Discovery of a New System Exhibiting Abundant Polymorphism: m

Article pubs.acs.org/crystal

Discovery of a New System Exhibiting Abundant Polymorphism: m-Aminobenzoic Acid P. Andrew Williams, Colan E. Hughes, Gin Keat Lim, Benson M. Kariuki, and Kenneth D. M. Harris* School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT Wales, U.K. S Supporting Information *

ABSTRACT: Given the importance of the phenomenon of polymorphism from both fundamental and applied perspectives, there is considerable interest in the discovery of new systems that exhibit abundant polymorphism. In the present article, the preparation strategies and structural properties of three new polymorphs (denoted Forms III, IV, and V) of m-aminobenzoic acid (m-ABA) are reported, elevating this system to the rare class of polymorphic systems with at least five known polymorphs. The crystal structures of the three new polymorphs have been determined directly from powder X-ray diffraction data, using the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement, demonstrating the opportunities that now exist for determining crystal structures when crystals of sufficient size and quality for single-crystal X-ray diffraction are not available. In two of the new polymorphs (Forms III and IV), the m-ABA molecules exist in the zwitterionic form (as in the previously known Form I), while the m-ABA molecules in the other new polymorph (Form V) are nonzwitterionic (as in the previously known Form II). Furthermore, disorder of the molecular orientation, and hence disorder in the intermolecular hydrogen-bonding arrangement, is revealed in Form V. The assignment of the tautomeric form in each polymorph is confirmed by X-ray photoelectron spectroscopy. Issues relating to the relative stabilities of the five polymorphs of m-ABA are discussed.

1. INTRODUCTION Although the phenomenon of polymorphism in crystalline solids (i.e., the existence of materials with identical chemical composition but different crystal structures) was first discussed in the scientific literature 180 years ago, the last 15 years or so have seen an immense upsurge of activity in this field,2 driven both by fundamental scientific curiosity and by industrial necessity. With regard to industrial applications of crystalline materials, it is often crucial to understand the diversity of polymorphic forms that are available to a given molecule, as different polymorphs can have significantly different solid-state properties and hence different performance in materials applications. Thus, an important aspect of polymorphism research is the discovery, structural characterization, and physicochemical understanding of the full range of polymorphic forms that are accessible to a given molecule, as well as to develop reliable and reproducible procedures for the formation of each specific polymorph. In the quest to understand fundamentals of the phenomenon of polymorphism, it is crucial to have access to systems that exhibit abundant polymorphism, comprising several wellcharacterized polymorphs of a given molecule. Thus, while the vast majority of reported polymorphic systems have only two known polymorphs, cases with a greater multiplicity of polymorphic forms provide more profound opportunities to explore the fundamentals of polymorphism. Thus, the discovery of new systems exhibiting abundant polymorphism clearly has the potential to contribute significantly toward advancing our understanding of polymorphic behavior. At present, the most © 2012 American Chemical Society

prolific polymorphic system is 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (denoted ROY), for which 10 polymorphs have been reported and the crystal structures of seven of these polymorphs have been determined.3 According to the Cambridge Structural Database (CSD),4 the next highest number of polymorphs with well-determined structures5 is five, of which there are only eight cases,6 including glycine,7 acridine,8 and oxalyl dihydrazide.9 Furthermore, there are only 34 cases with four polymorphs of well-determined structure. Given that the CSD contains a total of 2710 polymorphic systems (i.e., with at least two polymorphs of well-determined structure), it is clear that systems exhibiting abundant polymorphism, with four or more polymorphs with welldetermined structures, are very rare. In this article, we report the discovery and structural properties of three new polymorphs of m-aminobenzoic acid (m-ABA), which increases the number of reported polymorphs of this compound to five and increases the number of polymorphs with well-determined structures to four (the crystal structure of one of the two previously known polymorphs is still undetermined). For the three new polymorphs of m-ABA, single crystals of suitable size and quality for single-crystal X-ray diffraction (XRD) were difficult to prepare. Under such circumstances, structure determination was tackled instead from powder XRD data, although it is important to note that the task of carrying out structure Received: March 5, 2012 Published: April 10, 2012 3104

dx.doi.org/10.1021/cg3003178 | Cryst. Growth Des. 2012, 12, 3104−3113

Crystal Growth & Design

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prepared in the present work) and the new polymorphs discovered here (Forms III, IV and V) are shown in Figure 1.

determination from powder XRD data is considerably more challenging than structure determination from single-crystal XRD data, particularly in the case of organic molecular solids. Fortunately, however, the opportunities for carrying out structure determination of organic materials directly from powder XRD data have advanced considerably in recent years,10 particularly through the development of the directspace strategy for structure solution. Early studies of m-ABA11−14 and of the ortho and para isomers of aminobenzoic acid (denoted o-ABA and p-ABA) focused on assessing their propensity to exist as zwitterionic or nonzwitterionic tautomers. To clarify this nomenclature, the present paper uses the term zwitterionic to refer to the ammonium/carboxylate tautomer (illustrated for m-ABA in Scheme 1a) and the term nonzwitterionic to refer to the Scheme 1. Molecular Structures of m-ABA in (a) the Zwitterionic Form and (b) the Nonzwitterionic Form

Figure 1. Experimental powder XRD patterns (CuKα1 radiation) for the five polymorphs of m-ABA (note that the sample of Form IV contains an impurity amount of Form I).

