DOI: 10.1021/cg100934f
Understanding Growth Morphology Changes of γ-Glycine and DL-Alanine Polar Crystals in Pure Aqueous Solutions
2010, Vol. 10 4883–4889
Guangjun Han,*,† Sendhil K. Poornachary,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ †
Institute of Chemical and Engineering Sciences, A-STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833, and ‡Department of Chemical and Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 Received July 15, 2010; Revised Manuscript Received August 25, 2010
ABSTRACT: The growth kinetics of γ-glycine and DL-alanine crystals in pure aqueous solutions was studied systematically using in situ microscopic observations on single crystal seeds. It was found that the growth behaviors of these two polar crystals are very similar. A fairly large dead supersaturation zone is observed respectively for their growth along the polar c-axis. Over a wide supersaturation range, the growth of these crystals along the polar c-axis remains remarkably slower than that along other axes, leading to a drastic morphological change from needle-like to prismatic pyramidal shape. This slow growth and the existence of the dead zone are attributed to the preferential adsorption of solvent water at the polar c ends, which is supported by predicted binding energies for solvent-surface interactions. With the increase in supersaturation, however, the growth along the polar c-axis, predominantly at the -c end, changes from the slowest to the fastest thereby yielding the usual needle-shaped morphology. This observed growth acceleration is explained based on structural features of the faces. The implication of these growth phenomena for the previously reported competitive formation of R-glycine and γ-glycine is discussed.
*Corresponding author. Tel: þ65 6796-3879. Fax: þ65 6316-6183. E-mail:
[email protected] (G.H.);
[email protected]. edu.sg (R.B.H.T.).
glycine and DL-alanine exist as zwitterions2,15 (e.g., glycine zwitterion, NH3þCH2COO-) and are packed in zwitterionic form in their crystal structures.2,15,16 γ-Glycine is the thermodynamically most stable form2 among the three known glycine polymorphs (R, β, and γ)3,17-20 under ambient conditions. However, γ-glycine is much more difficult to form than the metastable R-glycine2,5,20 during solution crystallization, and this remains a riddle given that zwitterionic glycine monomers (viewed as γ-glycine building units2,8) rather than cyclic dimers (viewed as R-glycine building units2,8,17,18) are predominantly present8 in an aqueous glycine solution. Normally, γ-glycine can only be crystallized in the presence of tailormade-additives2 or under other particular conditions.7,19,21-25 It is worthy to note that the use of tailor-made-additives to induce γ-glycine can involve not only the expected inhibition of R-glycine growth but also the unexpected acceleration of γ-glycine growth, as observed in our recent study.26 The least stable β-glycine crystallizes from alcohol-water solutions, but it rapidly transforms to the metastable R-glycine when in contact with water.3,20,21,27,28 Polymorphs of DL-alanine have not been reported before (to the best of our knowledge). Interestingly, DL-alanine is remarkably akin to γ-glycine in crystal packing and in morphological features.15,29,30 Both crystals are packed in such a way that their zwitterions are arranged in a head-to-tail orientation along the polar c-axis. For each of the crystal, the (001) face at the flat -c end exposes the carboxylate (CO2-) groups and the hemihedral faces at the capped þc end expose the amino (NH3þ) groups. Notably, the CO2--rich (001) face at the -c end is relatively rough and contains “ridges” and “valleys”, while the NH3þ-rich faces at the þc end are comparatively smooth at the molecular level.15,29,30 On the one hand, some studies3,15,23,25,29-31 have shown that both γ-glycine and DL-alanine grow primarily along the polar c-axis in aqueous solutions, resulting in a needle-like crystal habit. The preferential growth along the polar c-axis
r 2010 American Chemical Society
Published on Web 10/13/2010
Introduction Solution crystallization is a key technique for separation and purification in pharmaceutical and many other specialty chemicals industries. It is of great interest to control crystal growth kinetics and habit1 as they exert a great impact on crystallization and the subsequent downstream processing (e.g., filtration and drying) of the product crystals. Furthermore, alteration of crystal growth kinetics by tailor-made-additives or solvents can offer a means for polymorph control,2-4 which is of paramount importance in solid drug dosage forms. Even though great efforts have been made, precise control of crystal habit and polymorphs remains challenging both academically and industrially, as the fundamental understanding of solution crystallization is still insufficient.5-9 Polar crystals, noncentrosymmetric in structure, possess a polar axis, with different functional groups at the opposing ends of the polar axis.10 Because of this characteristic packing arrangement, polar crystals generally have salient properties such as optical activity, electrical activity, and chemical reactivity.10 The importance of polar crystals in organic solid state chemistry has been previously demonstrated by their applications in nonlinear optics.10-12 In order to obtain desirable polar crystals for their characterization and application, it is essential to understand the growth mechanisms of polar crystals, especially the effect of solvents on crystal growth and morphology.10,13 γ-Glycine and DL-alanine are typical organic polar crystals.11,12 The molecular structures of glycine and DL-alanine are very similar, with an alanine molecule (CH3CH(NH2)COOH) having an additional methyl group, compared to a glycine molecule (NH2CH2COOH). As simple R-amino acids, they are substantially water-soluble.14 In aqueous solution,
