Control of Crystal Polymorphism by Tuning the Structure of Auxiliary

CRYSTAL GROWTH & DESIGN

Control of Crystal Polymorphism by Tuning the Structure of Auxiliary Molecules as Nucleation Inhibitors. The β-Polymorph of Glycine Grown in Aqueous Solutions

2005 VOL. 5, NO. 6 2190-2196

Vladimir Yu. Torbeev, Edna Shavit, Isabelle Weissbuch,* Leslie Leiserowitz,* and Meir Lahav* Department of Materials and Interfaces, The Weizmann Institute of Science, 76100-Rehovot, Israel Received May 5, 2005;

Revised Manuscript Received August 15, 2005

ABSTRACT: The control of crystal polymorphism of the trimorphic crystals of glycine (Gly) grown in aqueous solutions in the presence of R-amino acids operating as stereospecific nucleation inhibitors is reported. The presence of enantiopure R-amino acids phenylalanine (Phe), methionine (Met), and tryptophan (Trp) in the crystallizing aqueous solutions induces changes in the morphology of R-Gly leading to the formation of pyramidal instead of bipyramidal crystals. Increased concentrations of racemic Phe and Met inhibit both the R- and β-polymorphs of glycine and induce precipitation of the thermodynamically most stable γ-polymorph. R-Amino acids that bear bulky side groups such as racemic tryptophan (Trp), N-CH3-Trp, and R-naphthylalanine induce precipitation of the least stable β-Gly polymorph. Quasi-racemic mixtures of R-Trp and S-Phe (or S-Met), for example, lead to the precipitation of one of the enantiomorphs of β-Gly. The roles played by the different R-amino acids in affecting morphology and polymorphism are discussed in terms of their interactions with and stereoselective occlusion in the various sectors of the {010} faces of the β-Gly crystals. Introduction The ability to control crystal polymorphism is of paramount importance in pharmacology, solid-state chemistry, and material sciences.1-9 Theories and experimental studies on crystal nucleation suggest the formation of clusters in supersaturated solutions.10-14 Some time ago, we proposed a kinetically controlled process for the precipitation of metastable polymorphs based on a working hypothesis that among such clusters are crystallization nuclei whose structures and morphologies resemble those of the various mature polymorphs. Consequently, auxiliary molecules were designed to stereoselectively target the nuclei of the thermodynamically stable form and prevent their growth into crystals.3,15-19 A less stable polymorph can then precipitate from the solution, provided the auxiliary molecules do not interfere with its growth (Scheme 1). Such stereospecific inhibitors are generally composed of two moieties: one, referred to as the “binder”, whose role is to adhere to the surfaces of the targeted nuclei, and is modeled on the basis of the surface structures of the different faces to be inhibited.3,7 The task of the second moiety, referred to as the “perturber”, is to hinder the deposition of oncoming molecular layers and thus retard or, at best, prevent the transformation of these nuclei into crystals. A bulky perturber will impart to the auxiliary molecule the property of very efficient inhibition provided it does not interfere with the function of the binder. On the other hand, if the perturber prevents the molecule from adhering to a set of equivalent sites on the surface of the crystal nucleus, the * To whom correspondence should be addressed. E-mail: [email protected]; [email protected]; [email protected].

Scheme 1

perturber shall either reduce or eventually negate the inhibiting properties of the auxiliary molecules. Such a dual function of the auxiliary molecule can be taken advantage of for the control of crystal polymorphism in systems in which the different polymorphs are delineated by faces of similar surface structure but textured differently. We illustrate this approach with the control of glycine polymorphism in aqueous solutions, making use of different enantiomerically pure or racemic R-amino acids as auxiliary molecules. Experimental Section All R-amino acids were purchased from Sigma-Aldrich and Fluka and used without further purification. The identification of the polymorphs was carried out with powder X-ray diffraction (PXRD) measurements (Rigaku Rotaflex diffractometer, Cu KR rotating anode radiation) or by single-crystal X-ray diffraction (Enraf-Nonius Mach3 diffractometer, Cu KR radiation). The morphology of the crystals was determined on the single-crystal diffractometer. The characterization with PXRD was unambiguous because each polymorph has its unique diffraction pattern. Typical experimental procedure for growing crystals is as follows: 10 g of glycine (Gly) and the corresponding amount of auxiliary(ies) were dissolved in 30 mL of deionized water. The solution (filtered through cotton wool) was divided into three crystallizing dishes covered with filter paper. Crystals were grown by slow evaporation at room temperature.

