Experimental and Predicted Crystal Energy Landscapes of

Jan 11, 2011 - Solid-State Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Gla...
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DOI: 10.1021/cg1010049

Experimental and Predicted Crystal Energy Landscapes of Chlorothiazide

2011, Vol. 11 405–413

Andrea Johnston,† Julie Bardin,† Blair F. Johnston,† Philippe Fernandes,† Alan R. Kennedy,‡ Sarah L. Price,§ and Alastair J. Florence*,† †

Solid-State Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, U.K., ‡WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K., and §Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K. Received July 31, 2010; Revised Manuscript Received November 11, 2010

ABSTRACT: An experimental search for physical forms of the thiazide diuretic compound chlorothiazide comprising 402 different crystallizations identified one nonsolvated form and ten crystalline solvates. There are five distinct conformations in the experimental crystal structures which are in good agreement with the conformational minima found by ab initio optimization of the isolated molecule structure. An approximate rigid-body crystal energy landscape using these five conformations produced a diverse range of low energy crystal structures, with the anhydrous structure among the most stable. Inspection of the molecular packing adopted in both the experimental and predicted structures highlighted a number of chlorothiazide 3 3 3 chlorothiazide motifs that result from packing the different conformers. Specifically, four bimolecular faceto-face motifs were observed in most of the predicted structures and all of the experimental structures. The role of these robust intermolecular packing motifs and of the organic solvent molecules in stabilizing the experimental solvate structures of chlorothiazide is discussed. The results highlight the value of the approximate crystal energy landscape for flexible organic molecules in assisting with the interpretation of solid-state diversity in chlorothiazide crystal structures and identifying key stabilizing packing features.

Introduction Establishing effective approaches to achieve control and prediction of organic molecular solids remains a significant challenge for those concerned with the development and commercial exploitation of crystalline materials. The calculation of the crystal energy landscape has been shown to be a useful complement to experimental polymorph screening.1 Crystal structure prediction (CSP) can determine the range of preferred packing motifs and crystal structures that are thermodynamically favorable for a particular molecule, and so help rationalize the occurrence of polymorphs and solvates. For example, the low energy crystal structures for 5-fluorocytosine all contained the same hydrogen-bonded ribbon, which was found in two polymorphs and four solvates,2 whereas hydrochlorothiazide (HCT; Figure 1) showed 11 different bimolecular hydrogen-bonded ring motifs in the structures predicted within 12 kJ 3 mol-1 of the global minimum, six of which were observed in the experimental polymorphs and solvates.3 CSP results also provided the rationale leading to the discovery of a novel crystalline solid-solution in which carbamazepine adopts a predicted catemeric hydrogen bonded arrangement.4,5 However, accurate CSP is particularly challenging for molecules that contain conformational flexibility and multiple hydrogen bond donor and acceptor groups, both typical features of pharmaceutical compounds. In HCT for example, which is a small thiazide drug, relatively minor variations in the sulfonamide side-chain and sulfadiazine ring conformations impact significantly on the hydrogen bond component

Figure 1. Chlorothiazide (CT; left), atomic numbering scheme and torsion angle τ1 (CdC;S;N) and the structure of hydrochlorothiazide (HCT; right) for comparison.

*To whom correspondence should be addressed. E-mail: alastair. [email protected]. Telephone:þ44-141-548-4877. Fax: þ44-141- 5522562.

of the lattice energy calculations, adding considerably to the challenges in implementing a successful CSP search. While it is possible to allow molecular conformation to vary during a CSP search,6-8 this comes at considerable computational expense. Here, as a follow-up to our previous report on HCT,3 we implement the same computationally efficient CSP strategy of the related diuretic compound, chlorothiazide (CT, C7H7ClN3O4S2, Figure 1) to generate an approximate crystal energy landscape. The calculations on CT were performed to be comparable with those for HCT, establish how the differences in molecular structure in CT impact on the preferred intermolecular interactions in the solid-state, and help interpret the structures found in the experimental crystallization search9,10 for polymorphs and solvates of CT. In contrast to HCT, which can crystallize in at least two polymorphic forms,11,12 only one form of CT has been reported under ambient conditions,11,13 in addition to a number of crystalline solvates that are discussed below. The molecular structures of CT and HCT are very closely related, varying only at the C1-N1 bond in the thiadiazine ring (Figures 1 and 2). However, the resultant change in potential