In the crystallization experiments carried out in the present work (see section 4.1 for more details), Form I was obtained by rapid evaporation of solvent from a solution of m-ABA in either methanol or ethanol or by rapid cooling of a solution of m-ABA in DMSO. The powder XRD pattern of Form I (Figure 1) matches that published previously14 for this polymorph. So far, our attempts to index the powder XRD data for Form I have been unsuccessful (both using laboratory data and synchrotron data). We note that the extensive overlap of peaks in the 2θ range 20−30° imposes particular challenges in the indexing process. Form II of m-ABA was obtained by heating Form III until melting was observed to start, followed by immediate cooling, such that complete melting did not occur (as discussed below, if complete melting is allowed to occur, a different polymorph is obtained). Our attempts to reproduce the method reported previously14 for preparing Form II (i.e., crystallization from ethyl acetate) led instead to concomitant crystallization of Forms I, III, and IV. Form III was obtained by evaporation of solvent from a solution of m-ABA in methanol at ambient temperature and by antisolvent crystallization from a solution of m-ABA in methanol or DMSO using water as the antisolvent. Form IV was first identified in a sample obtained by melting (starting from Form III), followed by cooling to ambient temperature in a sealed aluminum pan (in a DSC experiment). Form IV was also obtained by sublimation and condensation onto a glass coldfinger at ambient temperature. Form V was obtained by melting (starting from Form III), followed by rapid cooling to room temperature in an open vessel under a nitrogen atmosphere. Formation of Form V under these conditions appears to be favored when only a thin layer of liquid is formed upon melting. When the same procedure was carried out in an open vessel under air, a multiphase product was obtained, which included Form V of mABA as one component and a purple material (which is presumably the product of a chemical transformation) as another component. Our preliminary assignment of the m-ABA molecules in Forms III, IV, and V as zwitterionic or nonzwitterionic was

amine/carboxylic acid tautomer (illustrated for m-ABA in Scheme 1b). We note that both of these tautomeric forms are electrically neutral. In the solution state, m-ABA exists as the zwitterionic form in water and ethanol but exists as the nonzwitterionic form in dioxan.11 In the solid state, two polymorphs of m-ABA (denoted Forms I and II) were identified by infrared spectroscopy in 1971,12 and the m-ABA molecules were assigned as zwitterionic in Form I and nonzwitterionic in Form II. Subsequently, the crystal structure of Form II was determined13 by single-crystal XRD, confirming that the m-ABA molecules are indeed nonzwitterionic in this polymorph. A more recent paper14 has explored the thermodynamics and nucleation kinetics of Forms I and II and confirmed the earlier published structure of Form II. However, suitable crystals of Form I to allow structure determination by single-crystal XRD were not obtained, and the crystal structure of Form I was not determined. Our initial interest in m-ABA was motivated by the aim of determining the crystal structure of Form I directly from powder XRD data by exploiting techniques that we are developing for this purpose.10b,i,j,s However, structure determination of Form I from powder XRD data has so far proved intractable due to challenges encountered in the indexing stage of the structure determination process and our research to determine the structure of this material remains ongoing. Nevertheless, during the course of our studies, we have discovered three new polymorphs of m-ABA (hereafter denoted Forms III, IV, and V). We report the structural properties of these three new polymorphs, determined directly from powder XRD data, together with an assessment of the relative stabilities of the five polymorphs of m-ABA.

2. RESULTS AND DISCUSSION 2.1. Preparation and Initial Characterization of Polymorphs of m-ABA. The commercial sample of m-ABA, purchased from Aldrich, was found (by powder XRD) to be a monophasic sample of a new polymorph, which we designate as Form III. The characteristic powder XRD patterns of the two known polymorphs (Forms I and II; data recorded for samples 3105



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established (independently of the powder XRD data) by X-ray photoelectron spectroscopy (XPS), with C(1s), N(1s), and O(1s) XP spectra recorded for all five polymorphs. As shown previously,15 the N(1s) XP spectra of aminobenzoic acids are sensitive to the protonation state of the nitrogen atom. Thus, −NH2 groups have a peak at 399.5 eV and −N+H3 groups have a peak at 402 eV. The N(1s) XP spectra of the five polymorphs of m-ABA (Figure 2) demonstrate that the m-ABA molecules exist as the zwitterionic tautomer in Forms I, III, and IV and as the nonzwitterionic tautomer in Forms II and V.

Figure 2. N(1s) X-ray photoelectron spectra for the five polymorphs of m-ABA.

2.2. Structural Properties. Details of the procedures for crystal structure determination of Forms III, IV, and V of mABA from powder XRD data are given in section 4.2. 2.2.1. Structure of Form III. In the crystal structure of Form III, determined directly from powder XRD data (Figure 3), the asymmetric unit comprises one molecule of m-ABA as the zwitterionic tautomer. The structure can be described in terms of bilayers of m-ABA molecules, with the plane of the bilayer parallel to the (100) plane (Figure 4a). In the internal region of a given bilayer, adjacent molecules are engaged in N−H···O hydrogen bonding (see below); the aryl rings project either above or below the mean plane of this hydrogen-bonding region, forming the upper and lower surfaces of the bilayer. The −N+H3 group is in the close vicinity of the −CO2− groups of four neighboring molecules. On the basis of geometric criteria, the most favorable hydrogen-bonding arrangement is that shown in Figure 4b, in which the −N+H3 group forms two almost linear N−H···O hydrogen bonds to oxygen atoms of two neighboring molecules, while the third N−H bond is involved in a bifurcated hydrogen-bonding arrangement with two oxygen atoms from the other two neighboring molecules. In the Rietveld refinement, the hydrogen atoms were restrained to the specific positions corresponding to the hydrogenbonding arrangement shown in Figure 4b. However, we note that rotation of the −N+H3 group about the C−N bond would lead to the formation of other (geometrically less optimal) sets of N−H···O hydrogen bonds, suggesting that the energy barrier to rotation of the −N+H3 group in this structure is probably relatively low. Within the bilayer, the planes of the aryl rings of all molecules are parallel to each other (see Figure 4b). In the periodic repeat along the a axis, there are two symmetry related bilayers (related by the a glide operation), which differ in the orientations of the constituent molecules. The upper and lower surfaces of each bilayer comprise the aryl rings, and adjacent