10.1021/cg050200s CCC: $30.25 © 2005 American Chemical Society Published on Web 10/01/2005

β-Polymorph of Glycine Grown in Aqueous Solutions

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An Olympus SZX9 microscope with an attached digital camera was used to obtain most of the photographs. A Leica DM IRE-2 fluorescence microscope with DAPI filter or Zeiss fluorescence microscope with UV filter (G365FT395LP420) was used to image the localization of Trp, N-methyl-tryptophan, and R-naphthylalanine occluded in the β-Gly crystals. Autoradiography measurements were performed using a Fuji Imaging plate (type BAS-III) and a Typhoon 9200 imager. S-[U-14C]-phenylalanine (16.6 GBq/mmol, 450 mCi/mmol) was purchased from Amersham Biosciences and used as 70 µL added to 30 mL of crystallizing solutions. A Breeze-Waters HPLC system including a 1525 pump, Waters 2487 UV absorbance detector was used in chiral HPLC measurements. The mobile phase (0.01 M HClO4, pH 2.0), thoroughly purged with helium, was pumped at room temperature through a CROWNPAK CR(+) chiral HPLC column (5 µm, 150 × 4 mm) at a flow rate of 0.4-1.2 mL/min and the absorbance was measured at 210 nm. The amino acids were separated by adjusting the flow rate or by using an elution gradient. The amount of auxiliaries found to be occluded within the β-Gly crystals grown in the presence of 2% (w/w Gly) RStryptophan (Trp) varied slightly about 0.1% (mol/mol of Gly) Trp, according to a reference mixture. In the nontwinned specimen β-Gly crystals, the “right” enantiomer predominated over the “wrong” one in the ratio of 10:1. Other R-amino acids were occluded according to their concentration in solution. For example, specimen crystals grown in the presence of a mixture of 2% RS-Trp (0.73 mol %) and 0.5% RS-phenylalanine (Phe 0.23 mol %) i.e., a mole ratio of 3.2:1, contained occluded RSTrp and RS-Phe in the same ratio i.e., 0.1% mol RS-Trp and 0.03% mol RS-Phe. Increasing the mole ratio of RS-Trp:RSPhe to 1:1 in the crystallizing solution led to a 1:1 ratio of additives occluded in the β-Gly crystals.

Results and Discussion Glycine crystallizes in three different polymorphs, R, β, and γ (Figure 1). The thermodynamically stable γ-form crystallizes in the enantiomorphous space group P31 (and P32) from basic or acidic aqueous solutions.20 A less stable centrosymmetric R-form21,22 (space group P21/n) always precipitates from supersaturated aqueous solutions in the form of bipyramids, via a kinetically controlled process dominated by the presence of glycine cyclic dimers7,23-25 formed in the solution. The β-polymorph, which appears in the chiral space group P21, is the least stable form of glycine and crystallizes from water/ethanol or water/methanol solutions.26-29 The various amino acid auxiliary molecules bear the same glycine unit as the binder but contain different side groups as perturber. The R- and the S-amino acid molecules bind to and inhibit growth of the centrosymmetric R-Gly primarily along the +b and -b directions of the crystals, respectively, predominantly affecting the corresponding enantiotopic (010) and (01 h 0) faces. Therefore, when Gly is crystallized from aqueous solution in the presence of the enantiopure R- or S-methionine (Met), R- or S-phenylalanine (Phe), or R- or S-tryptophan (Trp), the growth of the R-Gly crystals takes place faster along the unperturbed direction, either -b or +b, respectively, resulting in formation of R-Gly as chiral pyramids instead of the bipyramids (Figure 2a) that are formed in pure glycine solutions.30,31 To prevent nucleation of the R-Gly, it is imperative to inhibit growth along both +b and -b directions. Thus, glycine was crystallized in the presence of either of three different racemic R-amino acids, RS-Met, RS-Phe, or RS-Trp, that bear side groups of increasing bulkiness, to yield various Gly polymorphs, as described below and summarized in Table 1.