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was attributed to surface-roughening29 caused by preferential adsorption of water molecules at both the þc and -c ends. Furthermore, for the growth of γ-glycine and DL-alanine crystals, it was observed that the CO2--rich (001) face at the -c end develops faster than the NH3þ-rich faces at the þc end under the associated conditions,15,29,30 leading to unidirectional growth which may be rationalized by the “relay” mechanism.3,15,29-31 It should be pointed out that the unidirectional growth of DL-alanine was experimentally demonstrated by monitoring its growth in pure aqueous solution,15 while that of γ-glycine was inferred with the assistance of different tailor-made-additives.29 On the other hand, a few examples in literature have reported different morphologies of γ-glycine crystals grown from pure aqueous glycine solutions. For instance, during solution-mediated transformation of R-glycine to γ-glycine, platy γ-glycine crystals were observed;32 under a strong d.c. electric field, pyramidal γ-glycine crystals were obtained;23 via a controlled slow supersaturation generation of glycine solutions through a membrane, the formed γ-glycine crystals were prismatic bipyramids.22 These particular findings indicate that, under the associated crystallization conditions, γ-glycine may not grow faster along its polar c-axis than along other axes. Besides, the mechanisms underpinning the growth morphology of γ-glycine under these experimental conditions have not been addressed. In this work, in order to gain a better understanding of the growth fundamentals, we measured the growth rates of γ-glycine single seed crystals along the major growth directions in pure (additive-free) aqueous solutions at different supersaturations. The observed particular growth behavior and the changes in growth morphology of these γ-glycine seeds were explained. To assist the analysis of the obtained growth rates, molecular modeling was performed to estimate the water binding energies at specific sites on γ-glycine faces. The implication of the observed growth phenomena for glycine polymorphism was discussed. The experimental investigation on γ-glycine growth was then extended to the growth behavior of another similar polar crystal, DL-alanine. Experimental Section Glycine (>99%, Sigma), DL-alanine (>99%, AVOCADO), and acid (>99%, Sigma) were used as purchased. Ultra pure water (18 MΩ cm, Millipore Elix Milli-Q) was used to prepare various aqueous solutions. X-ray powder diffraction (Bruker D8 Advance Diffractometer) and Raman spectrometry20 (JY Horiba) were employed to verify the polymorphic form wherever applicable (refer to Supporting Information). The solubility of γ-glycine was reported26 to be 22.6 g/100 g H2O at 23 °C, lower than that of R-glycine (24.0 g/100 g water at 23 °C, determined in this study). The solubility of DL-alanine was measured using the method reported in our previous work26 and was found to be 16.1 g/100 g H2O at 23 °C. The needle-like γ-glycine seed crystals with well-developed faces were obtained by natural cooling of unstirred glycine aqueous solutions with an initial glycine concentration of approximately 35 g/100 g H2O, using DL-aspartic acid (0.7 g/100 g water) as the additive.9 The γ-glycine seed crystals were thoroughly rinsed with a saturated (with respect to γ-glycine) pure aqueous solution to remove any DL-aspartic acid adsorbed on the crystal surface and then dried at ambient condition. DL-Alanine seed crystals were prepared by evaporation of concentrated additive-free DL-alanine aqueous solutions at room temperature (∼ 23 °C). For the measurements of γ-glycine crystal growth at 23 °C, an aqueous glycine solution (pH 6.1-6.4) was prepared at an elevated temperature and cooled to 23 °C using a water circulator (with a temperature readability of 0.01 °C) to generate a supersaturation σ (σ = C/Csat, where C and Csat are the actual glycine concentration DL-aspartic
Han et al. and γ-glycine solubility respectively). About 12 mL of the supersaturated solution was gently filtered (0.22 μm, FroFill membrane filter) into a thermally pre-equilibrated (at 23 °C) glass crystallization dish (6 cm in diameter) in which a single γ-glycine seed crystal was loaded in advance. Growth of the seed crystal in a temperaturecontrolled environment (set at 23 °C) was monitored using an optical polarizing microscope (Olympus, BX51, equipped with a CCD camera) at a magnification of 4. Images of the seed crystal were acquired at regular time intervals using Analysis (Soft Imaging Systems) image capture software. Grids were drawn on the external bottom of the crystallization dish and used as reference for dimension measurement along particular directions of the seed crystal. In most cases, the duration of the seed crystal growth experiment was 5-15 min. When the duration was more than 60 min, the crystallization dish was sealed using a parafilm, with a small hole provided to focus the microscope objective. This ensured that the increase in concentration of sample solution due to evaporation was minimal (typically
