14 employing template substrates,15 or solution additives.16 However, when nucleation of the metastable polymorph is transient or when solution-mediated phase transformation rates are quite rapid, it becomes difficult to isolate the crystal form by employing one of these techniques. Received: November 1, 2012 Revised: December 16, 2012 Published: January 29, 2013 1180

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2.3. Microdroplet Evaporation. A 50 μL droplet of the mannitol solution (2.2 M) was placed on a microscope glass slide at room temperature and monitored using an optical polarizing microscope (Olympus, BX51) connected to a CCD camera. Images were recorded in situ using Soft Imaging System’s AnalySIS image capture software. The polymorphic form of mannitol as crystallized from the microdroplet was analyzed in situ using a Bruker Senterra Raman spectrometer. To this end, the crystal sample was irradiated using a 532 nm green laser of 20 mW power. A 20× objective lens was used to collect the backscattered light. Raman spectra were collected in the spectral range between 1740 and 287 cm−1 at 3−5 cm−1 resolution using the OPUS software (Version 6.5). For each experiment, multiple measurements (N > 10) were performed at different positions of the microdroplet. The same experimental procedure was followed to track crystallization of glycine polymorphs from aqueous solution microdroplets (2.5 and 4.0 M). 2.4. Spin Coating. A 20 μL droplet of mannitol solution (2.2 M) was spread out over a 18 mm diameter microscope coverslip (Fischer Scientific) using a WS-400B-6NPP/LITE spin coater (Laurell Technologies Corporation). The sample was spun for 3−5 min at 1000 rpm. Micron-sized mannitol crystallized upon rapid evaporation of water from a thin-film of the solution formed on the coverslip. 2.5. Spray Drying. Mannitol was crystallized by spray drying (Büchi Mini Spray Dryer B290, Germany) aqueous solutions with feed concentrations 0.55, 1.1, and 2.2 M respectively. The inlet and outlet temperatures were set to 130 and 60 °C, respectively. The feed rate, aspiration rate, and atomizing air flow rate were set to 2 mL/min, 80% and 0.47 N m3/h, respectively.

D-Mannitol (a naturally occurring hexa-hydric alcohol) has three known17 polymorphic forms namely, α, β, and δ. The stability of the polymorphs at ambient temperature (20 °C) follows the order: β > α > δ.6 While the β form is commercially used as a pharmaceutical excipient for tablets, the use of δ form as an excipient has been shown to improve the tablet formulation of poorly compactable APIs due to its excellent consolidation behavior.6,7 Mannitol has also demonstrated promising properties for inhalation drug delivery through dry powder inhalers (DPIs).18 The β form (P212121, orthorhombic) can be readily obtained from aqueous solutions by cooling crystallization. On the other hand, it has been difficult to isolate the metastable crystal forms by this route because of their tendency to undergo rapid solvent-mediated polymorphic transformation.9,19 In previous studies, the α form (P212121, orthorhombic) was crystallized either from melts20 or by slow cooling of ethanol−water solutions.6 The δ form (P21, monoclinic) was crystallized by antisolvent precipitation at higher supersaturations; however, the crystallized solid had to be isolated from the mother liquor immediately after formation in order to prevent any solution-mediated transformation to the stable form.9 In this work, serendipitously, we found that a mixture of β and δ polymorphs crystallized concomitantly upon evaporation of aqueous mannitol solutions under ambient conditions. Besides, yield of the δ form was increased on reducing the ambient relative humidity (RH). In light of these experimental observations, we investigated the mechanism underlying crystallization and stabilization of the δ polymorph by monitoring site-specific nucleation and growth of mannitol polymorphs from evaporating aqueous solution microdroplets placed on a glass substrate. Additional control experiments and theoretical analyses were performed to gain further insights into the factors influencing “contact mode” crystallization of the metastable polymorph. Furthermore, polymorphic crystallization behavior of glycine (the simplest amino acid) was investigated experimentally and compared to that of mannitol crystallization. Glycine was chosen as a model compound since previous studies21 have reported that all three polymorphs of glycine (α, β, γ) crystallize concomitantly upon evaporation of aqueous solution microdroplets.

