Expanding the Solid-State Landscape of l-Phenylalanine: Discovery of

Article pubs.acs.org/JPCC

Expanding the Solid-State Landscape of L‑Phenylalanine: Discovery of Polymorphism and New Hydrate Phases, with Rationalization of Hydration/Dehydration Processes P. Andrew Williams,† Colan. E. Hughes,† Asma B. M. Buanz,‡ Simon Gaisford,‡ and Kenneth D. M. Harris*,† †

School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, Wales, U.K. School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, U.K.

‡

S Supporting Information *

ABSTRACT: To date, only one crystal structure of Lphenylalanine has been reported, with no confirmed report of polymorphism of this material. In the present work, we report the discovery of a new polymorph of L-phenylalanine, with the structural properties determined directly from powder X-ray diffraction data. The new polymorph of L-phenylalanine is stable only under rigorously dry conditions. In addition, two new solid hydrate phases of L-phenylalanine have been discovered: a monohydrate and a hemihydrate. The hemihydrate is susceptible to partial water deficiency. The crystal structures of the monohydrate and hemihydrate phases have also been determined directly from powder X-ray diffraction data. On the basis of results from dynamic vapor sorption and other experiments, we demonstrate that the three new solid forms are readily interconvertible as a function of relative humidity.

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INTRODUCTION Recently, there has been interest in establishing the solid-state structural properties of the 20 genetically encoded amino acids found in proteins, given the rather surprising fact that the crystal structures of some of these amino acids had never previously been determined. Thus, within the last 12 months, the crystal structures of L-arginine1,2 and L-tryptophan3 have been reported for the first time. In some cases, the absence of reported crystal structures has been due to difficulties in obtaining crystals of sufficient size and quality for single-crystal X-ray diffraction (XRD) studies. However, in the case of Larginine,1,2 determination of the crystal structure was achieved by exploiting the opportunities that have emerged in recent years4−22 for determining crystal structures of organic materials directly from powder XRD data, particularly through the development of the direct-space strategy for structure solution. Furthermore, in many cases, crystallization of the amino acid of interest from solution results in solvate (e.g., hydrate) materials, the structural properties of which are also of interest within the present context. Recognizing that different crystalline forms of a given molecule can have significantly different solid-state properties, leading to contrasting performance in materials applications, it is important to understand the diversity of crystalline forms available to a given molecule, including polymorphs, hydrates, and other solvates. In this regard, we clarify that the term polymorphism23−35 refers to the situation in which two (or more) crystalline phases have identical chemical composition (as defined in the context of Gibbs’ phase rule) but different © 2013 American Chemical Society

crystal structures. Thus, a nonsolvate crystal form of a given molecule M and a solvate crystal form Mx(solvent)y are not classified as polymorphs, whereas two different solvate structures Mx(solvent)y of identical stoichiometry (i.e., with the same value of y/x) are correctly assigned as polymorphs. In this paper, we focus on the solid-state forms of Lphenylalanine (L-Phe, Scheme 1), recognizing that, hitherto, Scheme 1. Molecular Structure of L-Phe

structural characterization of crystalline L-Phe has presented challenges that are so far not satisfactorily resolved. The Cambridge Structural Database (CSD)36 contains four entries for L -Phe (with reference codes SIMPEJ, QQQAUJ, QQQAUJ01, and QQQAUJ02), although only one of these entries (SIMPEJ) actually contains atomic coordinates.37 However, even this structure (which we refer to as the “known phase” of L-Phe) has recently been called into question.38 It seems probable that the symmetry assigned to this structure is too high, although an experimentally Received: February 12, 2013 Revised: May 3, 2013 Published: May 3, 2013 12136

dx.doi.org/10.1021/jp401547f | J. Phys. Chem. C 2013, 117, 12136−12145

The Journal of Physical Chemistry C

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using ramped 1H → 13C cross-polarization42 and magic-angle spinning (MAS) at 12 kHz. Dynamic vapor sorption (DVS) experiments were carried out at 26.5 °C on a DVS Advantage 1 instrument (Surface Measurement Systems Ltd., London, U.K.). The sample was placed in a glass pan, and the relative humidity (RH) was kept at 0% for 2 h to allow an equilibrium moisture content to be established. The RH was then changed incrementally in 5% steps every hour from 0 to 90% and then back to 0%. The mass of the sample was recorded as a function of time and RH.

