Access to Single Crystals of (Â±)-Form IV of Modafinil by Crystallization

Article pubs.acs.org/crystal

Access to Single Crystals of (±)-Form IV of Modafinil by Crystallization in Gels. Comparisons between (±)-Forms I, III, and IV and (−)-Form I Published as part of a Crystal Growth and Design virtual special issue of selected papers presented at the 10th International Workshop on the Crystal Growth of Organic Materials (CGOM10) Julien Mahieux, Morgane Sanselme, and Gerard Coquerel* Normandie Université, France, EA 3233 SMS, Crystallogenesis Unit, 76821 Mont Saint Aignan Cedex, France S Supporting Information *

ABSTRACT: (±)-Modafinil is an active pharmaceutical ingredient that crystallizes in several polymorphic forms. However, up to now, only the crystal structures of (±)-Forms I and III have been described in the literature. The crystallization in TMOS-gel with an adapted procedure including the dissolution of an equivalent amount of (+) and (−) enantiomers led to single crystals of (±)-Form IV, a metastable polymorphic form at room temperature. The crystal structure, resolved by using single crystal X-ray diffraction, reveals that this polymorphic form crystallizes in a space group Fdd2 (occurrence ca. 0.3% in CSD version 2011). Single crystals of (±)-Form IV could also be obtained from the racemic compound in TMOS-gel, but prior to gelation it was necessary to heat the solution at reflux for 3 h. These results highlight that a solvated preassembly (from (±)-Form I or (±)-Form III) might exist in solution and could inhibit the formation of single crystals of (±)-Form IV in the standard conditions of crystallization in TMOSgel. The structural comparison between (±)-Forms I, III, and IV highlights clear differences in terms of conformation and packing, and the same structural comparisons between (±)-Form IV and (−)-Form I highlight similarities both in terms of conformation and packing. (±)-Form IV is an enantiotropic modification that is stable at high temperature (close to the melting point) and metastable at room temperature.

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INTRODUCTION

In pharmaceutical industry the metastable polymorph is sometimes desirable on account of its specific properties, such as higher bioavailability, better behavior during grinding or compression, or flowability. Furthermore, manufacturing processes and pharmaceutical processing, such a compaction, milling, wet granulation, and freeze-drying, can also result in polymorphic transitions.7 The relationship between a pair of polymorphs can be enantiotropic or monotropic. In enantiotropic cases, a transition point (Tt) below the melting points of both polymorphs exists, where the two polymorphs can undergo reversible solid−solid transformation.8 On the contrary, if one of the polymorphs is always stable below the melting points of the two polymorphs, the relationship is called monotropic. It is also possible to subdivide polymorphism into two main types: the packing polymorphism9 and the conformational polymorphism.10 The packing polymorphism is observed when the constitutive molecules exhibit the same conformation, for instance, when dealing with a rigid conformation with no degree of freedom, so that only the packings are different. By

Polymorphism corresponds to the ability of a molecule to crystallize into two or more crystalline phases with different arrangements and/or conformations of the molecule in the crystal lattice.1,2 Polymorphs differ in lattice energy and entropy; there are usually significant differences in their physical properties, such as density, hardness, melting point, crystal shape, optical and electrical properties, vapor pressure, solubility, enthalpy of fusion, etc.3 These differences disappear in the liquid and vapor states. It is generally considered that the polymorph with the higher crystal packing density is the thermodynamically favored one (i.e., “the density rule”4). However, other investigations suggest that factors, such as optimized orientation of molecules, hydrogen bonds, or nonhydrogen bonds in the crystal packing can play an important role in the lattice energy. Hence, at a given temperature, it is possible to have a stable thermodynamic polymorph with the lower crystal packing density (i.e., “the exceptions to the density rule”5). Therefore, the use of free energy calculations might be more appropriate to determine the relative stability between several polymorphic forms.6 Indeed, this type of calculation takes into account all interactions in the crystal packing. © 2012 American Chemical Society

Received: November 7, 2012 Revised: December 17, 2012 Published: December 20, 2012 908

dx.doi.org/10.1021/cg301630d | Cryst. Growth Des. 2013, 13, 908−917

Crystal Growth & Design

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III, and IV serve also to justify the particularities of the crystallization processes and to determine the difference in relative stability between these polymorphic forms.