Figure 3. Results from (a) Le Bail fitting and (b) final Rietveld refinement for Form III of m-ABA. In each case, the experimental (red, + marks), calculated (green, solid line), and difference (purple, lower line) powder XRD profiles are shown. Tick marks indicate peak positions.

bilayers are in contact with each other via van der Waals interactions. 2.2.2. Structure of Form IV. In the crystal structure of Form IV, determined directly from powder XRD data (Figure 5), there are two independent molecules in the asymmetric unit, both existing as the zwitterionic tautomer. Although the crystal symmetry of Form IV is different from that of Form III, the crystal structures of Forms III and IV share several common features. Thus, the structure of Form IV also comprises bilayers of m-ABA molecules (the plane of the bilayer is parallel to the (011̅) plane; Figure 6a). Within the bilayer, there are two different orientations of the aryl rings (evident from Figure 6b,c) and, in this respect, the structure of the bilayer differs significantly from that of Form III. As for Form III, adjacent molecules in the internal region of the bilayer are engaged in intermolecular N−H···O hydrogen bonding and the upper and lower surfaces of the bilayer comprise the aryl rings. Thus, adjacent bilayers (related to each other by translation) are in contact via van der Waals interactions. For each of the two molecules in the asymmetric unit, the −N+H3 group is in the close vicinity of the −CO2− groups of four neighboring molecules (as also observed for Form III). In each case, the orientation of the −N+H3 group that gives rise to the most favorable set of N−H···O hydrogen bonds (based on geometric criteria) is shown in Figure 6b,c, respectively, and the hydrogen 3106



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Figure 4. Crystal structure of Form III of m-ABA. (a) View of the crystal structure along the c axis, showing the bilayer nature of the structure (red dashed lines indicate the interface between adjacent bilayers; green dashed lines indicate N−H···O hydrogen bonds in the interior region of the bilayer). (b) N−H···O hydrogen-bonding interactions between the −N+H3 group and oxygen atoms of four neighboring molecules; all the molecules shown are in the same bilayer, illustrating that the planes of the molecules in a given bilayer are parallel to each other.

Figure 5. Results from (a) Le Bail fitting and (b) final Rietveld refinement for Form IV of m-ABA.

in the meta position with respect to the −NH2 and −CO2H groups). The refined occupancies of the two molecular orientations are 0.602(5) and 0.398(5), and their relative positions in the refined structure are shown in Figure 8. In rationalizing this type of disordered structure, we note that a crystal structure determined from XRD data gives an averaged representation of the actual structure, averaged over all unit cells in the crystal and averaged over time. In the present case, the average structure has disorder involving two molecular orientations, although from XRD data alone, the exact spatial distribution of the two molecular orientations cannot be determined directly. Thus, in general, an average crystal structure in which a molecule is disordered between two orientations (denoted A and B with occupancies xA and 1 − xA, respectively) may be compatible with either of the following scenarios: (i) a structure in which there are ordered domains containing only orientation A (with such domains representing a fraction xA of the crystal) and ordered domains containing only orientation B (with such domains representing a fraction 1 − xA of the crystal), or (ii) a structure in which each individual molecule throughout the crystal has a statistical probability of having orientation A (with probability xA) or orientation B (with probability 1 − xA). In case (i), the molecular orientations in a given domain are ordered, and the disorder in the average structure arises from averaging over the different domains. In case (ii), the disorder exists at the molecular level, and in principle, the orientation of a given molecule may be uncorrelated with the orientations of its

atoms of each −N+H3 group were restrained in these specific positions in the Rietveld refinement. However, for each of the two molecules in the asymmetric unit, rotation of the −N+H3 group about the C−N bond leads to the formation of other (geometrically less optimal) sets of N−H···O hydrogen bonds, suggesting that the energy barrier to rotation of the −N+H3 group is probably relatively low. 2.2.3. Structure of Form V. In the crystal structure of Form V, determined directly from powder XRD data (Figure 7), there is one m-ABA molecule in the asymmetric unit existing as the nonzwitterionic tautomer. Hence, the hydrogen-bonding pattern must necessarily be different from those in Forms III and IV. In Form V, pairs of m-ABA molecules are linked by the well-known hydrogen-bonded carboxylic acid dimer motif, denoted R22(8) in graph set notation16 (we recall that this motif cannot arise for m-ABA molecules in the zwitterionic form). Detailed consideration of the Rietveld refinement (including inspection of difference Fourier maps) indicated that the structure of Form V actually exhibits disorder in terms of two orientations of the m-ABA molecule in the average crystal structure, related by a 180° flip about an axis passing along the HO2C−C(aryl) bond. Thus, the two molecular orientations have different positions for the −NH2 group and the oxygen and hydrogen atoms of the −CO2H group, but they share the same positions of the six carbon atoms of the aryl ring, the carbon atom of the −CO2H group and three of the four hydrogen atoms of the aryl ring (excluding the hydrogen atom 3107



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Figure 6. Crystal structure of Form IV of m-ABA. (a) View of the crystal structure along the a axis, showing the bilayer nature of the structure (red dashed lines indicate the interface between adjacent bilayers; green dashed lines indicate N−H···O hydrogen bonds in the interior region of the bilayer). (b) N−H···O hydrogen-bonding interactions between the −N+H3 group of one molecule in the asymmetric unit and oxygen atoms of three neighboring molecules. (c) N−H···O hydrogen-bonding interactions between the −N+H3 group of the other molecule in the asymmetric unit and oxygen atoms of three neighboring molecules. In panels b and c, all the molecules shown are in the same bilayer, illustrating that the planes of the molecules in a given bilayer exhibit two distinct orientations.