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Johnston et al. Table 1. Outline of Crystallization Conditions Implemented in the Automated Parallel Crystallization Search for Solid Forms of CT. a saturation conditionb

crystallization method

agitation (rpm)

1. Tsat(max) 2. Tsat(40) þ acetone (50:50) 3. Tsat(25)

cooling to 25 °C cooling to 5 °C cooling to 5 °C

850 850 0

a Each condition was performed with the complete library of 67 solvents. b The temperature at which solutions were prepared (Tsat) is equivalent to the following: Tsat(max) = (minimum boiling point within group - 10) °C; Tsat(min) = 25 °C. For saturation condition 2, acetone was used as cosolvent.

Figure 2. Overlay showing the molecular structures of CT (blue) and HCT (red) illustrated using the conformers from CT form I13 and HCT form II.12

hydrogen bonding interactions (N1 acceptor in CT, N1-H axial donor in HCT) and the relative conformation of the sulfadiazine ring (approximately planar in CT, nonplanar in HCT) is likely to have a considerable impact on the potential packing arrangements that CT can adopt compared with HCT (Figure 2). The distinct physical form diversity for CT is also examined using the semiclassical density sums using the PIXEL method14-16 to assist in characterizing the intermolecular interactions that underpin CT molecular packing in the solid-state. Experimental Procedures Theoretical Calculations. Five low energy gas phase conformations of CT were estimated by optimization of the SCF 6-31G(d,p) energy using Gaussian.17 The minima were termed minoa, minot, minpa, minsa, and minst according to the conformation of the sulfonamide side chain (o, p, and s=opposite, parallel, and same side to S1; see Supporting Information; a and t=H3 and H4 pointing toward or away from the molecule). An MP2 6-31G(d,p) charge density was calculated for each minimum energy conformation and represented by a set of distributed atomic multipoles18 up to hexadecapole. This was used to calculate the electrostatic contribution to the lattice energy using all terms in the atom-atom multipole expansion up to R-5, thereby including the quadrupolequadrupole terms arising from π and lone pair electron density. All other contributions to the intermolecular lattice energy were calculated using an empirical isotropic atom-atom exp-6 repulsiondispersion model with the same parameters19,20 as used for HCT. Similarly, MOLPAK21 was used to generate around four thousand densely packed crystal structures for each conformation, covering common crystal packings in 26 space groups with Z0 = 1 (see the Supporting Information for a full listing). The crystal structures were optimized by minimizing the intermolecular lattice energy, with the molecule treated as rigid using DMAREL.22,23 The resulting minima were checked for being true minima by considering the second derivative Hessian matrix, and they were sorted into unique structures by comparing both the 15 molecule coordination geometry in the crystal24 and the simulated powder patterns.25 PIXEL. PIXEL calculations14-16 were performed to determine a ranked estimate of the relative stabilizing contributions of different CT 3 3 3 CT intermolecular interactions within predicted crystal structures. From all of the predicted structures based on mino conformers, the lowest energy structure with each CT pair type (see Results for definitions) was selected: specifically, type 1 = minot_aa46 (corresponds to form I; aa46 is a unique identifier for this predicted structure), type 2=minot_ai41, type 3=minot_am121, and type 4 = minoa_am60. Single-point PIXEL lattice energy calculations were carried out on each structure to obtain the lattice energy, Et, decomposed into the polarization (Ep), Coulombic (Ec), dispersion (Ed), and repulsive (Er) contributions and the rank contribution of individual pairwise interactions to the overall intermolecular interaction energy (see Supporting Information). These interactions were then subjected to individual dimer calculations to determine the Ep, Ec, Ed, and Er components for each CT 3 3 3 CT pair-type. Hydrogen bond lengths were adjusted to standard neutron values (C-H, 1.08 A˚; and N-H, 1.00 A˚)26 using