contrast, the conformational polymorphism is commonly encountered for molecules exhibiting several degrees of freedom and therefore might be easily folded into different conformations, therefore with different packing.11 Previous works on (±)-modafinil (Figure 1) highlighted the existence of several polymorphic forms12−14 and solvates.12

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EXPERIMENTAL SECTION

Analytical Techniques. X-ray powder diffraction measurements were carried out on a SIEMENS D5000 Matic diffractometer (Bruker analytical X-ray Systems, D-76187 Karlsruhe, Germany) with a Bragg− Brentano geometry, in theta/2-theta reflection mode. The instrument is equipped with a copper anticathode (40 kV, 40 mA, Kα1 radiation: 1.540 Å, Kα2 radiation: 1.544 Å) and a scintillation detector. The diffraction patterns were collected by steps of 0.04° (in 2-theta) over the angular range 3−30°, with a counting time of 4 s per step. The crystal structures were determined from single crystal diffraction on a SMART APEX diffractometer (with MoKα1 radiation: λ = 0.71073 Å). The structures were solved by direct methods (SHELXS26). Anisotropic displacement parameters were refined for all nonhydrogen atoms using SHEL-XL27 available with the WinGX28 package. All hydrogen atoms were located by Fourier-difference synthesis and fixed geometrically according to their environment with a common isotropic factor. The DSC analyses were performed on a DSC 204F1 Netzsch. For these experiments, ca. 5 mg of samples were heated in aluminum pans from 30 to 170 °C using a heating rate of 10 °C/min. Data obtained were analyzed using the Netzsch, Proteus Thermal Analysis software. Scanning electron microscopy (SEM) pictures were obtained with a JEOL JCM-5000 NeoScope instrument (secondary scattering electron) at an accelerated voltage of 15 kV. Samples were stuck on an SEM stub with gloss carbon and coated with gold to reduce electric charges induced during analysis with a NeoCoater MP-19020NCTR. The evolution of single crystals of (±)-Form I and IV in the gel was observed by optical microscopy using a Nikon Eclipse LV100 (Nikon imaging Ltd.) that enables a magnification of up to ×1000. The pictures and videos were recorded thanks to a CCD camera coupled to the microscope and connected to a computer. Access to Polycrystalline Sample (±)-Form IV from Solution.12 (±)-Modafinil (0.3 g) supplied by Cephalon Inc. was dissolved in methanol (10 mL) at reflux. Then, the homogeneous solution was poured into water (40 mL) in a thermostatted bath at 0.5 °C without stirring. Nuclei instantaneously appeared and were allowed to grow during 2 h at 0.5 °C in the quiescent suspension. Depending on filtration mode, the nature of the recovered polymorphic form could change. When the filtration was performed on a setup with a small residence time (i.e., an oversized Buchner or glass fritter) pure (±)-Form IV was recovered, whereas a mixture of (±)-Forms I and IV was obtained if the filtration occurred more slowly (i.e., by using glass fritter with smaller diameter). Actually, if the methanol was not removed quickly, several experiments have shown that (±)-Form IV evolved toward (±)-Form I. Therefore, after a rapid filtration, drying in a ventilated oven at 80 °C was performed on a thin layer of the filtration cake to ensure the total and fast removal of residual methanol (Figure 2). Single Crystals of (±)-Form IV in Gel. Single crystals of (±)-Form IV were obtained by crystallization in gel of tetramethoxysilane (TMOS: Si(OCH3)4 from Alfa Aesar, 98%). This chemical gel was found to be very convenient for crystallizing this compound: its formation involves water and methanol only. The ratio between these solvents can be modified in order to change the solubility inside the gel. The formation of the TMOS-gel was carried out in two steps (Figure 3). Large amounts of water were used because with a stoichiometric amount the hydrolysis remains partial.29 In this work, the single crystals were obtained by the gel-doping method: the liquid phase inside the pores contained the compound to crystallize. 0.15 g of (R)-modafinil and 0.15 g of (S)-modafinil from Cephalon Inc. (used without further purification) were placed in a flat bottom glass tube of 2 cm in diameter and 15 cm in length with a magnetic bar for stirring. Two milliliters of TMOS and 7 mL of methanol were added, and then the tube was placed in a thermostatted bath at 50 °C. The top of the tube was sealed with a plastic cork. After

Figure 1. Developed formula of (±)-modafinil, namely, 2(diphenylmethyl)sulfinyl)-N-acetamide or 2-benzhydrysulfinylethanamide. *The sulfur atom is the stereogenic center.