Figure 7. Results from (a) Le Bail fitting and (b) final Rietveld refinement for Form V of m-ABA.

neighbors. In case (i), the molecules in a given domain have a well-defined set of interactions with their neighbors (analogous to an ordered crystal structure) whereas, in case (ii), a range of different local intermolecular environments may exist depending on the orientation of a given molecule and the set of orientations of its neighbors. In some cases,17 disorder of type (ii) may be ruled out if it transpires that an individual molecule in orientation A surrounded by neighboring molecules in orientation B (or vice versa) would give rise to unfavorable intermolecular interactions between pairs of neighboring molecules. In the case of Form V of m-ABA, close inspection indicates that intermolecular hydrogen bonds (N−H···O or N−H···N) of reasonable geometry can be formed in each of the following situations (in which we denote the molecular orientation of higher occupancy as A and the molecular orientation of lower occupancy as B): (1) an ordered domain containing only molecular orientation A (Figure 9a), (2) an ordered domain containing only molecular orientation B (Figure 9b), (3) a molecule in orientation A surrounded by neighboring molecules in orientation B, and (4) a molecule in orientation B surrounded by neighboring molecules in orientation A. Clearly situations (3) and (4) represent two examples of the types of local structure that may exist in disorder of type (ii) discussed above. Importantly, in situations (3) and (4), we find that there are no unfavorable intermolecular interactions of the type that would allow disorder models of type (ii) to be categorically ruled out. Thus, from the knowledge of the average crystal structure determined from powder XRD data in

Figure 8. Molecules of the two disorder components in the crystal structure of Form V of m-ABA. Atoms unique to the major component are shown in cyan, atoms unique to the minor component are shown in magenta (with the two positions of the disordered hydrogen atom in green), and atoms common to both components are shown in gray (carbon) and white (hydrogen).

the present case, we cannot establish whether the disorder in the average structure represents disorder between two ordered domains (each containing only one molecular orientation), 3108



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Figure 9. Crystal structure of Form V of m-ABA viewed along the b axis (green dashed lines indicate N−H···O hydrogen bonds) for (a) ordered domains containing the molecular orientation of higher occupancy (i.e., A) and (b) ordered domains containing the molecular orientation of lower occupancy (i.e., B). Note that the aryl rings have the same positions and orientations in panels a and b, but the hydrogen-bonding arrangements are different.

of solubility measurements discussed below), Form III appears to be the most stable polymorph of m-ABA under ambient conditions. We have measured the solubility of Form III (at 20 °C in acetonitrile, ethyl acetate, and methanol), particularly to allow a comparison19 with the corresponding solubility data reported14 for Forms I and II, which led to the assignment of Form I as the more stable of the two polymorphs reported previously. For each solvent studied, the solubility of Form III is lower than that of Form I (and of Form II), as shown in Table 1. Subject

statistical orientational disorder of individual molecules, or a disorder model lying somewhere between these extremes. To illustrate the intermolecular hydrogen bonding that could arise in the types of structure discussed above, an ordered domain containing only molecular orientation A [Figure 9a; situation (1)] has neighboring molecules linked by N−H···O hydrogen bonds, involving one N−H bond of each −NH2 group and the CO oxygen atom of each −CO2H group. In this structure, the C−OH oxygen atom does not act as a hydrogen-bond acceptor (in this regard, we recall that the strongest hydrogen-bond acceptor in a −CO2H group is the CO oxygen atom18). On the other hand, an ordered domain containing only molecular orientation B [Figure 9b; situation (2)] has pairs of molecules linked by intermolecular N−H···N and N−H···O hydrogen bonds. We note that there is additional disorder in terms of the position of the hydrogen atom of the N−H···N hydrogen bond, corresponding to the fact that there is a crystallographic inversion center at the midpoint of the N···N distance. Thus, in the average structure, there are equal populations of the N−H···N and N···H−N hydrogen-bonding arrangements linking this pair of nitrogen atoms. We also note that the hydrogen atoms of the −NH2 and −CO2H groups shown in Figure 9a,b are the specific hydrogen atom positions considered to give the most favorable sets of intermolecular hydrogen bonds and were included in these positions (with suitable restraints) in the Rietveld refinement. The structure of Form V of m-ABA has some similarity to the structure of Form II reported previously,13 which also contains pairs of nonzwitterionic molecules in the R22(8) carboxylic acid dimer motif. However, details of the hydrogen bonding of the −NH2 group differs significantly in these structures. 2.3. Aspects of Stabilities of the Polymorphs of mABA. A range of experiments and observations provide insights concerning the relative stabilities of the five polymorphs of mABA. First, we note that, under dry conditions at ambient temperature, Forms II and V are observed to be unstable (Form II transforms to Form I over ca. 7 days and Form V transforms to Form II over ca. 2 days), whereas Forms I, III, and IV exist for several months without undergoing any transformation. However, in contact with a saturated methanol solution, Forms I and IV transform over ca. 12 h to yield Form III. At present, we have been unable to establish the relative stabilities of Forms I and IV. From these observations (and from the results

