Access to Several Polymorphic Forms of (Â±)-Modafinil by Using

Article pubs.acs.org/crystal

Access to Several Polymorphic Forms of (±)-Modafinil by Using Various Solvation−Desolvation Processes Published as part of the Crystal Growth & Design virtual special issue of selected papers presented at the 11th International Workshop on the Crystal Growth of Organic Materials (CGOM11 Nara, Japan), a joint meeting with Asian Crystallization Technology Symposium (ACTS 2014) Julien Mahieux,† Morgane Sanselme,*,‡ and Gerard Coquerel‡ †

Nestlé Research Center, Route du Jorat 57, CH-1000 Lausanne 26, Switzerland Normandie University, SMS Laboratory, University of Rouen, rue Lucien Tesnière, 76130 Mont Saint Aignan, France

‡

ABSTRACT: The solid state landscape of (±)-modafinil presents several polymorphic forms and solvates. Some of these polymorphic forms ((±)-Forms V and VI) can only be obtained by means of desolvation of solvates ((±)-modafinil chloroform solvate and acetonitrile solvate). Moreover, a new hydrate ((±)-modafinil monohydrate) is obtained from an original protocol which uses a physical mixture of both enantiomers rather than the racemic compound. All these solvates present an efflorescent behavior, and this study highlights the formation of various polymorphic forms from the same solvate according to the temperature of desolvation. Indeed, when the desolvation process is performed below or above the glass transition temperature (Tg) of the anhydrous modafinil, the resulting nonsolvated phases differ.

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INTRODUCTION The study of the solid state landscape of an active pharmaceutical ingredient (API) is required during the examination of new drug applications. This study aims at understanding the relationships between these solid phases. Indeed, pharmaceutical molecules could tend to form a range of phases: polymorphs,1,2 solvates,3 cocrystals, host−guest associations, and hybrids of all sorts. Moreover, these studies of the solid state landscape are used to prevent the appearance of unexpected solid forms after the approval of a drug4 and to ensure the robustness of industrial processes. The study of all the possible solvates that can be formed with an API is also important in the pharmaceutical industry. Indeed, solvates sometimes play a crucial role in which the solvent evaporation can generate new polymorphs which are only accessible via the preliminary formation of the solvates.5,6 Moreover, different desolvation mechanisms are described in order to understand the formation of the desolvated phases,7−9 and some examples can be found in the literature.10−16 (±)-Modafinil (Figure 1) is an API of Cephalon Inc., indicated to treat excessive sleepiness, commercialized under the name of

PROVIGIL, which crystallizes in several polymorphic forms17 and solvates.17,18 The crystal structure of (±)-Forms I, III, and IV have already been described in previous works. The crystal structure of (±)-Form I was determined by using single crystal X-ray diffraction, and the crystal structure of (±)-Form III was first solved by using the derived crystal packing model19 from (±)-Form I.20 Then, single crystals of (±)-Form III were harvested from crystallization in TMOS-gel.21 More recently, the crystallization in TMOS-gel with an original protocol has served to obtain single crystals of (±)-Form IV, and thus the crystal structure of this phase was resolved by using single crystal X-ray diffraction.22 This new study on (±)-modafinil describes the formation of (±)-modafinil monohydrate from the same nonobvious protocol as that used to obtain Form IV, and its crystal structure was determined by using single crystal X-ray diffraction. Moreover, the crystal structures of two solvates ((±)-modafinil chloroform solvate and (±)-modafinil acetonitrile solvate) were also determined by using single crystal X-ray diffraction. In addition, by applying various desolvation processes, different anhydrous polymorphic forms were obtained (±)-Forms III, IV, V, and VI; among these, (±)-Forms V and VI seem to be only accessible via the parent solvated phases.

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

Received: September 25, 2015 Revised: December 1, 2015 Published: December 3, 2015

© 2015 American Chemical Society

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DOI: 10.1021/acs.cgd.5b01384 Cryst. Growth Des. 2016, 16, 396−405

Crystal Growth & Design

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Figure 2. TGA−DSC−MS curves of fresh prepared sample of (±)-modafinil monohydrate. The red curve corresponds to the MS signal for m/z = 18. The blue curve displays the mass loss during the heating. The green one describes the thermal events.

Figure 3. Evolution of single crystals of (±)-modafinil monohydrate (elongated crystals) in the supersaturated methanolic solution under ambient conditions toward (±)-Form I (prismatic crystals).