Among these different phases, only the crystal structures of (±)-Forms I and III were described. The structure of (±)-Form I was obtained from single crystals and the structure of (±)-Form III was first predicted by using the Derived Crystal Packing model15 from (±)-Form I,16 and then suitable single crystals of (±)-Form III were obtained from crystallization of (±)-modafinil in TMOS-gel.17 The crystallization in gel is not a recent technique since it was first used at the end of the 19th century.18 A gel can be described as a solid network in which a liquid phase is confined. Using gels confers several advantages over conventional crystallization techniques in solution19 such as access to high supersaturation, different nucleation pathways, and growth mechanisms. The gel matrix acts as a nucleation inhibitor allowing the access to higher supersaturation in comparison to crystallization in solution. The nucleation process is influenced by the connectivity and the size of the pores. Even if the heterogeneous nucleation is present anyway, it seems that the homogeneous nucleation is predominant in gels, as shown by the experiment related by Henisch et al.20 Moreover, the transport of material is ensured only by diffusion within the pores of the gel, avoiding the convection movements and thus enabling a smooth continuous delivery of molecules at the growing faces (the depletion zone which surrounds a growing crystal is not disturbed by convection eddies). The morphologies of single crystals may be dissimilar from those observed in solution, because the growth is not physically hindered.21,22 The crystallization in gels is often applied to inorganic materials or macromolecules as proteins, mainly because many crystallizations involve the use of water with gels formed from silica. Crystallization of organic compounds in gels is less common,23 and few cases of crystallization in nonaqueous gels have been reported.24,25 The aim of this report is to present the crystal structure of (±)-Form IV of modafinil as well as the processes to obtain polycrystalline samples in solution and single crystals of this polymorph in TMOS-gel. In order to understand the need for specific protocols adapted for the access to polycrystalline sample and single crystals, comparisons between crystal structures of (±)-Form IV and (−)-Form I and comparisons between (±)-Form IV and (±)-Forms I and III crystal structures are presented. Moreover, comparisons between mechanical properties and thermal stabilities of (±)-Forms I, 909



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normally a racemic compound should have a density higher than that of the enantiomer.30 Moreover, (±)-Form IV corresponds to an exception to the density rule because it is a metastable polymorphic form (see Section Thermal Analysis and Relative Stability of (±)-Forms I, III, and IV) and still exhibits the highest density at room temperature. The asymmetric unit of (±)-Form IV is composed of a single molecule of modafinil (Figure 4). As detailed in Table 2, the two hydrogen atoms of the amide moiety establish two types of hydrogen bonds with neighboring molecules. The first type of hydrogen bonds involves the amide moiety and leads to heterochiral H-bond chains along the [100] direction (Figure 5). These heterochiral chains represent catemers and are connected through the second type of hydrogen bonds involving the sulfoxide moieties along c (Figure 6). The hydrogen bond network leads to slices of d040 thickness (Figure 7). The cohesion between the slices is ensured by Tshaped π interactions (Table 3). Two directions are observed: the strongest interaction spreads along c, and the second takes place on both sides of the previous one (Figures 7 and 8). Comparisons between (±)-Form IV and (−)-Form I. (−)-Form I Packing.31 The asymmetric unit is composed of two molecules which have different molecular conformations ((−)-Conf 1 and (−)-Conf 2). In 80% of the crystal structure with Z′ = 2, the two independent molecules have the same conformation.32 Here, these molecules are connected by two types of hydrogen bonds (Table 2), depending on the oxygen atoms implicated. The first type involves the carbonyl moiety and leads to chains along ac (Figure 9). These periodic band chains build catemers similar to those present in (±)-Form IV but they are obviously homochiral. These catemers are connected through the second type of hydrogen bonds that involved the sulfoxide moieties along c (Figure 10). The hydrogen bond network leads to slices of d020 thickness (Figure 11), and the cohesion between the slices is ensured by T-shaped π interactions (Table 3). Two directions are observed: the strongest interaction spreads along c, and the second takes place on both sides of the previous one. Structural and Conformational Comparisons between (±)-Form IV and (−)-Form I. Comparisons between (−)-Form I and (±)-Form IV packings highlight the common presence of catemers build from the hydrogen bonds involving the carbonyl moieties in both cases (Figures 5 and 9). Furthermore, the catemers lead to slices by the formation of hydrogen bonds between the amine and the sulfoxide of an adjacent catemer along the a direction. These slices of thickness