3. RESULTS AND DISCUSSION 3.1. Concomitant Crystallization of Mannitol Polymorphs. In a typical evaporative crystallization experiment, mannitol crystallized in two distinct morphologies (Figure 1a): prismatic needle-like crystals were formed toward center of the Petri dish (sample A) and sponge-like crystals grew near the rim of the Petri dish (sample B). The two distinctive type of crystals were isolated mechanically and oven-dried at 50 °C. PXRD analysis confirmed that the samples A and B were the β (stable) and δ (metastable) polymorphs, respectively (Figure 1b). The δ form thus obtained was found to be kinetically stable under ambient conditions (55% RH, 22 °C) and did not convert to the stable form for several months. It is rather intuitive to assume that crystallization of the δ form of D-mannitol could depend on the rate of solvent evaporation. In line with this notion, yield of the δ polymorph  estimated based on the total amount of mannitol crystals harvested from an evaporative crystallization experiment  was found to increase from 16% (±10) to 47% (±10) on reducing the RH from 55% (ambient) to 5%. At higher RH (85%), only the β form crystallized. 3.2. Investigating the Crystallization Mechanism. The nucleation and growth of mannitol crystals upon slow evaporation of aqueous solution microdroplets placed on a glass substrate were monitored in situ using optical microscopy. In this setup, the spatial distribution of nucleation sites and the type of polymorph crystallized could be examined in a horizontal plane. After an induction time of 15−30 min, thin needle-like crystals nucleated in the solution drop contact line region, where the solution−air interface meets the glass substrate (Figure 2a). Concurrently, dendrite-shaped crystals nucleated in this region and grew out from the solution drop in the horizontal plane. Raman spectroscopic analysis (cf. Figure 2d) revealed that both the thin needle and dendrite-shaped crystals were the δ polymorph, as characterized by the intensities at 887, 1052, 1144, and 1250 cm−1.6,9 In contrast,

2. EXPERIMENTAL SECTION 2.1. Materials. D-Mannitol (98% purity) and glycine (99%) were purchased from Sigma-Aldrich and used as received. Powder X-ray diffraction (PXRD) analysis confirmed that raw mannitol and glycine samples were the β and α forms, respectively. Deionized water was used to prepare the mannitol and glycine solutions. 2.2. Crystallization Experiments. Aqueous mannitol solution (2.2 M) was prepared by dissolving 4 g of mannitol in 10 g of water at 60 °C. The solution was transferred into a glass Petri dish and naturally cooled to room temperature resulting in an initial supersaturation of 1.8 (σ = C/Cs; C and Cs are the actual and equilibrium concentration of mannitol (β form) in g/100 g of water at 22 °C). The solution was allowed to evaporate at ambient conditions (55% RH, 22 °C), and mannitol crystals were harvested upon complete evaporation of the solution (typically within 8−12 h). PXRD analysis for the crystal samples was carried out using a Bruker D8 Advance X-ray diffractometer with Cu Kα radiation. The samples were scanned in the 2θ range 5° to 50° with an angular increment of 0.02° per second. The same experiments were performed at low (5% RH, 22 °C; inside a dry environmental cabinet) and high relative humidity (85% RH, 22 °C; inside a desiccator with saturated NaCl solution) conditions, respectively. 1181