Mercury.27 The valence electron densities of the molecular models were calculated using Gaussian at the MP2/6-31G** level of theory, and the electron density was described using medium cube settings and a step size of 0.08 A˚. Pixels were then condensed into superpixels with a condensation level n = 4. Lattice energy calculations were carried out on a cluster of molecules with a maximum distance of 18 A˚ from a central molecule and a maximum radius for the search of 35 A˚. A threshold of 2.5 kJ 3 mol-128 was then applied to identify the energetically most significant pairwise molecular interactions in the structures. Automated Parallel Crystallization. CT (formI, purchased from Roiga) was recrystallized from solution, with a total of 402 individual crystallizations carried out on a Chemspeed Accelerator SLT100 platform.10 Crystallization was induced in saturated, filtered solutions by either controlled cooling or cooling and evaporation (Table 1). The search utilized a diverse library of 67 solvents, covering a wide range of physicochemical properties, and three distinct crystallization conditions. Solutions were prepared by adding excess solid to each solvent to ensure that solutions were saturated at the set temperature prior to being filtered automatically into a clean crystallization vessel. The temperatures at which solutions were prepared, Tsat, for conditions 2 and 3 (Table 1) were 40 and 25 °C, respectively. For condition 1, solvents were grouped into four groups of ca. 16 solvents each and prepared (Tsat, Table 1) at 10 °C less than the minimum boiling point within each group. Crystallization was induced by cooling at a rate of approximately 3.5 °C per minute. Solutions which did not crystallize within 24 h on the platform were transferred into vials and kept at a constant temperature until precipitate was observed. Once crystallization occurred in each vessel, suspended solid was reclaimed by filtration and transferred to a sample holder for identification using multisample foil transmission X-ray powder diffraction (XRPD)9 (all experimental details are provided in full in the Supporting Information).

Results Low Energy Conformers and Crystal Energy Landscape. The five molecular conformational minima used in the search correspond very closely (Figure 3) to the conformations found in one or more of the experimental structures, except for the terminal NH2 protons on the sulfonamide side-chain, consistent with these proton positions being determined by hydrogen bonding interactions in the lattice. The relative energies of these conformations calculated at the MP2 6-31G(d,p) level (kJ 3 mol-1 with the SCF energies in parentheses), ΔEintra (relative to minsa), are minoa 0.65(0.50), minpa 5.78(8.01), minot 5.95(6.02), and minst 4.39(5.10). However, these relative energies are subject to significant error because of the large contribution of the intramolecular dispersion and basis set superposition error to the interactions between the non-hydrogen atoms29 and the need for higher levels of theory to calculate the barrier to amide pyramidalization,30 which may be very different in the solid state. However, if we ignore the variation in energy with the NH2 conformation, the two nonplanar conformations are very similar in energy, and the planar conformation (minpa) is of the order of 5 kJ 3 mol-1 less stable. This is

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Figure 3. Five CT ab initio conformational minima used in the CSP search (black), with τ1 values, overlaid on the equivalent conformations observed in the experimental structures (gray; see Table 2): (a) minoa, DMF (1/2) solvate; (b) minot, form I; (c) minpa, DMA and 1,4-dioxane solvates [*Note that the conformers in these solvates are actually minpt, with the NH2 group rotated by ∼180° relative to the minpa comformer]; (d) minsa, DMSO and formic acid solvates; and (e) minst, DMF (1/1) solvate and pyridine solvates.