Figure 2. Experimental X-ray powder patterns of pure (±)-Forms IV (red) compared with X-ray powder patterns of patent (black). 5 min, the dissolution was completed, the stirring was stopped (i.e., the magnetic rod was removed), and 7 mL of water was poured in the solution. After 45 min at 50 °C without stirring, the tube was placed in an oven at 40 °C for 16 h. The hydrolysis and the condensation of TMOS occurred during this storage at 40 °C. Then, the tube was put at room temperature to initiate the nucleation and growth. It is important for the gel to be set before any nucleation takes place; otherwise, the advantages brought by the gel would be jeopardized. After two days at room temperature, the first single crystals of (±)-Form IV appeared. These single crystals were harvested by breaking the gel using a needle. It was important to harvest the single crystals rather quickly because, after one week at room temperature, single crystals of (±)-Forms I and III began to grow; and after few weeks, there were only single crystals of (±)-Forms I and III remaining inside the gel. Moreover, by adapting this protocol of crystallization in gel, it was possible to obtain single crystals of (±)-Form IV starting from (±)-Form I or/and (±)-Form III. This protocol became: 0.3 g of (±)-modafinil were dissolved in 7 mL of methanol and refluxed for 3 h and then 2 mL of TMOS followed by 7 mL of water were added without stirring at 50 °C. The rest of the protocol remained unchanged.

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RESULTS AND DISCUSSION Structural Description of (±)-Form IV. A single crystal of (±)-Form IV, obtained in TMOS-gel by using the afforded mentioned protocol, was analyzed by single crystal X-ray diffraction. Crystallographic data are summarized in Table 1. These crystallographic data are compared with those of (±)-Forms I and III and (−)-Form I which were obtained from the CSD. (±)-Form IV crystallizes in a particularly uncommon space group: Fdd2 (occurrence ca. 0.3% in CSD version 2011). The density of (−)-Form I is higher than those of (±)-Forms I, III, and IV. This is an exception to the Wallach’s Rule since

Figure 3. Hydrolysis then condensation of TMOS. 910



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Table 1. Crystal Data of Racemic (±)-Forms IV, I, III and (−)-Form I name

(±)-Form I

(±)-Form III

(±)-Form IV

(−)-Form I

chemical formula CSD number molecular weight (g mol−1) crystal system a (Å) b (Å) c (Å) β (deg) unit cell volume (Å3) calculated density (g.cm−3) space group no. of formula per unit cell, Z, Z′ final R1 value (I > 2σI)

C15H15O2NS CCDC 229171 273.3 monoclinic 14.502(1) 9.687(1) 20.844(1) 110.17(1) 2748(1) 1.321 P21/a (No. 14) 8, 2 0.0359

C15H15O2NS CCDC 284321 273.3 orthorhombic 14.510(4) 9.710(3) 19.569(5) 90 2757(1) 1.317 Pna21 (No. 33) 8, 2 0.0302

C15H15O2NS CCDC 908057 273.3 orthorhombic 18.172(5) 52.375(10) 5.698(5) 90 5423(5) 1.339 Fdd2 (No. 43) 16, 1 0.0388

C15H15O2NS CCDC 241714 273.3 monoclinic 9.332(3) 26.504(4) 5.689(3) 105.96(3) 1352(1) 1.342 P21 (No. 4) 4, 2 0.0330