Table 1. Solubilities of Forms I, II, and III of m-ABA in Acetonitrile, Ethyl Acetate, and Methanol, Quoted As Mass of Solute (in mg) Per Unit Mass of Solvent (in g)a solvent

Form I

Form II

Form III

acetonitrile ethyl acetate methanol

7.15 ± 0.06 8.78 ± 0.27 51.73 ± 0.38

23.39 ± 0.05 29.61 ± 0.11

4.65 ± 0.05 4.95 ± 0.05 50.3 ± 0.4

a

Data for Forms I and II are from Svärd et al.,14 and data for Form III are from the present study.

to well-defined assumptions elaborated elsewhere,20 lower solubility among a set of polymorphs is indicative of higher thermodynamic stability, and comparison of our measured solubilities for Form III with those quoted in the literature for Forms I and II suggests that Form III is indeed the most stable polymorph of m-ABA discovered so far. DSC results reported previously14 for Forms I and II indicate that, on heating, Form II undergoes only melting (at 178 °C), whereas Form I either transforms to Form II (at 157 °C) or undergoes melting (at 172 °C). In the present work, DSC data were recorded on heating the three new polymorphs of m-ABA from ambient temperature. Form III undergoes an endothermic phase transition at 154 °C on heating (Figure 10). On subsequent cooling (after heating to 165 °C), no reverse phase transition is observed. The phase resulting from this transition is assigned as Form I (established from powder XRD analysis after cooling the sample to ambient temperature). The endothermic nature of the transition from Form III to Form I suggests that the relationship between these polymorphs is enantiotropic,21 with Form III having the higher relative stability below the phase 3109



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chains reported so far contain only zwitterionic molecules. However, among the polymorphs of o-ABA and p-ABA, the zwitterionic form appears less common than in the case of mABA; thus, with the exception of Form I of o-ABA34 (which contains both zwitterionic and nonzwitterionic molecules in a 1:1 ratio), all other reported polymorphs of o-ABA and p-ABA contain only nonzwitterionic molecules. Although none of the polymorphs of m-ABA contains both zwitterionic and nonzwitterionic molecules within the crystal structure, our discovery of two new polymorphs of m-ABA containing zwitterionic molecules and one new polymorph containing nonzwitterionic molecules suggests that the dividing line between these tautomeric forms is readily crossed in this system. According to the latest release of the CSD,4 only 43 compounds have four or more polymorphs of well-determined structure,5 representing a very small fraction of the total of 2710 known polymorphic systems with well-determined structures included in the CSD. Thus, our report of the crystal structures of three new polymorphs of m-ABA adds to a very rare class of systems exhibiting abundant polymorphism. An immediate priority of our ongoing research on this polymorphic system is clearly to establish the structure of Form I of m-ABA, which has so far eluded successful indexing from powder XRD data.

Figure 10. DSC data for Form III of m-ABA recorded for a heating rate of 20 °C min−1.

transition temperature (which includes ambient temperature). The fact that the reverse transition from Form I to Form III is not observed on cooling in the DSC experiment is presumably attributable to kinetic factors.22 Form IV also undergoes an endothermic phase transition at 169 °C on heating, which is not reversible on cooling. The resultant phase (again identified by powder XRD after cooling to ambient temperature) is Form II. Form V is observed to undergo melting at 167 °C, but the endothermic peak in the DSC data is broad, with a hint of an additional peak just below the melting temperature, which could not be separated from the peak due to melting. In assessing the relative stabilities of polymorphic systems, higher density is often associated with greater stability (as conveyed by the density rule of Burger23), although many counter examples are known. For the four polymorphs of mABA of known structure, the densities at ambient temperature are: Form II, 1.378 g cm−3; Form III, 1.553 g cm−3; Form IV, 1.522 g cm−3; and Form V, 1.372 g cm−3. Thus, the two zwitterionic forms (Forms III and IV) have significantly higher densities than the two nonzwitterionic forms (Forms II and V). It is noteworthy that, among the four polymorphs of known structure, the polymorph (Form III) assigned in the above discussion as the most stable at ambient temperature is also the polymorph of highest density.

4. EXPERIMENTAL METHODS AND STRUCTURE DETERMINATION 4.1. Experimental Methods. The sample of m-ABA studied in the present work was purchased from Aldrich and was shown to represent a new polymorph (denoted Form III). Crystallization studies of m-ABA, starting from the commercial sample and employing a wide range of crystallization strategies, led to the discovery of two additional new polymorphs. Experimental details of the crystallization strategies employed are now outlined. Crystallization from methanol was performed by evaporation of solvent at ambient temperature from an open glass sample tube (14 mL). Faster evaporation was carried out at 50 °C with a flow of air or nitrogen over the solution. Crystallization from DMSO was carried out by cooling a saturated solution from 80 °C to ambient temperature. Sublimation of m-ABA was carried out at 140 °C (for a sample held by a silicone oil bath) and condensed on a cold finger filled with water at ambient temperature. Crystallization of m-ABA was also carried out from the melt (within melting boats of aluminum foil) under an atmosphere of nitrogen gas. The specific polymorph(s) obtained in each case are discussed in section 2.2. For phase identification (fingerprinting) of the materials obtained by these crystallization procedures, powder XRD data were recorded on a Bruker D8 diffractometer operating in transmission mode with CuKα1 radiation (Ge monochromated). For structure determination of the new polymorphs of m-ABA (Forms III, IV, and V), high-quality powder XRD data were recorded using the same instrument. For Forms I, III, and IV, data were also recorded on beamline I11 at the Diamond Light Source (transmission mode, with capillary sample holder; λ = 0.826591 Å; 4° ≤ 2θ ≤ 50°; step size, 0.001°). The powder XRD data were indexed using the CRYSFIRE powder indexing suite.37 Profile fitting was carried out using the Le Bail technique38 in the GSAS package39 with EXPGUI,40 followed by structure solution using the direct-space genetic algorithm (GA) technique41 implemented in the program EAGER.42 Finally, Rietveld refinement43 was carried out using the GSAS39 program package with EXPGUI.40 Specific details of the structure determination procedures for Forms III, IV, and V are given in section 4.2. Differential scanning calorimetry (DSC) was carried out using a TA Instruments Q100 differential scanning calorimeter for samples contained in hermetically sealed aluminum pans. Several different heating and cooling rates were used, ranging from 1 °C min−1 to 20 °C min−1.