consistent with the only planar ortho-chlorophenyl primary sulphonamide in the CSD being the stable form I polymorph of furosemide, although calculations on a model for furosemide suggest that it has an even larger energy penalty for the planar conformation.31 The intermolecular lattice energy landscape generated by the search (Figure 4) shows that the planar conformation, minpa, can pack slightly more favorably than any of the nonplanar conformations, but not to an extent that overcomes the likely conformational energy penalty. However, all five conformations give rise to thermodynamically feasible low energy structures. The observed crystal structure of CT is the lowest energy structure for conformer minot and may well prove to be the most stable structure overall if the molecular conformations were to be refined with a realistic intramolecular energy penalty. Automated Parallel Screening. Of the 402 parallel crystallization experiments carried out (Table 1), 159 did not give sufficient solid for XRPD analysis due to poor solubility. 215 recrystallized samples were identified as CT form I, and 28 samples were crystalline solvates comprising a total of ten different solvated forms of CT. Of these, a total of seven crystal structures were determined, with the DMA,32 DMSO,32 formic acid,33 pyridine,34 and 1,4-dioxane solvates solved from single-crystal X-ray diffraction data and the DMF 1:135 and 1:236 solvate structures determined from laboratory XRPD data (Table 2). The CT/1,4-dioxane (1:2) solvate shows significant disorder of one of the solvent

molecules, and atom N1 of CT is disordered over two sites, as the molecule lies on a mirror plane. Although limited quality data and extensive disorder contributed to a final wR factor of ca. 10%, the structure yielded sufficient detail to show that CT adopts the minpt conformation. Due to poor quality crystals obtained and rapid transformation to form I, no crystal structures were obtained for the three remaining solvates identified in the search (CT/formic acid hydrate, CT/N-methyl pyrrolidone, and CT/aniline), and these will not be discussed further here (see Supporting Information). Packing Features and PIXEL Calculations. The crystal packing in the individual crystal structures has been described previously,3,32-34,36 and here we compare common packing features across the experimental and predicted crystal structures of CT. In the experimental structures, as expected, extensive hydrogen bonding is observed. In addition to CT 3 3 3 solvent hydrogen bond contacts, 1-dimensional hydrogen bonded chains involving N3-H 3 3 3 N1 contacts between CT molecules are observed in four of the eight structures, namely form 1 and the DMF 1, DMSO, and formic acid solvates (Figure 5). Also, the 1,4-dioxane solvate contains a bimolecular hydrogen bonded ring motif between CT molecules formed via N3-H 3 3 3 O1 contacts. This is the same as motif 5 {centrosymmetric R2,2(16) dimer formed via N3-H4 3 3 3 O3 hydrogen bonds}, one of 11 bimolecular hydrogen bonded motifs identified in our previous study of HCT packing.3 Four of these HCT bimolecular hydrogen bonded motifs cannot form with CT, as they require the

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Figure 4. Low energy crystal structures found in the computational search, classified by rigid molecule conformation and CT 3 3 3 CT pair-type interaction (see Packing Features and PIXEL Calculations). The open symbol represents the experimental structure of CT, calculated with the same computational model. Conformations are represented by color (minoa, light blue; minot, dark blue; minpa, green; minsa, light red; minst, dark red) and intermolecular pair-type by symbol (type 1, þ; type 2, 9; type 3, b; type 4, 2; type 5, ;; mixed, /). Only the intermolecular lattice energy, Uinter, has been plotted, for all structures whose lattice energy, Elatt = Uinter þ ΔEintra, lies within 15 kJ 3 mol-1 of the global minimum (see Supporting Information Table S11), and so this crystal energy landscape omits conformational energy differences, which destabilize the planar conformation (minpa) by ∼5 kJ 3 mol-1.