determined structure of lower symmetry has not yet been published. In the other three cases, all of which originate from the work of the same author,39,40 only unit cell information is given in the CSD and one entry (QQQAUJ02) is stated to be a redetermination of a previous entry (QQQAUJ). However, there has been no corroboration in the subsequent literature for any of the three reported unit cells.39,40 High-resolution solid-state 13C NMR studies41 have shown that crystallization of L-Phe from solutions containing water can lead to the formation of more than one type of solid form. In particular, two forms with clearly distinct solid-state 13C NMR spectra were observed:41 one obtained by crystallization from water and the other obtained by crystallization from water/ ethanol. However, no structure determination was reported, and it is therefore unclear whether either of these forms corresponds to the known phase of L-Phe.37 In this paper, we report the analysis of materials prepared by crystallization of L-Phe from aqueous solution, encompassing the identification, characterization, structure determination, and interconversion pathways of three new solid forms of L-Phe. As discussed below, two of the new phases are hydrate structures corresponding to different levels of hydration, and one phase is a new polymorph of anhydrous L-Phe.

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RESULTS Crystallization Experiments. Visual examination of polycrystalline samples obtained by crystallization of L-Phe from water revealed two distinctly different types of crystal morphology, suggesting the possible existence of two different phases. In one case, the crystals were large, well-formed, and block-like. In the other case, the entire solution appeared to crystallize as a single solid mass composed of very fine fiber-like crystallites and containing a significant amount of water. Crystallization experiments involving slow cooling (e.g., from 85 to 25 °C over 12 h in an incubator) were found to produce either of these crystal morphologies, in some cases concomitantly. However, crash cooling of the solution was found to favor the formation of crystals with the fibrous morphology. Powder XRD. Initially, powder XRD patterns were recorded for samples in which all crystallites had a given type of morphology (i.e., block-like crystals only or fibrous crystals only), and it was found that the two different morphologies gave rise to distinct powder XRD patterns. On this basis, the block-like crystals were identified as the known (anhydrous) phase of L-Phe37 (Figure 1a). This phase was found to be stable indefinitely under dry, ambient conditions. On the other hand, for samples comprising crystals with the fibrous morphology, two different powder XRD patterns were observed. When the powder XRD data were recorded using the foil sample holder, the pattern observed at a given time appeared to correlate with the relative humidity within the diffractometer cabinet and interconversion between the two powder XRD patterns was observed occasionally. Specifically, a changeover between the two patterns was observed at ca. 60% RH. These observations indicate that the solid phase changes with atmospheric humidity, and we refer to these phases at this stage as the “high-humidity” and “low-humidity” forms. Both the highhumidity and low-humidity forms were found to be stable when sealed in glass capillaries. The powder XRD pattern in Figure 1b was recorded for a sample of L-Phe which had been maintained under highhumidity conditions prior to being packed with a little excess water into three glass capillaries which were then sealed. The same powder XRD pattern was observed for the sample in the foil sample holder when RH was above ca. 60% (i.e., the highhumidity form). The powder XRD pattern in Figure 1c was recorded for a sample of L-Phe which had been kept in a desiccator containing silica gel drying agent before being packed into three glass capillaries which were then sealed. The same powder XRD pattern was observed for the sample in the foil sample holder when RH was below ca. 60% (i.e., the lowhumidity form). As discussed above, the powder XRD patterns of the highand low-humidity forms are clearly distinct from each other and are also distinct from the powder XRD pattern of the known (anhydrous) form of L-Phe.37