3. CONCLUDING REMARKS Polymorphism among amino acids is not uncommon, and among the proteinogenic amino acids, polymorphism has been reported for glycine,7 for five cases of enantiomerically pure crystals (leucine,24 serine,25 histidine,26 cysteine,27 and glutamic acid28), and for four cases of racemic crystals (valine,29 serine,30 cysteine,31 and methionine32). Furthermore, the ortho and para isomers of aminobenzoic acid both exhibit polymorphism, with three reported polymorphs for o-ABA33,34 and two reported polymorphs for p-ABA.35 The fact that one of the three new polymorphs of m-ABA discovered in the present work (Form III) is more stable (at ambient temperature) than the two polymorphs observed previously (Forms I and II) emphasizes that the earliest discovered polymorphs of a given molecule do not necessarily include the most stable polymorph.36An interesting aspect of the polymorphism of m-ABA is the fact that the molecule is zwitterionic in some polymorphs and nonzwitterionic in other polymorphs. In contrast, the crystal structures of the proteinogenic amino acids with neutral side 3110



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independent molecules of m-ABA in the asymmetric unit (Z′ = 2). Profile fitting using the Le Bail method38 gave a good quality of fit (Rwp = 2.82%, Rp = 2.10%; Figure 5a). The refined unit cell and profile parameters obtained from Le Bail fitting were used in the subsequent structure-solution calculation. Structure solution was carried out using the direct-space GA technique as described above for Form III. With a total of seven structural variables for each of the two independent molecules in the asymmetric unit, the total number of structural variables in the GA structure-solution calculation for Form IV was 14. Initial attempts to solve the structure (using powder XRD data recorded in transmission with a foil sample holder) were hindered by a very high degree of preferred orientation (as demonstrated by comparing relative peak intensities in the laboratory data and synchrotron data). The effects of preferred orientation were minimized by rerecording the laboratory powder XRD data for a sample in a glass capillary, leading to successful structure solution. In total, 16 independent GA calculations were carried out, with essentially the same structure solution obtained in each case. Rietveld refinement was carried out using the general strategy described above for Form III, resulting in a good fit to the powder XRD data (Rwp = 2.86%, Rp = 2.17%; Figure 5b) with the following final refined parameters: a = 3.80003(7) Å, b = 11.55389(32) Å, c = 14.6333(4) Å, α = 110.5047(14)°, β = 92.7424(16)°, γ = 96.5930(14)°; V = 595.108(35) Å3 (2θ range, 4−70°; 3867 profile points; 125 refined variables). 4.2.3. Structure Determination of Form V of m-ABA. The powder XRD pattern of Form V was indexed using the program TREOR44 within the CRYSFIRE package,37 giving the following unit cell with monoclinic metric symmetry: a = 14.76 Å, b = 4.95 Å, c = 9.09 Å, β = 95.2° (V = 662.1 Å3). The number of formula units in the unit cell was established as Z = 4, and the space group was assigned as P21/a (corresponding to Z′ = 1). Profile fitting using the Le Bail method gave a good quality of fit (Rwp = 2.45%, Rp = 1.83%; Figure 7a). Structure solution was carried out using the direct-space GA technique, as described above for Form III. Eight independent GA calculations produced the same good-quality structure solution in each case. Rietveld refinement was carried out using the same overall strategy described above for Form III. However, a small amount of a second phase identified as Form II of m-ABA was present in the powder XRD pattern of Form V and was included as a second phase in the Rietveld refinement. Furthermore, analysis of difference Fourier plots strongly suggested that the structure of Form V has positional disorder of the −NH2 group, with two sites related by a 180° flip of the molecule about the HO2C−C(aryl) bond. The −CO2H group was also disordered over two orientations corresponding to the same 180° flip of the molecule about the HO2C−C(aryl) bond (with the two orientations of the −CO2H group having the same occupancies as the two sites occupied by the −NH2 group). The relative occupancies of the two orientations of the molecule were refined. This disordered structural model gave an improved quality of fit in the Rietveld refinement. Hydrogen atoms were added to the molecule according to standard geometries, and the orientation of the −NH2 group was chosen such that the most reasonable set of intermolecular hydrogen bonds was formed, based on consideration of the disorder model with domains containing only the molecular orientation of higher occupancy and domains containing only the molecular orientation of lower occupancy [i.e., case (i) discussed in section 2.2.3]. The final Rietveld refinement (Figure 7b) gave Rwp = 4.08% and Rp = 2.79%, with the following refined parameters: a = 14.7870(7) Å, b = 4.95659(18) Å, c = 9.0814(4) Å, β = 95.2119(21)°; V = 662.85(7) Å3 (2θ range, 3−70°; 3867 profile points; 114 refined variables).