about 13 Å (d040 in (±)-Form IV and d020 in (−)-Form I) are connected by two types of T-shaped π interactions (Figures 7 and 11; Table 3). Further comparative analysis reveals that the conformation of the R enantiomer in (±)-Form IV corresponds to one of the two conformations in (−)-Form I (Figure 12). The main differences between (−)-Conf 1 and (−)-Conf 2 are the values of the torsion angles N1−C15−C14−S and C15−C14−S−C1 (Table 4). Comparisons between (±)-Form IV and (±)-Forms I and III. Prior to (±)-Form IV, (±)-Forms I and III were determined by single X-ray diffraction. These two structures contain two molecules in the asymmetric unit. Moreover, these molecules present the same conformation, within the same polymorphic form, as well as between them. (±)-Form I Packing.17 Modafinil molecules are connected by means of strong hydrogen bonds. There are two types of hydrogen bonds (Table 2). The first type (involving the amide moiety) connects two heterochiral molecules together generating centrosymmetric dimers (Figure 13). The second type connects the dimers together (involving the oxygen atoms of the sulfoxide moieties). Thus, every dimer is related to four adjacent dimers, giving rise to a planar hydrogen bond network spreading along ab. These slices exhibit a d002 = 9.78 Å thickness (Figure 14) and the cohesion along c is ensured by means of two types of π interactions: T-shaped and π stacking (Table 3). (±)-Form III Packing.17 The cohesion of the structure is ensured by the same types of interactions as in (±)-Form I. The hydrogen bond network gives rise to slices spreading along ab (Figure 15, Table 2), and exhibits a d002 = 9.78 Å thickness. These slices are connected through two types of π interactions: T-shaped and π stacking (Figure 16, Table 3). Comparisons between Modafinil Molecular Conformations in (±)-Forms I, III, and IV. When considering the asymmetric units of every racemic form, the main features that stand out are the similarities between the two independent molecules in (±)-Forms I and III, which are conformationally different from the molecule in (±)-Form IV. The torsion angles N1−C15−C14−S (α) are near opposite and the torsion angles S1−C1−C2−C3/C7 (β) and S1−C1−C8−C13/C9 (γ) are also clearly different (Figure 17, Table 5). The similarity of molecular conformations between (±)-Forms I and (±)-Form III highlights that the polymorphism between these forms corresponds to a packing polymorphism. By contrast, the

Figure 4. Asymmetric unit of (±)-Form IV, in thermal ellipsoidal representation (50% of probability) with atoms labels.

Table 2. Hydrogen Bondsa N−H···OC (±)-Form IV (−)-Form I

(±)-Form I

(±)-Form I

N(1)− H(1B)···O(2)#1 N(2)− H(30)···O(2)#2 N(1)− H(14)···O(4)#3 N(1)− H(27)···O(2)#4 N(2)− H(29)···O(4)#5 N(1)− H(29)···O(4)#6 N(2)− H(30)···O(2)#7

d(H···A) (Å) 2.20 2.08 2.25 2.06 2.18 2.07 2.10

N−H···OS N(1)− H(1A)···O(1)#8 N(2)− H(29)···O(1)#9 N(1)− H(13)···O(3)#10 N(1)− H(23)···O(1)#11 N(2)− H(25)···O(3)#12 N(1)− H(27)···O(3)#13 N(2)− H(28)···O(1)#14

d(H···A) (Å) 2.24 2.02 2.18 2.06 2.14 2.14 2.12

Symmetry transformation used to generate equivalent atoms #1 [x − 1/4, −y + 1/4, z − 1/4]; #2 [−x, −1/2 + y, −z]; #3 [1 − x, 1/2 + y, 1 − y]; #4 [1 − x, 1 − y, −z]; #5 [2 − x, 2 − y, 1 − z]; #6 [1 − x, 1 − y, −1/2 + z]; #7 [1 − x, 1 − y, 1/2 + z]; #8 [x − 1/4, −y + 1/4, z + 3/ 4]; #9 [1 − x, −1/2 + y, −z]; #10 [−x, 1/2 + y, 1 − z]; #11 [1/2 − x, 1/2 + y, −z]; #12 [3/2 − x, 1/2 + y, 1 − y], #13 [1/2 − x, −1/2 + y, −1/2 + z]; #14 [1/2 − x, −1/2 + y, 1/2 + z]. a

Figure 5. Heterochiral H-bonded chains spreading along a (H-bonds in dashed red lines): #2 [x − 1/4, −y + 1/4, z − 1/4]. 911



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Figure 6. The second type of hydrogen bonds connects the chains (dashed yellow lines). #1 [x − 1/4, −y + 1/4, z + 3/4].

Figure 9. Hydrogen bonded chains spreading along ac (hydrogen bonds in dashed red lines).

Figure 7. Projection along the c axis, the slices exhibit a d040 = 13.09 Å thickness (red lines). The cohesion between the slices is ensured by Tshaped π interactions. The strongest interaction spreading along the c axis is depicted by dashed blue lines. Shown in dashed green lines are the weakest interactions taking place on both sides of the main π interactions.