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EXPERIMENTAL SECTION The sample of L-Phe used in the present work was purchased from Sigma-Aldrich (purity ≥98%) and was used without further purification. This material was shown by powder XRD to be a monophasic sample of the known form of L-Phe.37 Crystallization was carried out by cooling an aqueous solution of L-Phe (ca. 50 mg of L-Phe per g of water, which is supersaturated at 25 °C), from 85 °C to ambient temperature. Powder X-ray diffraction (XRD) data were recorded on two Bruker D8 diffractometers (Cu Kα1, Ge monochromated) operating in transmission and reflection modes. For the measurements in transmission mode, the temperature and relative humidity inside the diffractometer cabinet were measured using a hygrometer. The temperature was held constant at 294 K, while the relative humidity was found to vary considerably (between 30 and 80%) due to meteorological changes. Two different sample containment methods were used for recording the powder XRD data in transmission mode. For some measurements, the sample was held between two pieces of tape (i.e., foil-type sample holder). In this case, the sample is not sealed sufficiently to prevent interaction with the atmosphere, and the sample is susceptible to changes in the humidity of the atmosphere. For other measurements in transmission mode, the sample was packed into a glass capillary, which was then flame-sealed. In this case, the sample does not interact with the external atmosphere, and the humidity inside the capillary may be assumed to be constant. For the measurement of powder XRD data in reflection mode, the sample was placed in an indentation in a copper disk. The reflection measurements focused on the study of materials in a completely anhydrous environment, which was achieved by maintaining the sample under vacuum at 295 K in an Oxford Cryosystems Phenix temperature controller. High-resolution solid-state 13C NMR spectra were recorded on a Bruker AVANCE III spectrometer at the UK 850 MHz Solid-State NMR Facility at the University of Warwick (13C Larmor frequency, 213.81 MHz). All samples were contained in 4 mm zirconia rotors. The 13C NMR spectra were recorded 12137



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Figure 2. High-resolution solid-state 13C NMR spectra recorded for (a) the known anhydrous phase of L-Phe (commercial sample), (b) the high-humidity form of L-Phe (subsequently assigned as the monohydrate phase), and (c) the low-humidity form of L-Phe (subsequently assigned as the hemihydrate phase). The inset in (a) shows the 13C resonances for the α-carbon environment. Asterisks denote spinning sidebands. Figure 1. Powder XRD patterns recorded for (a) the previously known anhydrous phase of L-Phe37 (commercial sample), (b) the high-humidity form of L -Phe (subsequently assigned as the monohydrate phase), (c) the low-humidity form of L-Phe (subsequently assigned as the hemihydrate phase), and (d) the new anhydrous phase of L-Phe. The broad background feature centered at around 2θ = 13° in (b) and (c) is due to scattering from the glass capillary sample holder.

Our solid-state 13C NMR spectrum recorded for the known form of L-Phe has at least three distinct isotropic peaks for the α-carbon environment (Figure 2a), suggesting that the crystal structure contains three (or more) independent molecules of LPhe in the asymmetric unit. This observation suggests that the published crystal structure37 of the known form of L-Phe is not correct, as it has only two independent molecules in the asymmetric unit. In a recent paper,38 a revised structure has been proposed in which there are four independent molecules in the asymmetric unit. Clearly, our solid-state 13C NMR results are consistent with the number of independent molecules in the asymmetric unit in this revised structure, although we cannot state definitively that our solid-state 13C NMR data corroborate other details of the proposed structure. The solid-state 13C NMR spectra for the high- and low-humidity phases (Figures 2b and 2c) show clear evidence that, in each case, there are at least two independent molecules of L-Phe in the asymmetric unit (but with no evidence that there are more than two independent molecules). Dynamic Vapor Sorption. To determine the water content of the low- and high-humidity forms, dynamic vapor sorption (DVS) measurements were carried out, starting from a sample of L-Phe that was crystallized from water and then dried under vacuum in the presence of P2O5 (to render the sample anhydrous). The results are shown in Figure 3. Starting at very low relative humidity (RH) in the DVS experiment, the starting