XPS data were recorded on a Kratos Axis Ultra DLD system, using a monochromatic Al Kα X-ray source operating at 120 W. Data were collected with pass energies of 160 eV for survey spectra and 20 eV for high-resolution scans. The system was operated in the hybrid mode, using a combination of magnetic immersion and electrostatic lenses, and data were acquired over an area of ca. 300−700 μm2. A magnetically confined charge compensation system was used to minimize charging of the sample surface, and all spectra were acquired with a 90° takeoff angle. A base pressure of ca. 10−9 Torr was maintained during data collection. Solubilities were measured by adding a known mass of m-ABA to a known mass of solvent inside a sealed sample vial. Several samples with different mass ratios were prepared, and the set of samples was held at 20 °C for several days with frequent agitation to promote dissolution. A qualitative assessment of complete dissolution was made for each sample by visual inspection. Further studies were then carried out for a more closely spaced set of mass ratios in the region corresponding to complete dissolution, allowing the solubility to be determined on an iterative basis. 4.2. Structure Determination from Powder XRD Data. 4.2.1. Structure Determination of Form III of m-ABA. The powder XRD pattern of Form III of m-ABA was indexed using the program TREOR44 within the CRYSFIRE package,37 giving the following unit cell with monoclinic metric symmetry: a = 21.38 Å, b = 7.30 Å, c = 3.78 Å, β = 94.8° (V = 587.7 Å3). Given the volume of this unit cell and consideration of density, the number of formula units in the unit cell was assigned as Z = 4. From systematic absences, the space group was assigned as P21/a (corresponding to Z′ = 1). Profile fitting using the Le Bail method38 gave a good quality of fit (Rwp = 2.45%, Rp = 1.77%; Figure 3a). The refined unit cell and profile parameters obtained from the Le Bail fitting procedure were used in the subsequent structure-solution calculation. Structure solution was carried out using the direct-space GA technique41 incorporated in the program EAGER.42 In the GA structure-solution calculation, the m-ABA molecule (comprising only non-hydrogen atoms) was defined by a total of seven structural variables: three positional variables, three orientational variables, and one torsion-angle variable (corresponding to rotation about the C−C bond linking the carboxylate group to the aryl ring). The evolution of each GA calculation was carried out for 100 generations. The population comprised 100 structures, with 40 mating operations and 30 mutation operations carried out per generation. In total, 16 independent GA calculations were carried out, with the same goodquality structure solution obtained in all cases. The structure solution (i.e., the trial structure with lowest Rwp obtained in the GA calculations) was used as the initial structural model for Rietveld refinement, which was carried out using the GSAS program.39 Standard restraints were applied to bond lengths and bond angles, planar restraints were applied to the aryl ring and a global isotropic displacement parameter was refined for the non-hydrogen atoms. Hydrogen atoms were added to the molecule according to standard geometries, and the orientation of the −N+H3 group was chosen such that the most reasonable set of N−H···O hydrogen bonds was formed (intermolecular restraints were applied to maintain reasonable hydrogen-bond geometry). The isotropic displacement parameter for the hydrogen atoms was set as 1.2 times the value of the refined isotropic displacement parameter for the non-hydrogen atoms. Preferred orientation was taken into consideration using the March− Dollase function.45 The final Rietveld refinement gave a good fit to the powder XRD data (Rwp = 2.45%, Rp = 1.80%; Figure 3b), with the following final refined parameters: a = 21.3393(6) Å, b = 7.29604(16) Å, c = 3.77733(8) Å, β = 94.8240(12)°; V = 586.018(33) Å3 (2θ range, 4−70°; 3867 profile points; 74 refined variables). 4.2.2. Structure Determination of Form IV of m-ABA. The powder XRD pattern of Form IV was indexed using the program ITO46 within the CRYSFIRE package,37 giving the following unit cell with triclinic metric symmetry: a = 3.82 Å, b = 11.60 Å, c = 14.69 Å, α = 110.5°, β = 92.8°, γ = 96.6° (V = 602.5 Å3). From the volume of this unit cell and consideration of density, the number of formula units in the unit cell was assigned as Z = 4. For space group P1̅, there are thus two

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information (cif files) for the new polymorphs (Forms III, IV, and V) of m-ABA. This material is available free of charge via the Internet at http://pubs.acs.org. 3111