Figure 4. Highlight of the efflorescent behavior of single crystals of (±)-modafinil monohydrate under ambient conditions. (the yellow arrow indicates the defective tip of the crystal that “promotes” the collapse of the crystal structure).

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of the analyses was regulated by helium flux (40 mL min−1), and heat runs were conducted at 5 K/min heating rate. The data treatment was performed with the Netzsch, Proteus Thermal Analysis software. The differential scanning calorimetry coupled with thermogravimetry analyses (TGA-DCS) were performed on a TG/DSC Netzsch STA 449 C instrument. Samples were put in a 25 μL aluminum crucible with pierced lids and heated at a rate of 5 K/min. Helium was used as purging gas. The chemical nature of escaping gases during heating was identified by using a Netzsch QMS 403 C mass spectrometer coupled with the 449C TG/DSC apparatus. The evolution of single crystals of (±)-modafinil monohydrate in solution 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 with a CCD camera coupled to the microscope and connected to a computer. The amorphous phase of (±)-modafinil was prepared by using a Bü chi B-190 laboratory scale spray dryer (Flawil, Switzerland). (±)-Modafinil (2 g) supplied by Cephalon Inc. was dissolved in methanol (200 mL). The homogeneous feed solution was atomized

EXPERIMENTAL SECTION

Analytical Techniques. X-ray powder diffraction (XRPD) analyses were performed using a D8 diffractometer (Bruker, Germany) equipped with a modified goniometer of reverse-geometry (-θ/-θ) and a LynxEye detector (Bruker, Germany), using Cu Kα radiation (λ = 1.54059 Å) with a tube voltage and amperage set at 40 kV and 40 mA respectively. XRPD analyses were performed with a step of 0.04° (in 2θ) and a 0.5 s/step counting time from 3 to 30° (2θ). The crystal structures were determined from single crystal diffraction on a SMART APEX diffractometer (with Mo Kα1 radiation: λ = 0.71073 Å) at room temperature. The structures were solved by direct methods (SHEL-XS23). Anisotropic displacement parameters were refined for all non-hydrogen atoms using SHEL-XL24 available with the WinGX25 package. All hydrogen atoms were located by Fourier-difference synthesis and fixed geometrically according to their environment with a common isotropic factor. The differential scanning calorimetry (DSC) analyses were conducted on DSC 204 F1 Netzsch. Solid sample (mass of ca. 17 mg) were placed in a 25 μL aluminum crucible with pierced lids. The atmosphere 397



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Figure 5. TGA−DSC curves of fresh prepared sample of (±)-modafinil acetonitrile solvate.

Figure 6. TGA−DSC curves of wet sample of (±) modafinil chloroform. After the drying step, the desolvation phenomenon begins at ca. 65 °C. On the DSC curve, after the complete desolvation (section a), a recrystallization is observed (event labeled b), followed at ca. 155 °C by one endothermic event (event labeled c), and an immediate recrystallization (event labeled d) that might be attributed to the fusion of the Form V and the recrystallization of Form I. The event labeled (e) and (f) corresponding respectively to the fusion of Form I and the degradation of the (±)-modafinil compound.

Table 1. Crystal Data of the Solvated Phases name

(±)-modafinil monohydrate

(±)-modafinil chloroform solvate

(±)-modafinil acetonitrile solvate

(±)-modafinil dihydrate10

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

C15H15O2NS,H2O CCDC 1415721 289.3 monoclinic 32.674 (19) 5.756 (3) 18.024 (11) 117.948 (10) 2994 (3) 1.284 C2/c (No. 15) 8, 1 6.84

C15H15O2NS,CHCl3 CCDC 1415720 392.71 monoclinic 5.689 (5) 17.736 (5) 17.827 (5) 92.246 (5) 1797.4 (17) 1.451 P21/n (No. 14) 4, 1 6.07

C15H15O2NS,CH3CN CCDC 1415719 314.39 monoclinic 12.956 (3) 5.733 (14) 22.529 (6) 104.943 (4) 1616.7 (7) 1.292 P21/n (No. 14) 4, 1 5.85

C15H15O2NS,2H2O CCDC 969516, refcode: SOCMOO 305.34 monoclinic 12.898(1) 5.673(1) 22.580(1) 104.000(1) 1603.2(1) 1.265 P21/n (No. 14) 4, 1 4.19

according to the following parameters: the feed flow rate was 6.0 mL/min, the inlet temperature was set at 90 °C, the outlet air temperature recorded was 55 °C, and the aspiration was fixed at 30 m3/h.