Solid-State 13C NMR. High-resolution solid-state 13C NMR spectra were recorded for the high- and low-humidity forms, together with the known form of L-Phe (using the commercial sample without recrystallization). The sample of the highhumidity form was stored in the presence of excess water until packed into the NMR rotor, and the sample of the lowhumidity form was stored together with a drying agent (silica gel) for several days at ambient temperature before carrying out the NMR measurement. In each case, the sample was sealed in the NMR rotor while recording the data, and there was no evidence for interconversion between the high- and lowhumidity forms during the measurements. The solid-state 13C NMR spectra are shown in Figure 2. From comparison of our solid-state 13C NMR spectra with those published by Frey et al.,41 it is clear that the sample they prepared from ethanol/ water corresponds to our low-humidity form (Figure 2c) whereas the sample that they prepared from water is identified as the known form of L-Phe37 (Figure 2a). 12138



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(initially the monohydrate phase) that was held under vacuum inside the Phenix temperature controller (at 21 °C). Our assignment of the sample as the new anhydrous polymorph of L -Phe was confirmed by the result of the structure determination, as detailed below. The powder XRD patterns recorded for the hemihydrate and monohydrate phases (Figures 1c and 1b) were indexed using the TREOR43 and DICVOL9144 codes in the program CRYSFIRE,45 leading to unit cells with monoclinic metric symmetry in each case. The unit cells obtained, following transformation into the standard form using the program PLATON,46,47 are as follows: monohydrate phase, a = 13.05 Å, b = 5.44 Å, c = 13.98 Å, β = 101.2° (V = 973.5 Å3); hemihydrate phase: a = 12.13 Å, b = 5.42 Å, c = 13.78 Å, β = 100.1° (V = 892.3 Å3). In each case, profile fitting and unit cell refinement were carried out using the Le Bail procedure48 implemented in the GSAS program.49 On the basis of systematic absences, the space group was assigned as P21 in each case. In the final Le Bail fits using space group P21, good quality fits were obtained (monohydrate phase, Rwp = 1.41%, Rp = 1.06%; hemihydrate phase, Rwp = 2.67%, Rp = 2.01%). The refined unit cells and profile parameters obtained from the Le Bail fitting procedure were used in the subsequent structuresolution calculations. Density considerations suggest that both the monohydrate and hemihydrate structures have two molecules of L-Phe in the asymmetric unit, consistent with the results of our solid-state 13 C NMR study (Figure 2c) discussed above. Structure solution was carried out from the powder XRD data using the directspace genetic algorithm (GA) technique50−54 in the program EAGER.1,55−62 In the structure solution calculations for the monohydrate and hemihydrate phases, one L-Phe molecule (with hydrogen atoms included) was defined by a total of eight variables: two positional variables (for space group P21, the origin can be fixed arbitrarily along the b-axis, allowing the positional variable along the b-axis to be fixed for one molecule), three orientational variables, and three torsion-angle variables. The second L-Phe molecule was defined similarly but with three positional variables to give a total of nine variables. Both L-Phe molecules were defined as zwitterions, based on the identification of zwitterions in the crystal structure of the known phase of L-Phe.37 (This assignment was subsequently vindicated in the final refinement of the structure by the fact that the observed hydrogen-bonding scheme for the L-Phe molecules in the zwitterionic form is completely reasonable on both structural and chemical grounds.) The structural model for the monohydrate phase included two water molecules in the asymmetric unit, while the structural model for the hemihydrate phase included one water molecule in the asymmetric unit. Each water molecule (with hydrogen atoms included) was defined using three positional variables and three orientational variables. Thus, the total number of direct-space structural variables was 29 for the monohydrate phase and 23 for the hemihydrate phase. For the monohydrate phase, each GA structure-solution calculation involved the evolution of 400 generations for a population of 200 structures, with 20 mating operations and 100 mutation operations per generation. In total, 16 independent GA calculations were carried out, with the same good quality structure solution obtained in four cases. The best structure solution (i.e., the trial structure with lowest Rwp obtained in the GA calculations) was used as the initial

Figure 3. DVS data recorded on increasing RH from 0% to 90% (red line) starting from a sample of the new anhydrous polymorph of L-Phe prepared by drying the hemihydrate phase under vacuum. The data recorded on subsequently decreasing RH from 90% to 0% (blue line) are also shown. The dashed horizontal lines correspond to the lowest mass observed in the experiment (6.319 mg), assigned as the new anhydrous polymorph of L-Phe, and the predicted masses for the hemihydrate and monohydrate.