Table 3. π Interactions Lengthsa and Angles (±)-Form IV (-)-Form I (±)-Form I (±)-Form III

type of interactions

d/ang

strong T-shaped π interactions weak T-shaped π interactions strong T-shaped π interactions weak T-shaped π interactions T-shaped π interactions π stacking interactions T-shaped π interactions π stacking interactions

4.05 Å/82° 4.04 Å/58° 3.89 Å/84° and 4.08 Å/80° 3.92 Å/56° 3.43 Å/83° and 3.88 Å/85° 3.52 Å/22° and 3.58 Å/22° 3.44 Å/85° and 3.89 Å/85° 3.43 Å/23° and 3.55 Å/23°

a

The distances are measured from carbon to centroid for the T-shaped π interactions and from carbon to carbon for the π stacking interactions. Figure 10. The second type of hydrogen bonds connects the chains (dashed yellow lines).

structural relationship between (±)-Forms IV and (±)-Forms I or III corresponds more to conformational polymorphism. The ways the molecules are connected enhance those differences. The hydrogen bond networks are composed of two types of hydrogen bonds for each polymorph. The secondary hydrogen bonds network (N−H···OS) generates slices in the three cases, whereas the primary hydrogen bond network (N− H···OC) corresponds to dimers in (±)-Forms I and III, but catemers in (±)-Form IV (Figures 7, 14, and 16). Considering the π interactions, there are two geometries (T-shaped and π stacking) in (±)-Forms I and III, whereas T-shaped only in (±)-Form IV.

Figure 8. Projection along the c axis, the chirality of the molecules is represented in green and blue, the hydrogen bonds are represented in dashed red/yellow lines and the T-shaped π interactions are in blue/ green dashed lines.

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Figure 13. Hydrogen bond network slice of (±)-Form I. Two types of hydrogen bonds represented by red dashed lines (dimers), and the yellow dashed lines (connecting dimers).

Figure 11. Projection along c axis, the slices exhibit a d020 = 13.25 Å thickness (red lines). The cohesion between the slices is ensured by Tshaped π interactions. The strongest interaction spreading along the c axis is depicted in dashed blue lines. Shown in dashed green lines are the weakest interactions taking place on both sides of the main π interaction.

Figure 14. Projection along the b axis of (±)-Form I, the π interactions are featured in dashed green lines for the π stacking interactions and in dashed blue lines for the T-shaped π interactions.

Figure 12. Superimposition of the molecular conformations of (±)-Form IV and (−)-Form I. In green (−)-Conf 2, in white (−)-Conf 1 and in standard color (±)-Form IV.

Table 4. Changing Torsion Angles in (±)-Form IV and (−)-Form I N1−C15− C14−S (±)-Form IV (−)-Conf. 1 (−)-Conf. 2

S−C1−C2− C3/C7

S−C1−C8− C9/C13

C15−C14− S−C1

144°

−58°/122°

55°/-125°

−163°

147° −156°

−55°/125° −57°/123°

55°/-125° 62°/-118°

−164° 41°

Figure 15. Hydrogen bond network of (±)-Form III. Two types of Hbonds symbolized by red and yellow dashed lines.

The relative stability of the different conformations of the molecules has been investigated by using SYBYL software.33 These calculations were performed on molecules without taking into account the intermolecular interactions resulting from the crystal packing. The computational parameters used during the minimization are listed below: • Method: Powell • Termination: Gradient • Max iterations: 10000

• Min energy change: 0.050 kcal/mol • Force field: Tripos • Partial charges: Gasteiger-Marsili First of all, the torsion angle α was constrained to three different values: −155°, −151° then 144° (i.e., angles observed in (±)-Forms I, III, and IV, respectively). Then, the conformational energy versus β and γ angles was computed 913