Figure 1. Packing arrangements of the three polymorphs of Gly delineated by the most important crystal faces: (a) The R-form showing the enantioselective adsorption of R- and S-Met molecules; (b) The (+)- and (-)-β-forms showing the adsorption of R- and S-Trp molecules, respectively; (c) the P31 and P32 γ-forms.

In the presence of 1-3% RS-Met (w/w of Gly) or up to 1% RS-Phe, R-Gly precipitates as well-formed plates (Figure 2b), which become thinner with increasing auxiliary concentration. On the other hand, 4-7% RSMet yields a mixture of the R- and γ-polymorphs. At 8% RS-Met, only the γ-polymorph precipitates as long

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Torbeev et al. Table 1. Summary of the Gly Polymorph and Crystal Habit Obtained during Crystallization in Aqueous Solutions in the Presence of Various Auxiliary Molecules

auxiliary

Figure 2. Gly crystals grown from aqueous solutions in the absence and the presence of auxiliaries: (a) R-Gly, no additive; (b) R-Gly from 1% (w/w of Gly) RS-Phe (or RS-Met, or RSTrp); (c) γ-Gly from 8% RS-Met; (d) γ-Gly from 3.5% RS-Phe.

needles (Figure 2c). In some experiments, we observed first the precipitation of thin platelike crystals of R-Gly that subsequently dissolved when crystals of γ-Gly started to appear. In other experiments, R-Gly crystals were not observed prior to the appearance of γ-Gly crystals. Similarly, addition of an increased amount of RS-Phe, 2-4%, induced the precipitation of γ-Gly as needles, shorter and thicker compared to those obtained via RS-Met (Figure 2d). Previous studies19 have shown that γ-Gly crystals appear as [001] needles growing along the polar c-axis much faster at the CO2- end (flat face) than at the opposite capped end (Figure 1c). This unidirectional growth was interpreted in terms of a “relay” mechanism, according to which the corrugated face at the CO2- end has ridges covered by bound water and pockets weakly hydrated and thus amenable to fast filling by NH3+ groups of an oncoming Gly molecules that, in turn, induce stripping of the water molecules from the ridged surfaces.32 The differences in the aspect ratio of the γ-Gly crystals obtained in the presence of Met and Phe (Figure 2c,d) indicate the steric hindrance exerted by a perturber that inhibits growth along the otherwise fast growing CO2- crystal end (Figure 3). The Met perturber hinders growth primarily perpendicular to the side prismatic faces, whereas Phe perturber containing an aromatic ring may adopt a conformation that hinders growth along the polar c-axis resulting in the formation of shorter and thicker crystals. By contrast, addition of increasing amounts of racemic hydrophilic R-amino acids such as up to 16% serine, 17.5% histidine, 5-30% lysine, or 3-6% glutamic acid (up to their maximal solubility) led to the appearance of only the R-Gly polymorph as {010} plates that became thinner and thinner. These results are in keeping with the notion that the perturber moiety of the auxiliary molecules plays a decisive role in the control of crystal polymorphism. Addition of 1-3% R- or S-Trp in various concentrations and up to 1% RS-Trp yielded precipitation of R-Gly as pyramids and thin plates (Figure 2b), respectively. A completely different behavior was observed with increasing RS-Trp concentration. Addition of 1-1.5%

auxiliary conc in solution (% w/w of Gly)

Gly polymorph type

crystal habit

R- or S-Met R- or S-Phe R- or S-Trp RS-Met RS-Met RS-Met RS-Phe RS-Phe

1-6 1-3 1-3 1-3 4-7 8 0.1 - 1 2-4

R R R R R+γ γb R γ

RS-Trp RS-Trp RS-Trp

0.1 - 1 1 - 1.5 1.5 - 1.8

R R R

RS-Trp

1.9 - 2.4

RS-Ser RS-His RS-Lys RS-Glu RS-Trp + S-Met RS-Trp + R-Met RS-Trp + S-Phe RS-Trp + R-Phe R-Trp + S-Met R-Trp + S-Phe S-Trp + R-Met S-Trp + R-Phe RS-Met + RS-Trp RS-Phe + RS-Trp RS-Met + R- or S-Trp RS-Phe + R- or S-Trp RS-Nmethyl-Trp RS-R-naphthylalanine