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Article

N. Angew. Chem., Int. Ed. 2003, 42, 2029−2032. (i) Harris, K. D. M. Cryst. Growth Des. 2003, 3, 887−895. (j) Harris, K. D. M.; Cheung, E. Y. Chem. Soc. Rev. 2004, 33, 526−538. (k) Tremayne, M. Phil. Trans. Roy. Soc. A 2004, 362, 2691−2707. (l) Favre-Nicolin, V.; Č erný, R. Z. Kristallogr. 2004, 219, 847−856. (m) Brodski, V.; Peschar, R.; Schenk, H. J. Appl. Crystallogr. 2005, 38, 688−693. (n) Tsue, H.; Horiguchi, M.; Tamura, R.; Fujii, K.; Uekusa, H. J. Synth. Org. Chem. Jpn. 2007, 65, 1203−1212. (o) Thun, J.; Seyfarth, L.; Senker, J.; Dinnebier, R. E.; Breu, J. Angew. Chem., Int. Ed. 2007, 46, 6729−6731. (p) David, W. I. F.; Shankland, K. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 52−64. (q) Altomare, A.; Caliandro, R.; Cuocci, C.; Giacovazzo, C.; Moliterni, A. G. G.; Rizzi, R.; Platteau, C. J. Appl. Crystallogr. 2008, 41, 56−61. (r) Pagola, S.; Stephens, P. W. J. Appl. Crystallogr. 2010, 43, 370−376. (s) Harris, K. D. M. Top. Curr. Chem. 2012, 315, 133−178. (11) (a) Hunt, H.; Briscoe, H. T. J. Phys. Chem. 1929, 33, 1495− 1513. (b) Gopal, L.; Jose, C. I.; Biswas, A. B. Spectrochim. Acta 1967, 23A, 513−518. (12) Théorêt, A. Spectrochim. Acta 1971, 27A, 11−18. (13) Voogd, J.; Verzijl, B. H. M.; Duisenberg, A. J. M. Acta Crystallogr., Sect. B: Struct. Sci. 1980, 36, 2805−2806. (14) Svärd, M.; Nordström, F. L.; Jasnobulka, T.; Rasmuson, Å. C. Cryst. Growth Des. 2010, 10, 195−204. (15) Yoshida, T.; Sawada, S. Bull. Chem. Soc. Jpn. 1976, 49, 3319− 3320. (16) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (b) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr., Sect. B: Struct. Sci. 1990, 46, 256−262. (c) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew. Chem., Int. Ed. 1995, 34, 1555−1573. (17) Robinson, J. M. A.; Kariuki, B. M.; Harris, K. D. M.; Philp, D. J. Chem. Soc., Perkin Trans. 2 1998, 2459−2469. (18) (a) Ramanadham, M.; Jakkal, V. S.; Chidambaram, R. FEBS Lett. 1993, 323, 203−206. (b) Kariuki, B. M.; Bauer, C. L.; Harris, K. D. M.; Teat, S. J. Angew. Chem., Int. Ed. 2000, 39, 4485−4488. (19) In order to check the compatibility of our solubility measurements with those reported in the literature, we also measured the solubility of Form I in acetonitrile as (7.1 ± 0.1) mg/g, which is in agreement, within experimental errors, of the published value of (7.15 ± 0.06) mg/g. (20) Gu, C. H.; Grant, D. J. W. J. Pharm. Sci. 2001, 90, 1277−1287. (21) Giron, D. J. Therm. Anal. Calorim. 2001, 64, 37−60. (22) The importance of kinetic factors in this phase transition is also consistent with our observation that the measured temperature of the transition from Form III to Form I on heating depends significantly on the heating rate in the DSC experiment. (23) (a) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, 2, 259− 271. (b) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, 2, 273−316. (24) (a) Coll, M.; Solans, X.; Fontaltaba, M.; Subirana, J. A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1986, 42, 599−601. (b) Yamashita, M.; Inomata, S.; Ishikawa, K.; Kashiwagi, T.; Matsuo, H.; Sawamura, S.; Kato, M. Acta Crystallogr., Sect. E 2007, 63, o2762− o2764. (25) (a) Kistenmacher, T. J.; Rand, G. A.; Marsh, R. E. Acta Crystallogr., Sect. B: Struct. Sci. 1974, 30, 2573−2578. (b) Moggach, S. A.; Allan, D. R.; Morrison, C. A.; Parsons, S.; Sawyer, L. Acta Crystallogr., Sect. B: Struct. Sci. 2005, 61, 58−68. (c) Drebushchak, T. N.; Sowa, H.; Seryotkin, Y. V.; Boldyreva, E. V.; Ahsbahs, H. Acta Crystallogr., Sect. E 2006, 62, o4052−o4054. (26) (a) Averbuch-Pouchot, M. T. Z. Kristallogr. 1993, 207, 111− 120. (b) Madden, J. J.; Seeman, N. C.; McGandy, E. L. Acta Crystallogr., Sect. B: Struct. Sci. 1972, 28, 2377−2382. (27) (a) Kerr, K. A.; Ashmore, J. P.; Koetzle, T. F. Acta Crystallogr., Sect. B: Struct. Sci. 1975, 31, 2022−2026. (b) Gorbitz, C. H.; Dalhus, B. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1996, 52, 1756−1759. (c) Moggach, S. A.; Allan, D. R.; Clark, S. J.; Gutmann, M. J.; Parsons, S.; Pulham, C. R.; Sawyer, L. Acta Crystallogr., Sect. B: Struct. Sci. 2006, 62, 296−309. (28) (a) Hirayama, N.; Shirahata, K.; Ohashi, Y.; Sasada, Y. Bull. Chem. Soc. Jpn. 1980, 53, 30−35. (b) Lehmann, M. S.; Koetzle, T. F.; Hamilton, W. C. J. Cryst. Mol. Struct. 1972, 2, 225−233.

AUTHOR INFORMATION

Corresponding Author

*E-mail: HarrisKDM@cardiff.ac.uk. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Cardiff University for financial support, to the Government of Malaysia for a studentship (to G.K.L.) and to Diamond Light Source for the award of beam-time for experiments on beamline I11 (Dr. Chiu Tang is particularly thanked for his assistance during these experiments). We thank Dr. David Morgan for carrying out the XPS measurements at the Cardiff XPS Access facility, funded by EPSRC.

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Discovery of a New System Exhibiting Abundant Polymorphism: m

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