anhydrous sample readily absorbs water. Even below 5% RH, the uptake of water corresponds to ca. 0.25 molecules of water per molecule of L-Phe. As RH is increased further, there is a regime of more gradual uptake of water and, by around 60% RH, the amount of absorbed water is close to ca. 0.5 molecules of water per molecule of L-Phe. When RH is then increased to 65%, a second stage of water absorption occurs, characterized by a very abrupt increase in water uptake to ca. 1 molecule of water per molecule of L-Phe. Thereafter, on increasing RH from 65% to 90%, there is essentially no further uptake of water. On subsequently decreasing RH from 90%, the events described above are reversed, although with hysteresis in the value of RH corresponding to the abrupt change in water content from ca. 1 to 0.5 molecules of water per molecule of LPhe (which occurs at about 55% RH in the desorption cycle). If we define the stoichiometry of the observed phases as LPhe(H2O)x, it is clear from the DVS results that, starting from the anhydrous phase (x = 0), a hydrate phase with variable water content from x ≈ 0.25 to x ≈ 0.5 exists at low RH (less than ca. 55−65%), whereas a second hydrate phase with water content corresponding to x ≈ 1 exists at high RH (greater than ca. 55−65%). Thus, the solid form present at low humidity is nonstoichiometric and can exist with a continuous range of stoichiometries from approximately the quarterhydrate (x = 0.25) to the hemihydrate (x = 0.5), whereas the solid form present at high humidity is a stoichiometric monohydrate corresponding to x = 1. Henceforth, we refer to these three phases as the monohydrate (x = 1; hitherto called the highhumidity form), the hemihydrate (0.25 ≤ x ≤ 0.5; hitherto called the low-humidity form), and a new polymorph (denoted polymorph II) of anhydrous L-Phe (x = 0). We now refer to the previously known form of anhydrous L-Phe37 as polymorph I. Structure Determination from Powder XRD Data. In the present work, the crystal structures of the three new phases of L-Phe have been determined directly from powder XRD data. For the monohydrate and hemihydrate phases, the powder XRD data were recorded in transmission mode on the samples in sealed capillaries described above. These capillaries were then mounted on the foil sample holder for data collection. For the new anhydrous polymorph of L-Phe, the powder XRD data (Figure 1d) were recorded in reflection mode for a sample 12139



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structural model for Rietveld refinement,63 which was carried out using the GSAS program.49 Standard restraints were applied to bond lengths64 and bond angles, planar restraints were applied to aromatic rings and carboxylate groups, and four separate global isotropic displacement parameters were refined for the non-hydrogen atoms of the two L-Phe molecules and the two water molecules. The isotropic displacement parameter for the hydrogen atoms was set as 1.2 times the refined isotropic displacement parameter for the non-hydrogen atoms in the same molecule. Hydrogen bonding between the NH3+ groups and neighboring carboxylate groups was loosely restrained based on optimal hydrogen-bond geometries. As discussed below, disorder of the hydrogen-bonding between water molecules was also incorporated into the refined model. The final Rietveld refinement (Figure 4a) gave a good fit to the