1 - 16 1 - 17.5 5 - 30 3-6 (1.5 - 2) + (1 - 5) (1.5 - 2) + (1 - 5) (1.5 - 2) + (0.5 - 2) (1.5 - 2) + (0.5 - 2) (1.5 - 3) + (1 - 5) (1.5 - 3) + (0.5 - 2) (1.5 - 3) + (1 - 5) (1.5 - 3) + (0.5 - 2) (7 - 8) + (1.5 - 2) (7 ÷ 8) + (1.5 - 2) (7 ÷ 8) + (1.5 - 2) (7-8) + (1.5 - 2) 1.5

(+)- and (-)-βb,c R R R R (+)-β

pyramid pyramid pyramid platea plate + needle long thin needle platea shorter and thick needle plate unusual habit thin oval with steps {010} plate or prismatic platea platea platea platea {010} plate

(-)-β

{010} plate

(+)-β

{010} plate

(-)-β

{010} plate

(+)-β

{010} plate

(+)-β

{010} plate

(-)-β

{010} plate

(-)-β

{010} plate

(+)- and (-)-β (+)- and (-)-β (+)- and (-)-β (+)- and (-)-β (+)- and (-)-β (+)- and (-)-β

{010} thin plate

1.5

{010} thin plate {010} thin plate {010} thin plate {010} plate {010} plate

a The thickness of the R-Gly plates decreases with the increase in the concentration of the auxiliary molecules. b γ- and β-polymorphs each appear as two enantiomorphs labeled P31 and P32 for γ, and (+) and (-) for β. The enantiomorphs of β-Gly can be differentiated by the addition of the chiral DNPLys dye (see below). However, the dye does not differentiate between the two enantiomorphs of the γ-Gly polymorph. c When left overnight, β-Gly crystals underwent partial dissolution followed by precipitation of γ-Gly as relatively short and thick needles.

led to the formation of fewer but larger R-Gly crystals displaying an unusual habit with high index {01l} (l ) 10-12) faces (Figure 4a). Increasing the concentration of RS-Trp to 1.5-1.8% induced the appearance of thin oval R-Gly crystals displaying well-developed steps (Figure 4b). This morphology suggests that the Trp molecules bind to the steps of the {010} faces and, owing to the bulkiness of the Trp side group, hinder the regular progress of the growing ledges on these faces


Figure 3. Packing arrangement of γ-Gly crystal (space group P32) showing the adsorption of R-Trp, R-Met, and R-Phe auxiliary molecules.

Figure 4. Gly crystals grown from aqueous solutions in the presence of various amounts of RS-Trp: (a) R-Gly from 1.5% w/w RS-Trp; (b) R-Gly, from 1.8% RS-Trp; (c, d) β-Gly from 2% RS-Trp displaying a platelike, as in (c), or prismatic habit as in (d) showing two views, with assigned (hkl) indexes of the crystal faces; (e) γ-Gly from 2% w/w RS-Trp when the crystallizing solution was left overnight.

resulting in an oval habit possessing pronounced steps. A further increase in concentration of RS-Trp to 1.92.4%, the limit of its solubility in water, results in the precipitation of crystals of the β-Gly polymorph exhibiting two morphologies, either {010} platelike (Figure 4c) or prismatic (Figure 4d) that were found to be composed of two enantiomorphous segments twinned about the {010} plane (vide infra). These crystal morphologies are in contrast to the β-Gly needlelike habit obtained from water/ethanol solutions.29 When the β-crystals were left


Figure 5. Crystals of β-Gly grown from aqueous solutions in the presence of a mixture of 2% RS-Trp and 0.1% R- or RSDNPLys: (a) Two views of the same yellow colored crystal; bottom, view along the c direction showing the color at only one side, and top, view along the b direction showing coloring in the (100) and (1h 00) sectors when grown from R-DNPLys; (b) view along c direction of a crystal colored at both b sides due to twinning when grown from RS-DNPLys.