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This study highlights that the packings of (±)-Forms I and III have approximately the same energy, whereas the energy of (±)-Form IV is much higher at 0 K. (±)-Form IV can be considered as a metastable polymorphic form at low temperature. The variation of hydrogen bond energy is due to weakest hydrogen bonds in (±)-Form IV than in (±)-Forms I and III (Table 2). Then, the decrease of van der Waals energy is due to the density (Table 1). Indeed, in some cases, as in (±)-modafinil, energetically favorable hydrogen bonds compensate for the loss of van der Waals energy and thus stabilize the lowest density polymorph (e.g., acetazolamide35) so that the density rule is not of general applicability. The molecular conformation found in (±)-Form IV is necessary to build up slices of catemers. Indeed, a change of molecular conformation toward the molecular conformation of (±)-Forms I or III, simulated with Material Studio software, leads to a large energetic penalty (ΔE = 32 kcal mol−1). The constraints existing in the crystal packing of (±)-Form IV explain the necessity of this unfavorable molecular conformation. Duality of the Access to (±)-Form IV in TMOS-gel. According to the first trials, the access to single crystals of (±)-Form IV in TMOS-gel requires the unusual use of a physical mixture of both enantiomers. Indeed, by using the racemic compound ((±)-Forms I or III) with the initial process, no single crystals of (±)-Form IV were obtained in TMOS-gel. The solution seems to keep some kind of memory of the initial solid, even if the initial powder was fully dissolved.36 A solvated synthon might remain in the solution.37 Two hypotheses can be considered: (i) a solvated assembly from the physical mixture of both enantiomers exists that maintains the catemers and thus favoring the nucleation of (±)-Form IV; (ii) a solvated assembly from (±)-Form I or (±)-Form III exists as dimers and thus inhibits the formation of single crystals of (±)-Form IV in TMOS-gel. The similarity of the packing and the conformation between (−)-Form I and (±)-Form IV explains the possibility to access to single crystals of (±)-Form IV from a physical mixture of both enantiomers. Indeed, during the preparation of the gel, if a solvated assembly from the enantiomers exists, it should be close to that of (±)-Form IV and therefore facilitate the formation of single crystals of (±)-Form IV. A CSD survey revealed that there are 1151 crystals structures in which at least one primary amide functional group is present. 34% of these structures exhibit the dimer motif versus 23% only for the catemer motif.38 When competing donors and/or acceptors of hydrogen bonds are absent, the percentage of the occurrence of dimer/catemer shifts to 82%/16% respectively. Thereby, the catemers observed in the enantiomer crystal structure might ensure the crystallization of (±)-Form IV by remaining long enough as a solvated assembly. Consistently, polycrystalline sample of (±)-Form IV can be obtained from the racemic compound (either (±)-Form I or (±)-Form III), but this involves the heating of the solution at reflux prior the addition of water without stirring. One hypothesis is that this heating seems to break the solvated dimers. Therefore, the formation of single crystals of (±)-Form IV in TMOS-gel from the racemic compound can be only carried out after the heating of the solution at reflux for 3 h. This heating brings a sufficient amount of energy to overcompensate the stabilization ensured by the dimers.

Figure 16. Projection along b axis of (±)-Form III, the π interactions are featured in dashed green lines for the π stacking interactions and in dashed blue lines for the T-shaped π interactions.

Figure 17. Superimposition of the asymmetric units (A.U.) of the three polymorphic forms (only one molecule of the A.U. for (±)-Form I, and (±)-Form III because both molecules of the A.U. are approximately identical). In green (±)-Form I, in white (±)-Form III and in standard color (±)-Form IV.

Table 5. Changing Torsion Angles in (±)-Form I, III, and IV

(±)-Form I (±)-Form III (±)-Form IV

α (N1−C15− C14−S1)

β (S1−C1−C2− C3/C7)

γ (S1−C1−C8− C13/C9)

−155° −151°

−40°/140° −40°/141

−112°/67° −112°/67°

144°

−58°/120°

−124°/55°

by 5° increments (i.e., up to a rotation of 180° because the corresponding relative energies are modulo π) (Figure 18). Figure 18 shows that a single orientation is favorable for the aromatic rings when the torsion angle α has fixed values. The one in (±)-Form IV is the most disadvantaged. This conformational study was completed by some energy calculations on the three different crystal packing with Material Studio molecular modeling software.34 The total energy of the packing and the contributions to this energy for every form are summarized in Figure 19. 914



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Figure 18. Relative energy of the molecule for a variation of the torsion angles β and γ.