For the hemihydrate phase, each GA structure-solution calculation involved the evolution of 200 generations for a population of 200 structures, with 20 mating operations and 100 mutation operations per generation. In total, 16 independent GA calculations were carried out, with the same good-quality structure solution obtained in eight cases. The best structure solution was used as the initial structural model for Rietveld refinement. Standard restraints were applied in the manner described above for the monohydrate phase including hydrogen bonding of the NH3+ groups. In recognition of the possible nonstoichiometric character of the hemihydrate phase, the occupancy of the water molecule (represented by a single oxygen atom, as discussed below) was initially treated as a variable. However, as the refined value of the occupancy was very close to 1 (corresponding to a hemihydrate), the occupancy was fixed at this value in the final refinement. Three separate global isotropic displacement parameters were refined for the non-hydrogen atoms of the two L-Phe molecules and the water molecule. The final Rietveld refinement (Figure 4b) gave a good fit to the powder XRD data (Rwp = 2.96%, Rp = 2.21%), with the following refined parameters: a = 12.1112(5) Å, b = 5.42130(17) Å, c = 13.7691(5) Å, β = 100.0115(35)°; V = 890.29(8) Å3 (space group P21; 2θ range, 4°−70°; 3867 profile points; 170 refined variables). The new polymorph of (anhydrous) L-Phe was prepared at ambient temperature by evacuating the sample environment within the Phenix temperature controller on the reflection powder XRD instrument, starting from a sample of the monohydrate phase. The powder XRD pattern recorded for this sample of the monohydrate phase (i.e., before subjecting it to vacuum) indicated that there was a significant degree of preferred orientation in this powder sample. After subjecting this sample to vacuum and recording the powder XRD pattern of the new anhydrous polymorph, the sample was exposed to the atmosphere at the end of the measurement. The powder XRD pattern recorded at this stage was characteristic of the hemihydrate phase but, again, with evidence for significant preferred orientation. Consequently, it is reasonable to anticipate that the powder XRD data recorded for the new anhydrous phase may also be affected by significant preferred orientation. Given the similarity between the powder XRD patterns of the hemihydrate phase and the new anhydrous phase, the crystal structure of the hemihydrate phase was used as the starting model for structure refinement of the new anhydrous phase. Profile fitting using the Le Bail method led to a good quality of fit65 (Rwp = 3.38%, Rp = 2.35%). In the Rietveld refinement, the water molecule present in the hemihydrate phase was retained in the structural model, and the occupancy of this water molecule was allowed to vary in the refinement. However, the occupancy of the water molecule was found to refine to a small, negative value and was subsequently fixed at zero, confirming that this phase is anhydrous. Preferred orientation was taken into account using the March−Dollase function.66,67 To correct for surface roughness, a normalized form of the function proposed by Suortti68 was used. Other aspects of the Rietveld refinement (e.g., the use of restraints and the handling of atomic displacement parameters) were carried out as described above for the monohydrate phase. The final Rietveld refinement (Figure 4c) gave a good fit (Rwp = 4.50%, Rp = 3.01%) with the following refined parameters: a = 12.063(11) Å, b = 5.412(5) Å, c = 13.676(13) Å, β =

Figure 4. Results from the final Rietveld refinements for (a) the monohydrate phase of L-Phe, (b) the hemihydrate phase of L-Phe, and (c) the new polymorph II of anhydrous L-Phe. 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.

powder XRD data (Rwp = 1.60%, Rp = 1.18%), with the following refined parameters: a = 13.0075(4) Å, b = 5.43017(11) Å, c = 13.93996(33) Å, β = 101.1125(14)°; V = 966.16(6) Å3 (space group P21; 2θ range, 4°−70°; 3867 profile points; 183 refined variables). 12140



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Figure 5. Crystal structures of (a) the monohydrate phase of L-Phe, (b) the hemihydrate phase of L-Phe, and (c) the new polymorph II of anhydrous L-Phe. In each case, the view along the b-axis is shown on the left and the view along the c-axis is shown on the right (in this view, only one layer within the hydrogen-bonded double-layer is shown and the phenyl rings of the L-Phe molecules have been omitted for clarity). In (a) and (b), one water channel (which runs along the b-axis) is highlighted by cyan shading. In (c), the position of the empty channel (which also runs along the baxis) is outlined. In (a), only one orientation of the O−H···O−H···O−H···O−H hydrogen-bonded chain along the water channel is shown. The hydrogen-bonded motif highlighted by the asterisk is discussed in the text.

99.5976(26)°; V = 880.3(24) Å3 (space group P21; 2θ range, 6.25°−41.75°; 2196 profile points; 160 refined variables).