N1-H1 donor. However, of the remaining seven motifs, the three most frequently occurring in the predicted HCT structures {motifs 2 [centrosymmetric R2,2(8) dimer formed via N3-H3 3 3 3 O4 hydrogen bonds], 4 [centrosymmetric R2,2(16) dimer formed via N2-H2 3 3 3 O4 hydrogen bonds], and 5} are also the most frequently observed in the CT predictions (occurring 28, 31, and 26 times, respectively, out of 138 structures). All of the experimental CT structures also contain one or more of four distinct bimolecular CT 3 3 3 CT pairwise faceface motifs that differ in the relative orientation of constituent CT molecules (Figure 6; detailed descriptions in Supporting Information). These interactions form the basic structural unit of 1D stacks of CT that are observed in all of the experimental structures. {Stacks of molecules in CT pyridine solvate (1:3) consist of repeating type 3 pairs of CT molecules alternating with pyridine molecules.} The type 1 motif in CT form I is accompanied by an N3-H 3 3 3 O4 hydrogen bond between the molecules in the pair. However, hydrogen bonding is not a prerequisite for the formation of these motifs, and types 2, 3, and 4, in particular, are predominantly non-hydrogen bonded contacts. None of the remaining experimental structures display hydrogen bonding between CT molecules engaged in the pairwise motifs. Using the packing feature search in the materials module of Mercury CSD 2.2, the predicted crystal structures were analyzed for the frequency of occurrence of each of the four CT 3 3 3 CT interaction motifs. At least one of the four pairwise interactions was observed in 117 out of the 138 (85%) structures included in Figure 4. The remaining 21 (15%) predicted structures contain an alternative edge-to-face CT 3 3 3 CT interaction involving an N2;H2 3 3 3 OdS hydrogen bond (Figure 7). This arrangement is most commonly

observed with the minoa conformer (13/21) and is not observed in any of the experimental structures. Those predicted structures that contain this motif lie relatively high on the crystal energy landscape, indicating this is a less favorable packing arrangement for CT compared with types 1 to 4. The PIXEL calculations on each of the four structures (type 1=minot_aa46, type 2=minot_ai41, type 3= minot_ am121, and type 4 = minoa_am60) identified several dimer arrangements within the 2.5 kJ 3 mol-1 threshold, and the type 2, 3, and 4 motifs were found to be the dominant dimer interactions in their respective structures, by over 30 kJ 3 mol-1 compared with the next most stabilizing interaction (Table 3). In minot_aa46, the type 1 interaction makes a significant contribution to the overall stabilization of the structure; however, it is ranked third overall and is therefore less dominant compared with types 2, 3, and 4 in the structures analyzed. The total interaction energies, Et, are similar across pair types 2, 3, and 4, and Coulombic and dispersive energy terms dominate the attractive forces, with values ranging from -43.4 to -51.1 kJ 3 mol-1 and -53.6 to -59.8 kJ 3 mol-1 for Ec and Ed, respectively. It is significant that although the Ed value for the type 1 interaction is on a par with these at -56 kJ 3 mol-1, the stabilizing Ec contribution to the type 1 motif is significantly reduced (-1.7 kJ 3 mol-1). This may result from the closer approach between atoms O1/O2 and O3/O4 on adjacent CT molecules in this pair type that may offset the contribution of the N3-H 3 3 3 O4 hydrogen bond to the Ec value in this pair type. Discussion The approximate energy landscape (Figure 4) produced from the five conformers indentified a substantial number of

See Packing Features and PIXEL Calculations section for definitions. b Low-T redetermination CCDC deposition number 783506. c CCDC deposition number 783507. a