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Moreover, in all our experiments, the “global” supersaturation of mannitol solution drops was less than the threshold value for nucleation of the δ form reported previously. Considering this analysis, it is implied that the “local” supersaturation level in the contact line region of the solution drop should be higher (as compared to the center of the drop) in order to favor nucleation of the metastable form. The kinetic preference for crystallization of the δ polymorph was assessed based on the measured growth rates of δ and β single crystals during a microdroplet evaporation experiment. For the δ polymorph, advancement of the tip of a single crystal of a δ spherulite was tracked as a function of time (Figure 3a,b). In the case of β polymorph, linear crystal growth along the needle axis was measured (Figure 3c,d). Consequently, growth rates were calculated from the slopes of the resulting linear plots and found to be 1.5 ± 0.2 μm/s and 0.3 ± 0.1 μm/s for the δ and β polymorphs, respectively. The faster growth rate of the δ form (ca. 5 times) can be attributed, in part, to its higher aqueous solubility.9 Herein, we note that the supersaturation in the solution drop changed with time due to solvent evaporation and concomitant nucleation and growth of mannitol polymorphs. Hence, the data could provide only a relative analysis of the polymorphic crystallization kinetics. Following this, the impact of solvent evaporation rates on preferential nucleation of the δ polymorph was analyzed. A faster evaporation rate of water from a thin-film of solution in contact with the substrate could generate higher levels of supersaturation and thus enhance the possibility of producing metastable crystal forms. Toward verifying this proposition, control experiments were performed whereby rapid solvent evaporation was achieved by spin coating mannitol solutions on a glass substrate. Although not widely employed in the field of pharmaceutical sciences, recent studies24 have used spin coating as a screening technique to assess the solidification and subsequent crystallization behavior of APIs upon rapid solvent evaporation. Figure 4 shows photomicrographs of different regions of a glass substrate spin coated with mannitol solution. It can be seen that several micrometer-sized crystals are formed on the glass surface. Spatial distribution of the polymorphic form was identified using specific point analysis of mannitol crystals (N > 10) using Raman spectroscopy. The analyses revealed that the nucleated crystals were predominantly the β form (Figure 4a). The α form crystallized concomitantly in small quantities (identified by Raman intensities at 1030, 1130, and 1258 cm−1),6,9 mostly as spherulites by cross-nucleating on the β crystals (Figure 4b). Interestingly, the later observation is consistent with the previous melt crystallization data for mannitol,25 wherein the metastable α polymorph crossnucleated on the surface of β (stable form) seed crystals. As noted in these earlier studies,20,23 cross-nucleation makes seeding ineffective for achieving polymorphic selectivity. Also, it is important to pay attention to this phenomenon in the context of polymorphic control in industrial crystallization. Contrary to expectation, δ mannitol had not crystallized under these experimental conditions, suggesting that its nucleation may not be influenced by the rate of solvent evaporation. The same inference was also drawn from the polymorphic outcome of spray crystallization experiments, which always yielded the β form at the different solution feed concentrations investigated. 3.3. Crystallization of Glycine Polymorphs by Microdroplet Evaporation. Glycine is a well-studied organic model compound from the point of view of its polymorphism. He et

Figure 1. (a) Concomitant crystallization of δ and β polymorphs of mannitol on evaporation of aqueous solution in a glass Petri dish; (b) powder X-ray diffraction patterns of δ and β crystals obtained from the evaporation experiment. The inset shows microscope images of the δ (acquired under cross-polarization) and β crystals, respectively.

in the immersed region of the solution drop  where the solution is in contact with the substrate  mostly the β polymorph crystallized as prismatic needles (Figure 2b). However, a few δ sperulites crystallized concomitantly in this region of the solution drop. As the δ crystals grew out from the drop, a thin film of the solution was entrapped in the region between the dendritic crystals through a capillary effect (Figure 2c). With solvent evaporation, higher supersaturation levels were generated in the direction of dendritic crystal growth. As a result, the δ crystals appeared to escape the Petri dish upon evaporative crystallization (cf. Figure 1a). Evaporation of the thin film of solution effectively removed the water around the crystals and consequently prevented any solution-mediated transformation9 to the stable form. This type of growth behavior is analogous to the ring-shaped deposition22 commonly observed during salt crystallization (also known as encrustation) and the formation of crystalline arrangement of particles deposited from colloidal suspensions.23 The crowning behavior observed on the walls of the crystallizers, particularly during unstirred crystallization and in those with solvent reflux, could also be related to the observations reported in this work. Previous work by Cornel et al.9 has reported a supersaturation threshold value (S = 2.1) for nucleation of δ mannitol by cooling crystallization of bulk aqueous solution. Below this threshold value, the β form nucleated. In contrast, in this work, the metastable (δ) polymorph always preferentially nucleated at the solution drop contact line independent of the supersaturation levels prevailing at the point of nucleation. 1182