Figure 20. Comparison of DSC analyses of (±)-Forms I and IV.

related.4 Nevertheless, as no transformation was observed during the heating up to the melting-decomposition point, (±)-Form I being the stable variety at room temperature, (±)-Form IV should correspond to an enantiotropic polymorph (stable variety at high temperature). Another method to investigate the relative stability between polymorphic forms is to compare their solubilities in a solvent at different temperatures and build two solubility curves.39 Nevertheless, in the case of (±)-modafinil, a polymorphic transformation of (±)-Form IV toward (±)-Form I occurred rapidly in solution.14 Thus, this proves that (±)-Form I is the stable polymorphic form at room temperature. This polymorphic transformation was also observed in gel (Figure 21). It corresponds to a destruction/reconstruction mechanism because no contacts were needed to obtain single crystals of (±)-Form I after a few hours. Then, the polymorphic transformation was also studied without solvent. A polycrystalline sample of (±)-Form IV was placed in a glass tube. A light milling was applied by using a magnetic bar. This gentle milling provoked the polymorphic transition toward (±)-Form III in less than 2 h. Even in the solid state (±)-Form IV cannot stand any mechanical stress, whereas (±)-Form I can stand fairly strong mechanical stress (but above a certain threshold, Form I transforms into (±)-Form III13). According to the shape of the solid particles (Figure 22), the thin platelets of (±)-Form IV might be more sensitive to milling than isotropic prism of (±)-Form I. Moreover, the presence of many defects in single crystals of (±)-Form IV (Figure 21) gives higher sensitivity to mechanical stress; therefore milling is likely to induce cleavages in the single crystals with high energy surfaces. By contrast, for other molecules (e.g., 2-(methylthio)nicotinic acid40), single crystals with an elongated shape are less sensitive to mechanical stress and can undergo bendings. Therefore, regarding the resistance to mechanical stress, a hierarchy can be assigned: (±)-Form IV ≪ (±)-Form I < (±)-Form III.

concomitantly degrades and melts preventing even a rough approximation of the enthalpy. Thus, there is no possibility to use the Burger and Ramberger’s heat of fusion rule of polymorphs, which postulates that if the higher melting polymorph has a lower heat of fusion to that of the lower melting polymorph then the polymorphs are enantiotropically

CONCLUSION Access to single crystals of (±)-Form IV of modafinil was possible by using TMOS-gel. It is noteworthy that the required conditions to obtain single crystals of (±)-Form IV in the gelified medium are similar to those necessary to isolate a polycrystalline sample of (±)-Form IV from solution. The

Figure 19. Relative energy of the packing and the contributions to relative energy of packing. (±)-Form I was considered as the reference.

Thermal Analysis and Relative Stability of (±)-Forms I, III, and IV. The DSC analyses have shown meltingdecompositions for pure (±)-Form IV at 165.8 °C, and at 164.2 °C for (±)-Form I (Figure 20). Indeed, the product

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Figure 21. Evolution of single crystals of (±)-Forms I and IV in the gel.

Figure 22. SEM pictures of powder of (±)-Forms I, III, and IV.

conception of tablets and no plastic bending can be observed

protocols used highlighted: (i) the importance of the dissolved species, (ii) the absence of stirring. Indeed, when (±)-Form I or (±)-Form III were used as starting material, a preliminary prolonged heating was found mandatory to dismantle putative centrosymmetric solvated building blocks probably remaining in solution. The presence of this solvated preassembly at 50 °C inhibited the formation of single crystals of (±)-Form IV in TMOS-gel. Structural comparisons between (±)-Forms I, III, IV and (−)-Form I show that the periodic band chains of hydrogen bonds correspond to catemers [(±)-Form IV and (−)-Form I] or dimers [(±)-Forms I and III]. (±)-Form IV exhibits an uncommon space group (Fdd2, occurrence ca. 0.3% in CSD version 2011) with a big parameter b (>50 Å) compared to a (∼18 Å) and c (∼5 Å). Moreover, the study of the relative stability highlights that (±)-Form IV is a metastable polymorphic form at room temperature with an enantiotropic relationship with (±)-Form I. It should correspond to the stable variety at high temperature. Then, the study of the mechanical properties serves to establish a hierarchy of resistance to mechanical stress: (±)-Form IV ≪ (±)-Form I < (±)-Form III. The low resistance on mechanical stress shows that (±)-Form IV cannot be used in the

in single crystals.

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information file (CIF) and movie file in AVI format. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

The authors are thankful to Cephalon Inc. (West Chester, PA) for continuous support during this study. 916



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Access to Single Crystals of (Â±)-Form IV of Modafinil by Crystallization

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