1 2, 3 2, 3 4 2, 3 4 3 2 -70 -166.98 -53.57 59.38, -60.49 59.55, -57.31 60.84 57.21 -180 P1 P21/n P1 P21/c P1 P21/c P1 C2/m 262.47 (2) 2066.21 (11) 728.41 (7) 3816.00 (4) 1460.07 (9) 1439.89 (15) 1222.1 (4) 1550.8(3) 80.44(3) 90.00 73.20(7) 90.00 96.25(2) 90.00 98.13(7) 90.00 83.81(3) 105.23(2) 75.08(3) 92.88(26) 103.38(2) 106.25(3) 98.67(8) 106.24(7) 74.42(3) 90.00 86.69(3) 90.00 109.01(2) 90.00 100.69(7) 90.00 9.9251(4) 10.644(3) 11.108(6) 37.30(5) 15.892(5) 8.38(5) 11.875(2) 7.8638(8) 6.380(3) 24.523(6) 8.883(5) 8.856(7) 11.208(4) 21.23(14) 11.863(2) 7.6282(8) 123 123 100 298 123 123 123 293 form I 11,37,b DMA solvate (1:2)32 DMF solvate 1 (1:1)35 DMF solvate 2 (1:2)36 DMSO solvate (1:1)32 formic acid solvate (1:2)33 pyridine solvate (1:3)34 1,4-dioxane solvate (1:2) c

4.861(2) 8.204(3) 7.982(4) 12.35(8) 9.097(3) 8.27(5) 9.070(15) 26.927(3)

T (K) crystal form

a (A˚)

b (A˚)

c (A˚)

R (deg)

β (deg)

γ (deg)

volume (A˚3)

space group/Z

1 4 2 8 4 4 2 2

minot minpt minst minoa minsa minsa minst minpt

motif typesa conf.

τ1 (deg)

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Table 2. Lattice Parameters for CT Crystal Structures Found in the Experimental Search (Standard Uncertainties in Parentheses) As Well As Observed CT Conformations (conf and τ1) in Each Structure

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structures (138) within 15 kJ 3 mol-1 of the global minimum lattice energy. While form I is likely to be the most thermodynamically favorable structure, there are several structures within a few kJ 3 mol-1 of form I that are therefore well within the likely range for polymorphism. While the experimental search included a variety of crystallization conditions capable of impacting on nucleation and/or crystal growth,38 no evidence of polymorphism was found under the range of conditions tested, with form I (produced from 215 out of 243 recrystallizations) the only nonsolvated structure produced. The relatively poor solubility of CT in many solvents did limit the number of solution experiments that successfully produced recrystallized sample; however, acetone proved an effective cosolvent (condition 2, Table 1), increasing the range of accessible crystallization conditions compared with single solvent. The extensive solution crystallization search has shown the propensity of CT to form crystalline solvates, a tendency that is shared with HCT (seven). So, under the experimental conditions tested, the potential alternative packing arrangements for CT found in the approximate landscape have translated into multiple solvates rather than multiple polymorphs. It is notable that the solvate structures all display pair-types 2, 3, and 4 either alone or in combination (Table 2), in preference to pair-type 1, which is only observed in CT form I. This confirms that these CT 3 3 3 CT motif types can and do form during nucleation and growth in supersaturated solution and, when further stabilized by hydrogen bonding and/or close packing interactions with suitable solvent molecules, lead to the formation of the related multicomponent solvate crystal. Evidently, in the absence of a solvent molecule with the requisite complementary packing properties, pairtype I and the associated stabilizing CT 3 3 3 CT interactions identified by the PIXEL calculations (Table 3) are favored and form I results. Given that the solvate structures are based on pair types 2, 3, or 4 and these motifs are found in the predicted thermodynamically feasible structures, samples of each solvate form were subjected to thermal desolvation to assess whether this might lead to an alternative polymorph in which the pairwise motif type from the starting solvate was retained. However, desolvation of each CT solvate also produced form I. This result, in conjunction with the findings from the experimental search, highlights that form I appears to be favored both thermodynamically and kinetically over other potentially feasible structures and packing arrangements. Alternative crystallization methods, for example, growth from the vapor phase39 or crystallization with additives,40 that may stabilize crystalline forms based on pair-types 2, 3, or 4 and/or disfavor the type 1 motif, would merit exploration in further attempts at obtaining new polymorphs of CT. Interestingly, a highpressure polymorph of CT, form II, has recently been reported to form above 4.2 GPa by direct compression of form I.41 This new form was not recoverable at ambient pressure. However, this form is structurally very similar to form I (rms difference between forms I and II of only 0.195 A˚), with a small conformational change distinguishing the structures, and within the accuracy of the current rigid body landscape, it is, in thermodynamic terms, essentially identical to form I, highlighting the overall stability of this structure. CT does show more conformational variability than HCT in the experimental structures, adopting five conformers [mins(a and t), mino(a and t), and minp(t)], compared with only two, minst and minot, in HCT structures.3 The “a” and