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Figure 2. Optical microscope images of mannitol crystallized from a solution drop: (a) δ crystals nucleate at the contact line where the solution−air interface meets the glass substrate surface; (b) a mixture of δ and β crystallize concomitantly within the solution drop; (c) δ crystals grow out from the solution drop as dendrites. (d) Raman spectra of δ and β polymorphs.

γ-glycine predominantly crystallized from microdroplets of aqueous solution at very slow solvent evaporation rates. Given that α-glycine is usually crystallized from pure aqueous solutions, nucleation of γ-glycine under these slow evaporation conditions was ascribed to a thermodynamically controlled process. Other studies21,27 on nucleation of glycine polymorphs used patterned substrates of self-assembled monolayers (SAMs) to confine small solution droplets within hydrophilic islands (of size range 25−725 μm). While fast evaporation of droplets from the large-sized islands predominantly produced the α form, the polymorph distribution shifted toward the β form on decreasing the island size. On the other hand, slow cooling of the solution droplets constrained on 1 μm sized islands predominantly produced the least stable β form. βGlycine was also crystallized from aqueous glycine-in-oil macroemulsions (droplet size in the range of 10−15 μm)28 and from aqueous solutions confined inside polymeric nanofibers and porous polymer monoliths of nanoscale dimensions.29,30 These experimental observations suggest that nucleation of the β polymorph is induced either at high degree of supersaturation or in a confined volume at a much lower supersaturation level. The current study investigated the crystallization of glycine polymorphs at the solution−substrate contact line. In Figure 5a−c are shown in situ optical microscope images acquired during microdroplet evaporation of aqueous glycine solution. Needle-shaped β-glycine (metastable form) crystallized along

Figure 3. In situ optical microscope images of mannitol crystal growth (along the needle axis) in a solution drop: (a−b) δ polymorph; (c−d) β polymorph. The growth directions are indicated by the arrow symbols (scale bars represent 200 μm).

al.26 used an evaporation-based crystallization platforms to study the dependence of nucleation of glycine polymorphs on the rates of supersaturation generation. In that work, the stable 1183

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Figure 4. Optical microscope images of mannitol crystallized by rapid solvent evaporation on spin-coated glass coverslips: (a) β crystals and (b) α crystals cross-nucleated on β crystals.

α-glycine exhibits21,29 characteristic intensities at 1324, 1411, 2972, and 3008 cm−1 and β-glycine at 1321, 1409, 2954, and 3010 cm−1. As new α-glycine crystals nucleated and grew in the contact line region, the β polymorphs dissolved (cf. Figure 5b,c), this observation being consistent with the solutionmediated transformation of β- to α-glycine.11 In the above experiments, glycine solution microdroplets were open to the laboratory environment and the crystallization was driven by free evaporation. The rate of evaporation was calculated by measuring the weight loss of glycine solution droplets placed on a glass slide as a function of time. On the basis of these evaporation rates, the rate of supersaturation generation was derived for different droplet volumes (2−50 μL) and found to vary between 0.34−2.12 per hour. All these crystallization experiments produced a mixture of α and β crystal polymorphs, with the β form preferentially nucleating in the contact line region. This observation indicates that the rate of solvent evaporation  which increased by ca. 5 times with a decrease in the droplet volume  did not influence crystallization of the least stable (β) crystal form. In contrast, previous studies21,28 have obtained mostly α-glycine crystals under similar supersaturation generation rates. Given that the polymorphic analysis was performed off-line in these previous works, it is possible that β-glycine nucleated in the solution drop contact line region transiently and subsequently transformed to the α form. In this context, we are prompted to refer to another related work31 in which the stable γ polymorph of glycine was crystallized on the walls of glass vessel and the α polymorph in the bulk solution. However, this report conflicts with our current experimental findings as well as the aforementioned studies on evaporative crystallization of glycine polymorphs. 3.4. Discussion. During quiescent evaporation of a liquid drop, the heat required by the vaporization process is conveyed from the bulk liquid to the surface both by conduction and convection. Temperature gradients on the liquid−air interface can generate nonuniform surface tension and consequently induce convection cells inside the droplet.32−34 This phenomenon is usually referred as the Marangoni convection and has previously22,23 been linked with the formation of ring-shaped patterns upon evaporation of colloidal suspension droplets. The Marangoni convection effect has also been associated with enhanced mass transfer in gas−liquid and liquid−liquid contacting systems such as gas absorption and liquid−liquid extraction.35,36 During crystallization from aqueous microdroplets, a Marangoni-driven convection can aid in the transport of solute from the center of the droplet to the contact line. As a result,