overnight in the crystallizing aqueous solutions containing the RS-Trp, they underwent partial dissolution followed by the precipitation of the γ-Gly polymorph as relatively thick and short needles (Figure 4e). This crystal morphology indicates inhibition of γ-Gly growth along the -c direction similar to Phe. However, this morphology does not reflect why Trp inhibits nucleation of γ-Gly much more efficiently than that of β-Gly. An attempt to assign the sense of polarity of specimen β-Gly crystals via the Bijvoet method was unsuccessful because the atoms are weak anomalous X-ray scatterers and the molecular arrangement, when only O, N, C atoms are considered, is nearly centrosymmetric (space group pseudo-P21/m). Thus, we made use of “tailormade” auxiliaries for this purpose.3,33 For convenience, we define the two enantiomorphous crystals of β-Gly as follows. The enantiomorph in which the Gly C-H bonds point along the +b direction, and thus would emerge from the (010) face, is defined as (+) (Figure 1b left). Replacement of these H atoms by deuterium (to form a C-D bond) would yield Gly molecules of “R-configuration”. By symmetry, the opposite (-) enantiomorph contains Gly molecules whose C-H bond vectors emerge from the (01 h 0) face would be of “S-configuration” (Figure 1b right). Thus, on crystal growth, any R-amino acid additives are expected to bind selectively to the (010) face of (+) β-Gly and S-amino acids onto the (01 h 0) face of (-)-β-Gly. To differentiate between the (+)- and (-)-β-enantiomorphs, we colored them enantioselectively by growing the β-Gly crystals in the presence of mixtures of 2% RSTrp and 0.1% of either R- or S-N-(2,4-dinitro-phenyl)lysine (DNPLys). Indeed, the β-Gly platelike crystals grown in the presence of S-DNPLys appeared as a mixture of colorless (+)-enantiomorphs (Figure 4c) and (-)-enantiomorphs colored only at the (01h 0) face (Figure 5a). Furthermore, an enantiomeric analysis, by chiral HPLC, of the Trp occluded in the β-Gly plates revealed an excess of R-Trp (enantiomeric excess, ee ∼ 65-88%) in the colorless (+) crystals and S-Trp in the colored (-) crystals. These results also prove that S-Trp and S-DNPLys are occluded in the colored (-) crystals by replacing the C-H bond of a glycine host molecule with the side group of the additive. By symmetry, R-Trp and R-DNPLys are occluded in the same manner but in the (+) crystals.

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Figure 7. (a) Yellow crystals of (-)-β-Gly crystals grown in the presence of mixture of 2% (w/w) RS-Trp 2% R-Phe and 0.1% S-DNPLys; (b) colorless (+)-β-Gly crystals grown in the presence of a mixture of 2% RS-Trp, 2% S-Phe, and 0.1% S-DNPLys. Figure 6. (a) Schematic representation of the {010} face of β-Gly crystals displaying three types of sectors; (b) images of β-Gly crystals taken under a fluorescence microscope showing, as lighter regions, Trp occluded primarily within the (1 h 01) and (101 h ) sectors; (c) autoradiography image of a (-)-β-Gly crystal grown in the presence of a mixture of RS-Trp and minor amount of S-[U-14C]-Phe.