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Figure 5. N-H 3 3 3 N hydrogen bonded chain motif in the structure of the CT/DMSO solvate (1:1), in which atom N1 acts as a hydrogen bond acceptor and solvent molecules are connected to the CT chain via N-H 3 3 3 O hydrogen bonds.

Figure 6. The four CT 3 3 3 CT pairwise face-face interaction types observed in the eight experimental crystal structures: type 1 (CT form I); type 2 (CT/DMA, DMF1, DMSO, and 1-4-dioxane solvates); type 3 (CT/DMA, DMF1, DMSO, and pyridine solvates); type 4 (CT/DMF2 and formic acid solvates). Left, viewed from above; right, viewed side-on. Chlorine atoms shown as space filling to highlight the relative CT orientations in each pair type.

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Figure 7. Edge-to-face CT 3 3 3 CT motif observed in 15% of predicted structures. N-H 3 3 3 O hydrogen bond shown as thin line (termed type 5 in Figure 4). Table 3. Total and Partitioned Intermolecular Energies (kJ 3 mol-1) for the Top Three Ranked Dimer Interactions in Each of the Four Predicted CT Structures structure

typea

minot_aa46 (form I) minot_am121

1 2

minot_ai41

3

minoa_am60

4

rankb

Ecc

Epd

Ede

Erf

Etg

COM (A˚)h

1st 1st 3rd 1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd

-41.5 -33.7 -1.7 -51.1 -34.7 -20.1 -43.4 -38.5 -29.2 -45.7 -44.1 -24.1

-12.9 -9.5 -21.8 -13.4 -47.1 -13.6 -17.8 -11.6 -13.1 -15.2 -14.9 -12.6

-28.1 -22.8 -56.0 -53.6 -21.2 -42.4 -59.8 -24.2 -15.3 -57.2 -23.3 -18.4

33.7 17.1 40.9 35.9 26 29.2 42.7 27.4 20.7 40.7 24.6 19.4

-48.8 -48.8 -38.6 -82.1 -47.1 -46.9 -78.3 -47 -36.8 -77.3 -57.8 -35.7

7.36 6.38 4.86 4.98 7.49 5.66 4.92 7.32 8.92 4.91 6.58 7.92

a CT motif type as shown in Figure 6. b Rank contribution of the dimer pair to the overall intermolecular interaction energy in the structure studied. Ec Coulombic term. d Ep polarization term. e Ed dispersion term. f Er repulsion term. g Et total intermolecular interaction energy = Ec þ Ep þ Ed þ Er. h Distance between the centers of mass of the two molecules in the dimer (A˚). c

“t” designations relate only to differences in the orientation of H3 and H4, so excluding these differences in H-atom positions; the biggest difference between CT and HCT is the occurrence of the coplanar conformation, minp, in the CT/1,4dioxane and CT/DMA solvates (Table 2). In the 1,4-dioxane solvate, the minpt conformation allows CT 3 3 3 CT hydrogen bonding while, in the DMA solvate, the coplanar side-chain forms hydrogen bonds to adjacent solvent molecules rather in preference to CT. The absence of the minp conformation in HCT structures may be associated with the axial hydrogen bond donor group, N1-H1, which can provide more favorable hydrogen bonding opportunities without having to accommodate the intramolecular energy penalty associated with the minp conformer. Indeed, the estimated crystal energy landscape for CT shows a larger number of structures based on the minpa conformer, compared with our previous HCT CSP study.3 Since the van der Waals excluded volumes of the CT and HCT molecules are very similar (see Figure 2), we looked for isostructures on their respective crystal energy landscapes. Two structures are very similar (Figure 8), although both are relatively unfavorable, lying ∼10 kJ 3 mol-1 above the global minimum in each landscape. Although differences in molecular structure clearly impact on the opportunities for favorable hydrogen bonding interactions in the crystal structures of CT and HCT, the similarity of shape and the dominant dispersion interaction suggest that both molecules