Figure 5. Optical microscope images of glycine crystallized from a solution drop: (a−c) α and β crystals nucleate concomitantly at the contact line where the solution−air interface meets the glass substrate surface (dashed curve); metastable β crystals undergo solutionmediated transformation to the stable α form. (d) Only α crystallize within the solution drop; (e) Raman spectra of α and β polymorphs.

the solution drop contact line after an induction time of 20−30 min. Prismatic-shaped α-glycine also crystallized concomitantly in the contact-line region of the microdroplet. A few β -glycine crystals nucleated at the solution drop contact line and grew out by entrapping a thin film of the solution. Within the solution drop (bulk), mostly the kinetically stable α polymorph crystallized (Figure 5d). The polymorphic forms of glycine crystals were confirmed from their Raman spectra (Figure 5e): 1184

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crystallization experiments performed under accelerated solvent evaporation rates, we suggest an alternative mechanism. As per this, nucleation of the metastable polymorph(s) is aided by Marangoni-driven convective solute transport that develops a higher supersaturation level at the solution−substrate contact line. These findings could have direct implications on pharmaceutical crystallization process development. For one, the phenomenon of site-dependent polymorphic nucleation may be exploited to generate and identify new polymorphs of a drug compound as demonstrated in the previous work37 on capillarybased crystallization. Further, this study emphasizes the importance of paying attention to potential appearance of high energy crystal forms around the edges of small vessels that are typically used in high-throughput crystallization42 and automated solubility measurement experiments. From a broader perspective, nucleation at the solution−substrate contact line could hold particular relevance in crystallization on template substrates15 and other heteronucleation modifiers.43

the solution at the contact line becomes supersaturated relative to the metastable phases with a corresponding increase in the metastable zone width. A similar physical process is known37 to occur in capillary tubes wherein slow evaporation of solution generated higher levels of supersaturation near the meniscus, consequently providing an environment conducive to nucleation of the metastable form. In that study, the effect of highly supersaturated conditions on the nucleation of polymorphic phases was evaluated theoretically in the context of classical nucleation theory. From the analysis, it was inferred that nucleation of the metastable phase becomes more probable as the supersaturation increased. Further, the supersaturation level required for nucleation of the metastable phase to dominate the system decreased with an increase in the equilibrium solubility of the stable form. Given the relatively higher equilibrium solubility of mannitol (β form) at the crystallization temperature (190 g/kg water at 22 °C),9 it could be deduced from the aforesaid analysis that a “small” increase in supersaturation in the contact line region could favor nucleation of the metastable form. In the above discussion, nucleation of metastable crystals in the region close to the droplet−glass−air contact line was reasoned due to the Marangoni effect inducing higher supersaturations in this region. However, the contact line itself might promote crystal nucleation by supplying an energetically favorable position to form. For example, the metastable polymorph of paracetamol (form II)  yet another crystal form that has been difficult to isolate by bulk solution crystallization  was previously38 found to nucleate at the edge of aqueous solution meniscus during solvent evaporation. On the other hand, the stable form I crystals always formed in the center of the crystallization vessel. In that case, nucleation of the metastable polymorph was attributed to a favorable meniscus geometry leading to higher evaporation rates in the contact line region. Furthermore, it was reasoned that heterogeneous nucleation is more energetically favored at the contact line as the nucleating crystal is constrained between the sides of the vessel and the solution−air interface, thus resulting in a smaller area of the crystal surface in contact with the solution. Additionally, previous theoretical and modeling studies39,40 have explained the role of thermodynamic factors in inducing crystal nucleation at the solution−substrate contact line. By estimating the Gibbs free energy for heterogeneous nucleation of ice crystals, it was inferred that the droplet surface thermodynamically favored crystal nucleation under the contact mode over the immersion mode. In view of these theoretical analyses, we could envisage that the growth morphology of a nucleating crystal may affect the solid−liquid interfacial energy41 and, in turn, the supersaturation threshold for heterogeneous nucleation. However, within the scope of this work, it might be difficult to verify this conjecture.