As anticipated, the twinned β-Gly crystals grown from mixtures of 2% RS-Trp and RS-DNPLys were colored at both (010) and (01h 0) sides (Figure 5b). Furthermore, the chiral HPLC analysis demonstrated that both Rand S-Trp (ee ∼ 6-12%) were occluded in the whole twinned crystals. However, specimen crystals cut in three pieces perpendicular to the b direction contained 83-86% ee of R- or S-Trp occluded at opposite {010} sides. Inspection of the colored β-Gly crystals indicates that the DNPLys dye is present in some crystals preferentially in the (100) and (1h 00) sectors of the {010} face (Figures 5a and 6a).34,35 Moreover, occlusion of Trp in β-Gly crystals is also restricted but primarily to the (1h 01) and (101h ) sectors of the {010} face as demonstrated by the images taken with a fluorescence microscope (Figure 6b). These observations imply that the attachment of the R-amino acid auxiliary with a bulky perturber group to the appropriate {010} face is controlled by steric factors exerted presumably by growing steps and kinks at the {010} surface on the perturber group during the binding process. The occlusion of Trp at certain sectors of the {010} surface is sufficient to induce only morphological changes of β-Gly but not to inhibit efficiently its crystal nucleation. This assumption is further supported by the results obtained with the R-amino acids bearing the less bulky groups that interact with all the sectors of the fast growing {010} surface of β-Gly, thus inducing the precipitation of the stable γ-polymorph. Selective Inhibition of β-Gly Enantiomorphs. The observation that the less bulky perturbers of Phe and Met eventually induce the formation of γ-Gly but not of the β-polymorph may be explained on the assumption that they prevent its precipitation by binding at all sectors of the {010} face. This deduction was confirmed experimentally by, first, crystallization of the β-Gly crystals in the presence of quasi-racemic mixtures of 1.5-3% R-Trp and 0.5-2% S-Phe (or 1-5% S-Met) and 0.1% S-DNPLys that resulted in the appearance of

a mixture of mainly thick and colorless (+)-β-plates and some very thin yellow (-)-β-plates. By symmetry, the presence of quasi-racemic mixtures of 1.5-3% S-Trp and 0.5-2% R-Phe (or 1-5% R-Met) and 0.1% S-DNPLys resulted in the appearance of a mixture of mainly thick and yellow (-)-β-plates and some very thin colorless (+)β-plates. Second, mixtures of 1.5-2% RS-Trp and 0.52% R-Phe (or 1-5% R-Met) and 0.1% S-DNPLys yielded thick, colored (-)-β-Gly plates, whereas the few thin (+)β-plates were colorless. In some experiments with 2% R-Phe, only the thick, colored (-)-β-Gly crystals were observed and, by symmetry, in the experiments with 2% S-Phe only the colorless (+) β-Gly crystals were observed (Figure 7). These results demonstrate that the enantiomerically pure R-Phe and R-Met are very efficient and enantioselective inhibitors of nucleation and growth of the (+)-β-enantiomorph, whereas S-Trp retards growth of only two sectors within the {010} face of (-)-β-Gly accounting for the precipitation of only this enantiomorph. In addition, to test possible asymmetric induction by Trp, crystallization of β-Gly in the presence of 2.5% nonracemic Trp (ee up to 40% R or S) yielded equal numbers of (-)- and (+)-enantiomorphs. To prove conclusively that Phe is adsorbed at all the sectors of the {010} face, the β-Gly crystals were grown in the presence of mixtures of RS-Trp, a very small amount of S-[U-14C]-Phe and S-DNPLys (used as a label to identify the (-)-enantiomorph). The autoradiography image36 in Figure 6c is in agreement with this hypothesis. Inhibition of γ-Gly by Trp. To analyze the role played by Trp on the nucleation of the γ-form, we crystallized Gly in aqueous solutions containing a mixture of 7-8% RS-Met (or 3-3.5% RS-Phe), which would yield γ-Gly, and 1.5-2% of either RS- or R (or S)-Trp. The addition of Trp induces the precipitation of β-Gly as very thin plates. These experiments demonstrated that both R- (or S)- and RS-Trp operate as most efficient inhibitors of both γ-enantiomorphs. Chiral HPLC analysis of single crystals of the γ-form grown in the presence of racemic amino acids demonstrated that both enantiomers are occluded inside these crystals, implying that γ-Gly polymorph, in contrast to the two other polymorphs, does not discriminate during growth between R- and S-R-amino acid auxiliaries. To further confirm that the precipitation of β-Gly crystals is a result of inhibition of the R and γ-poly-