could also adopt similar structures. Such isostructurality between the low energy structures has been shown to predict the formation of a 1:1 solid-solution of carbamazepine and 10,11-dihydrocarbamazepine.5 However, in this case, the relative instability of the predicted isostructures suggests that formation of the pure components upon cocrystallization is more likely. Preliminary solution crystallization experiments appear to support this in that only physical mixtures of CT and HCT were obtained, although a more systematic survey would be required to confirm this assumption. The computational search method used here requires far less computational resources than would have been expended in order to predict the crystal structure of CT, using the method we successfully used for the flexible molecule in the recent blind test of crystal structure prediction.42 Optimizing the molecular conformation within the crystal structure6 would undoubtedly have refined the conformations and relative energies somewhat, but the computational expense of doing this with an ab initio method capable of modeling the intramolecular (conformational) energy change to the same accuracy as the intermolecular lattice energy is prohibitive, and adds little understanding of the solid form diversity of CT. The good overall correspondence between the experimental structures and the CSP at the level of favorable packing arrangements shows the value of a computational search method in providing an insight into the packing behavior of CT.

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Figure 8. Overlay of a 15 molecule cluster for two higher energy computed structures of CT and HCT (turquoise), illustrating very similar packing of the each molecule in the respective structures with an overlay of 15 out of 15 molecules, yielding an rms of only 0.274 A˚. Hydrogen atoms omitted for clarity. Both the structures are predicted as orthorhombic, space group P212121, with unit cell parameters, a, b, c (A˚) = (minsa_aq15, CT) 6.407, 7.493, 9.273 and (minoa_aq74, HCT) 6.067, 7.635, 9.412.

Conclusion The combination of parallel crystallization searches and crystal structure prediction has identified a variety of solid forms of CT, and in conjunction with PIXEL calculations, has enabled the identification and characterization of the favorable structural motifs that underpin their formation. In addition to the solvate structures, there may be further potential structures of CT that lie beyond the scope of the predicted landscape, e.g. structures that have Z0 g 2 or include disorder, and comprehensive experimental searches remain vital components of any approach for the discovery, control, and selection of solid-state pharmaceutical forms. In this context, a key finding from this work is that the appearance of an alternative polymorph of CT from standard solution crystallizations is unlikely. However, the approximate energy landscape for CT does highlight the molecule’s potential to form alternative polymorphs based on a range of conformers and packing motifs. This knowledge helps to provide an understanding of the molecular interactions that direct the formation of different structures, and so provides opportunities to develop targeted approaches that may promote the formation of specific structures or packing arrangements using alternative recrystallization conditions. These may include templating or epitaxy, or the use of specific solvent systems designed to stabilize CT pair-types 2, 3, and 4, for example, while avoiding solvate formation. Acknowledgment. EPSRC’s Basic Technology Translation award is acknowledged for funding this work under the project Control and Prediction of the Organic Solid-State (www.cposs.org.uk). Supporting Information Available: Full experimental details comprising physicochemical solvent properties, principal component analysis results, individual crystallization conditions and results, thermal analysis data, powder diffraction figures, and tables detailing the structure and properties of all low-energy hypothetical

structures. This material is available free of charge via the Internet at http://pubs.acs.org. The low energy predicted structures are available in .res format from the authors.

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