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AUTHOR INFORMATION

Corresponding Author

*Tel: (65) 6796 3842. E-mail: [email protected] (S.K.P.); [email protected] (J.Y.Y.H.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge Dr. Saif Khan (National University of Singapore) for generously providing permission to use the spin coater for the crystallization experiments. We thank Ms. Grace Lau (ICES) for helping with the crystallization experiments.

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REFERENCES

(1) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, U.K., 2002. (2) Hilfiker, R., Ed. Polymorphism in the Pharmaceutical Industry; Wiley−VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2006. (3) Bernstein., J. Cryst. Growth Des. 2005, 5 (5), 1661. (4) Zhang, G. Z.; Law, D.; Schmitt, E. A.; Qiu, Y. Adv. Drug. Delivery Rev. 2004, 56, 371. (5) Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.; Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.; McFarland, K. Org. Process Res. Dev. 2000, 4, 413. (6) Burger, A.; Henck, J.-O.; Hetz, S.; Rollinger, J. M.; Weissnicht, A. A.; Stöttner, H. J. Pharm. Sci. 2000, 89 (4), 457. (7) Yoshinari, T.; Forbes, R. T.; York, P.; Kawashima, Y. Int. J. Pharm. 2003, 258, 121. (8) Ostwald, W. Z. Phys. Chem. 1897, 22, 289. Cardew, P. T.; Davey, R. J. J. Faraday Discuss. 1993, 95, 160. (9) Cornel, J.; Kidambi, P.; Mazzotti, M. Ind. Eng. Chem. Res. 2010, 49, 5854. (10) Varshney, D. B.; Kumar, S.; Shalaev, E. Y.; Sundaramurthi, P.; Kang, S. W.; Gatlin, L. A.; Suryanarayanan, R. Pharm. Res. 2007, 24 (3), 593. (11) Ferrari, E. S.; Davey, R. J.; Cross, W. I.; Gillon, A. L.; Towler, C. S. Cryst. Growth. Des. 2003, 3, 53. (12) Bag, P. P.; Reddy, C. M. Cryst. Growth Des. 2012, 12, 2740. (13) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Quayle, M. J.; Fuller, S. Cryst. Growth Des. 2001, 1, 59.

4. CONCLUSION Slow evaporation of aqueous solution microdroplets at ambient conditions, contrary to expectation, resulted in crystallization of the extremely metastable polymorphs of mannitol (δ form) and glycine (β form), respectively. The metastable crystal forms preferentially nucleated around the solution−substrate contact line region wherein the rate of solvent evaporation is likely to be higher. In the first instance, this experimental observation appeared to be in line with the notion that high energy crystal forms will be favored at higher rates of supersaturation generation by evaporation. However, based on control 1185

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Crystal Growth & Design

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dx.doi.org/10.1021/cg301597d | Cryst. Growth Des. 2013, 13, 1180−1186