morphs by R-amino acid auxiliaries that comprise bulky perturber groups, we performed similar crystallization experiments of Gly in the presence of RS-N-methyl-Trp or RS-R-naphthylalanine; the addition of these auxiliaries, in concentrations of 1.5% up to their limit of solubility in water, also induces the precipitation of the β-Gly polymorph. Conclusions We conclude that in the design of “tailor-made” auxiliaries for the control of crystal polymorphism one should put emphasis not only on the role played by the binder moiety but also that played by the perturber moiety of the auxiliary molecules. Crystallization of trimorphic glycine in the presence of R-amino acid auxiliaries that comprise the same binder is a convenient model system to probe the role played by the perturber. As discussed previously, the precipitation of R-Gly in aqueous solutions is driven primarily by a proposed high concentration of centrosymmetric dimeric building blocks. The addition of enantiomerically pure R-amino acids to the crystallizing solutions perturbs the growth of this polymorph either along the +b or -b direction of the crystals, whereas the addition of increasing amounts of some racemic R-amino acid inhibits the nucleation and growth of the R-polymorph along both directions. Therefore, glycine can precipitate in the form of one of the enantiomorphous polar polymorphs. The {010} surfaces of the R- and β-polymorphs are very similar in structure; thus, a priori one could anticipate that racemic R-amino acids that bind to this surface of the R-polymorph will bind also efficiently to the analogous surface of the β-polymorph and inhibit its nucleation and growth. This expectation was confirmed using Phe and Met auxiliaries that led to the precipitation of the γ-polymorph. On the other hand, the textures of the {010} surfaces of the R- and β-polymorphs are different to the extent that the R-amino acids with more bulky groups such as Trp, N-CH3-Trp, and R-naphthylalanine cannot bind at all the sectors of these surfaces. Since the rates of growth of the various sectors along the b direction are linked to each other, it seems, from the present study, that the occlusion of the growth inhibitors at some sectors of the crystals only is insufficient to prevent nucleation of the β-polymorph, but it only retards its growth. Such a mechanism implies that one may tune the structures of the auxiliary molecules for the control of crystal nucleation and crystal growth by considering their attachments not at a flat surface of a growing face but rather at the various kinks and step sites of the to-be-inhibited growing faces where the perturber may introduce additional steric hindrance. Therefore, depending upon the bulkiness of the perturber, one can tune the auxiliary molecules to the crystalline motif of the affected surfaces to inhibit the nucleation of the unwanted polymorphs. This principle is currently being applied to other systems. Finally, the ability to crystallize the chiral β-form in aqueous solutions and the demonstration that this polymorph selects from the aqueous food stock enantioselectively optically resolved amino acids of a single handedness provides another plausible “prebiotic” route for a spontaneous symmetry breaking and amplification