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plane and containing the carboxylate and ammonium groups; in the monohydrate and hemihydrate structures, the water molecules are also located within these hydrogen-bonded double layers. The phenyl rings of the L-Phe molecules are located in the region between adjacent hydrogen-bonded double layers. In each structure, there are two crystallographically independent L-Phe molecules with slightly different molecular conformations (in each structure, corresponding

DISCUSSION

As shown in Figure 5, the crystal structures of the three new solid phases of L-Phe have several features in common (see also Table 1). In particular, all three structures are described in terms of hydrogen-bonded double layers parallel to the ab12141



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Table 1. Crystallographic Data for the Three New Solid Forms of L-Phe Reported in This Paper and the Previously Known Form (Polymorph I)37 space group a/Å b/Å c/Å β/deg V/Å3 reference

monohydrate

hemihydrate

polymorph II

polymorph I

P21 13.0075(4) 5.43017(11) 13.93996(33) 101.1125(14) 966.16(6) this work

P21 12.1112(5) 5.42130(17) 13.7691(5) 100.0115(35) 890.29(8) this work

P21 12.063(11) 5.412(5) 13.676(13) 99.5976(26) 880.3(24) this work

C2 8.804 6.041 31.564 96.6 1667.6 37

Another notable difference between the structures of the hemihydrate and monohydrate phases concerns the helical hydrogen-bonded motif that follows the 21 screw axis in each of these structures (parallel to the b-axis and highlighted by an asterisk in Figure 5). In the hemihydrate structure, this hydrogen-bonded motif involves only N−H···O hydrogen bonds between L-Phe molecules in the two layers of the double layer. In the monohydrate structure, on the other hand, the corresponding L-Phe molecules are instead engaged in an N−H···O−H···O hydrogen-bonded arrangement, involving the O−H bond of an intervening water molecule, which forms part of the repeating unit within this helical hydrogen-bonded motif. The crystal structure of polymorph II of anhydrous L-Phe is very similar to the structure of the hemihydrate phase, with only minor displacements in the positions of the L-Phe molecules between these two structures. Indeed, polymorph II of L-Phe may be referred to as an “isomorphic desolvate” of the hemihydrate.69 The fact that the water molecules occupy channels in both the monohydrate and hemihydrate structures and the fact that this channel remains empty (without collapse) in the structure of polymorph II of anhydrous L-Phe are fully consistent with our observation that water loss and water uptake occur in a very facile manner within this set of materials. We note that the density (1.25 g cm−3) of polymorph II of LPhe is significantly lower than the density of polymorph I of LPhe (1.32 g cm−3), which may suggest that form II is thermodynamically less stable than form I. However, conversion from polymorph II to polymorph I has not been observed in our work, at least on a time scale of several days, with the sample maintained under vacuum throughout this time. As discussed above, exposure of polymorph II of anhydrous L-Phe to the atmosphere leads to facile uptake of water, even at very low humidity, to give the hemihydrate structure or, at sufficiently high humidity, to give the monohydrate structure. The comparatively low density of polymorph II of L-Phe is undoubtedly related to the retention of the channel-like structure of the hemihydrate phase, from which it is obtained by dehydration. This type of open channellike feature is not present in the structure of polymorph I of LPhe. The phenomenon of “channel hydrates” is well-known, and several examples of this class of hydrate structure have been discussed in the literature.70−73 Of particular relevance in the present context is the crystal structure of DL -proline monohydrate.74 In this structure, the water molecules are located in channels and each water molecule is hydrogen bonded to both adjacent water molecules in the channel and to the carboxylate group of a neighboring proline molecule. This hydrogen-bonding arrangement strongly resembles that observed in the structure of L-Phe monohydrate reported here.

torsion angles in the two L-Phe molecules differ by up to ca. 20°). Within the hydrogen-bonded double layers in the monohydrate and hemihydrate phases, the water molecules can be considered to be located in channels (highlighted by blue shading in Figures 5a and 5b) parallel to the b-axis. In the monohydrate structure, the two crystallographically distinct water molecules are engaged in strong O−H···O hydrogen bonding with each other (the O···O distances along the water channel alternate between 2.82 and 2.98 Å). This hydrogen-bonding motif is described as an O−H···O−H···O− H···O−H chain that may run either along the positive direction of the b-axis or along the negative direction of the b-axis. (The chains running in the positive and negative directions have the same oxygen atom positions but different hydrogen atom positions, corresponding to O−H···O−H···O−H···O−H and H−O···H−O···H−O···H−O arrangements.) The final refined structure of the monohydrate phase invoked disorder of these two orientations of the hydrogen-bonded chain, with fractional occupancies of xH and 1 − xH for the hydrogen atom positions in the positive and negative chain orientations, respectively. The refined value of the occupancy xH did not depart significantly from 0.5, indicating that the populations of the two chain orientations are essentially equal. Each water molecule is also engaged in hydrogen bonding to L-Phe molecules. Specifically, one water molecule is the donor in an O−H···O hydrogen bond with a carboxylate group of an L-Phe molecule and is the acceptor in an N−H···O hydrogen bond with an ammonium group in a different L-Phe molecule. The other water molecule forms only one hydrogen bond to an LPhe molecule, as the donor in an O−H···O hydrogen bond. In the hemihydrate structure, the O···O distance between adjacent water molecules along the water channel is 5.42 Å (corresponding to the unit cell translation along the b-axis), which is significantly too long to represent hydrogen bonding between adjacent water molecules. On the other hand, the O···O distances (2.84 and 2.87 Å) between the water molecule and oxygen atoms of carboxylate groups in different L-Phe molecules may be interpreted as O−H···O hydrogen bonds. However, the O···O(water)···O angle (162.6°) is too large to allow relatively linear O−H···O hydrogen bonds to be formed simultaneously with both of these oxygen atoms as acceptors. It is therefore probable that, at the local level (both spatially and temporally), each water molecule forms a strong linear O− H···O hydrogen bond with only one of these acceptors (with the other hydrogen atom not engaged in a significant hydrogenbonding interaction). However, as there is considerable uncertainty with regard to the time-averaged location of the hydrogen atoms of the water molecule in this structure, the hydrogen atoms of the water molecule were omitted from the refinement. 12142



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CONCLUDING REMARKS The structural properties of the three new solid phases of L-Phe reported in the present work and our rationalization of the conditions for transformations between these phases add clarity to the hitherto confused picture concerning the solid-state forms of L-Phe. We emphasize that the crystal structures reported here were determined directly from powder XRD data, as single crystals of suitable size and quality for singlecrystal XRD studies could not be prepared. Thus, this work further demonstrates the opportunities that now exist for determining the crystal structures of organic materials directly from powder XRD data. The monohydrate and hemihydrate structures discovered in the present work are the first hydrate phases of L-Phe for which crystal structures have been reported. Analysis of the CSD indicates that, prior to the present work, five of the 20 genetically encoded amino acids (specifically arginine, asparagine, aspartic acid, proline, and serine) were known to form hydrate structures as the enantiomerically pure amino acid.75−79 In four cases (serine,80 arginine,81,82 glutamic acid,83 and proline74,84), hydrate structures of the racemic DLamino acid have also been reported (including, in the case of 81 DL-arginine, both a monohydrate and a dihydrate82). However, L-Phe is the first case of an enantiomerically pure amino acid for which more than one distinct hydrate phase has been discovered and structurally characterized. In addition, the present work has revealed a new polymorph of pure (anhydrous) L-Phe, representing the sixth case among the 20 genetically encoded amino acids for which polymorphism has been confirmed by structure determination.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

* Supporting Information S

Crystal information files (cif) for the three crystal structures reported in this paper. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail: HarrisKDM@cardiff.ac.uk (K.D.M.H.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Dr Gareth Lloyd for useful discussions and to Cardiff University for financial support. We thank Dr Dinu Iuga for assistance in carrying out experiments at the UK 850 MHz Solid-State NMR Facility, which was funded by EPSRC and BBSRC as well as the University of Warwick including via part funding through Birmingham Science City Advanced Materials Projects 1 and 2 supported by Advantage West Midlands (AWM) and the European Regional Development Fund (ERDF).

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