of chirality of racemic amino acids in aqueous solutions using the Gly crystals as an auxiliary matrix.37 Acknowledgment. We thank the US-Israel Binational Science Foundation and the G. M. J. Schmidt Minerva Center for financial support. References (1) McCrone, W. C. In Physics and Chemistry of the Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Ed.; J. Wiley & Sons: New York, 1965; Vol. 2, p 726. (2) Byrn, S. R. In Solid-State Chemistry of Drugs; Academic Press: New York, 1982. (3) Weissbuch, I.; Popovitz-Biro, R.; Lahav, M.; Leiserowitz, L. Acta Crystallogr. Lead Article 1994, B51, 115. (4) Beyer, T.; Day, G. M.; Price, S. L. J. Am. Chem. Soc. 2001, 123, 5086. (5) Bernstein, J. In Polymorphism in Molecular Crystals; Oxford University Press: New York, 2002. (6) Blagden, N.; Davey, R. J. Cryst. Growth Des. 2003, 3, 873. (7) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Cryst. Growth Des. 2003, 3, 125. (8) Boerrigter, S. X. M.; van den Hoogenhof, C. J. M.; Meekes, H.; Bennema, P.; Vlieg, E.; van Hoof, P. J. C. M. J. Phys. Chem. B 2002, 106, 4725. (9) Agarwal, P.; Berglund, K. A. Cryst. Growth Des. 2003, 3, 941. (10) Popovitz-Biro, R.; Weissbuch, I.; Jacquemain, D.; Leveiller, F.; Leiserowitz, L.; Lahav, M. In Advances in Industrial Crystallization; Garside, J., Davey, R. J., Jones, A. G., Eds.; Butterworth-Heinemann: Oxford, 1991; pp 3-19. (11) Larson M. A. In Advances in Industrial Crystallization; Garside, J., Davey, R. J., Jones, A. G., Eds.; ButterworthHeinemann: Oxford, 1991; pp 20-30. (12) Mullin, J. W. In Crystallization; Butterworth-Heinemann: Oxford, 1993, Chapter 6, pp 202-263. (13) Vekilov, P. G. Cryst. Growth Des. 2004, 4, 671. (14) Aber, J. E.; Arnold, S.; Garetz, B. A.; Myerson, A. S. Phys. Rev. Lett. 2005, 94, 145503 and references therein. (15) Weissbuch, I.; Addadi, L.; Berkovitch-Yellin, Z.; Gati, E.; Lahav, M.; Leiserowitz, L. Nature 1984, 310, 161. (16) Weissbuch, I.; Zbaida, D.; Addadi, L.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1987, 109, 1869. (17) Staab, E.; Addadi, L.; Leiserowitz, L.; Lahav, M. Adv. Mater. 1990, 2, 40. (18) Weissbuch, I.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1991, 113, 8941. (19) Weissbuch, I.; Leiserowitz, L.; Lahav, M. Adv. Mater. 1994, 6, 952. (20) Iitaka, Y. Acta Crystallogr. 1961, 14, 1. (21) Marsh, R. E. Acta Crystallogr. 1958, 11, 654. (22) Legros, J.-P.; Kvick, Å. Acta Crystallogr. 1980, B36, 30523059. (23) Myerson, A. S.; Lo, P. Y. J. Cryst. Growth 1990, 99, 1048. (24) Carter, P. W.; Hiller, A. C.; Ward, M. D. J. Am. Chem. Soc. 1994, 116, 944. (25) Gidalevitz, D.; Feidenhans’l, R.; Matlis, S.; Smilgies, D. M.; Christensen, M. J.; Leiserowitz, L. Angew. Chem., Int. Ed. Engl. 1997, 36, 955. (26) Fischer, E. Ber. Dtsch. Chem. Ges. 1905, 38, 2917. (27) Iitaka, Y. Acta Crystallogr. 1960, 13, 35. (28) Ferrari, E. S.; Davey, R. J.; Cross, W. I.; Gillon, A. L.; Towler, C. S. Cryst. Growth Des. 2003, 3, 53. (29) Weissbuch, I.; Torbeev, V. Y.; Leiserowitz, L.; Lahav, M. Angew. Chem., Int. Ed. 2005, 44, 3226. (30) Weissbuch, I.; Addadi, L.; Berkovitch-Yellin, Z.; Gati, E.; Weinstein, S.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1983, 105, 6615. (31) Weissbuch, I.; Addadi, L.; Lahav, M.; Leiserowitz, L. Science 1991, 253, 637. (32) Shimon, L. J. W.; Vaida, M.; Addadi, L.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1990, 112, 6215. (33) Addadi, L.; Berkovitch-Yellin, Z.; Weissbuch, I.; Lahav, M.; Leiserowitz, L. In Topics in Stereochemistry; Eliel, E. L., Willen, S. H., Allinger, N. L., Eds.; John Wiley & Sons Inc.: New York, 1986; Vol. 16, p 1. (34) For more examples of sector-selective additive occlusion, see Kahr, B.; Gurney, R. W. Chem. Rev. 2001, 101, 893.

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(35) RS-DNPLys is not an appropriate additive to induce polymorphic transformation due to its poor solubility (less than 0.5% w/w of Gly). (36) Chmielewski, J.; Lewis, J. J.; Lovell, S.; Zutshi, R.; Savickas, P.; Mitchell, C. A.; Subramony, J. A.; Kahr, B. J. Am. Chem. Soc. 1997, 119, 10565.

Torbeev et al. (37) Weissbuch, I.; Leiserowitz, L.; Lahav, M. In Topics in Current Chemistry; Walde, P. Ed.; Springer-Verlag GmbH: New York, 2005; Vol. 256, DOI 10.1007/b137067.

CG050200S

Control of Crystal Polymorphism by Tuning the Structure of Auxiliary

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