Access to (±)-Modafinil Monohydrate from Methanolic Solution. Saturated solutions of (−)-modafinil and (+)-modafinil, were prepared in methanol (technical grade) at room temperature. 398



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Figure 8. Representation of the hydrogen bonds between (±)-modafinil in the three new solvates. The first type of H-bonds (dashed blue lines) produces a centrosymmetric dimer of modafinil molecules (light/dark gray for the two enantiomers); then through the second type of H-bonds (dashed green lines), molecular columns are generated along one crystallographic axis.

Figure 7. Superimposition of the supramolecular synthon of (±)-modafinil monohydrate (in standard color), (±)-modafinil chloroform solvate (in green), and (±)-modafinil acetonitrile solvate (in blue).

Table 3. π Interaction Lengthsa and Angles Encountered in the Different Solvates

The same volume of these saturated solutions was added in order to obtain a supersaturated solution of (±)-modafinil. After 5−10 min, single crystals appeared in the solution, and the XRPD analysis exhibited an unknown phase. The TGA−DSC−MS analysis performed on this solid highlighted the presence of water molecules with a 1−1 stoichiometry (Figure 2). Therefore, this new phase obtained in methanol is a (±)-modafinil monohydrate. Some Karl Fisher measurements were performed on technical grade methanol used in these experiments; the quantity of water present was found to vary from 2000 ppm up to 4000 ppm. The theoretical mass loss for the monohydrate is 6.1%; however, the experimental value is at ca. 4%. This disparity is due to the efflorescent character of that phase leading to the presence of nonsolvated form within the sample (Figure 3; at t = 0, crystals of Form I are already noticeable). Consistently, the enthalpy of dehydration is measured at ca. 52 J/g (∼15 kJ/mol) is likely to be underestimated compared to other values in the literature.11,16 Nevertheless, this order of magnitude could also be due to the weak interactions between the water molecules and the crystalline network (i.e., weak hydrogen bonds with the molecular network of (±)-modafinil molecules). Nevertheless, these single crystals are metastable in the supersaturated solution because the spontaneous nucleation of (±)-Form I occurred after approximately 1 h and caused the disappearance of these single crystals by means of dissolution/recrystallization mechanism (Figure 3). Therefore, these single crystals should be rapidly harvested. As this protocol gave directly single crystals in the solution, a single crystal X-ray diffraction analysis was undertaken. However, (±)-modafinil monohydrate presents an efflorescent behavior under ambient conditions (Figure 4), and the single crystal should be analyzed in a capillary containing the methanolic saturated solution to inhibit this dehydration phenomenon. Furthermore, without nuclei of (±)-Form I, the evolution of the monohydrate toward this desolvated form is delayed; therefore it was possible to perform a single crystal X-ray analysis in capillary. Accesses to (±)-Modafinil Chloroform Solvate and (±)-Modafinil Acetonitrile Solvate. The solute was dissolved in chloroform

(±)-modafinil monohydrate type of interactions strong T-shaped π interactions (dashed purple lines) strong T-shaped π interactions (dashed black lines) weak T-shaped π interactions (dashed orange lines) Cl−π interaction Csp···Csp (acetonitrile solvent) a

d/Ang 4.04 Å/88°

(±)-modafinil chloroform solvate d/Ang 3.76 Å/76°

(±)-modafinil acetonitrile solvate d/Ang 3.76 Å/83°

3.95 Å/88°

4.05 Å/84°

3.85 Å/54°

3.70 Å/54°

3.41 Å/3.92 Å 3.39 Å

The distance are measured from carbon to centroid.

(or acetonitrile) in order to obtain a saturated solution at room temperature, and single crystals were obtained by slow evaporation. As (±)-modafinil monohydrate, (±)-modafinil chloroform, and acetonitrile solvates present an efflorescent behavior under ambient conditions, the single crystals need to be analyzed in a capillary containing the saturated solution in chloroform to inhibit the desolvation phenomenon.17,18 The TGA−DSC analysis performed on the acetonitrile solvate (Figure 5) highlighted the presence of acetonitrile molecules with a 1−1 stoichiometry. The mass loss (10.34%) corresponds to one molecule of solvent (theoretical loss = 13.0%). As encountered, in the case of (±)-modafinil hydrate, the discrepancy might be attributed to the efflorescent character of that solvate which leads to a partial desolvation

Table 2. Hydrogen Bondsa (±)-modafinil monohydrate type of interactions generating supramolecular synthons (dashed blue lines) connecting supramolecular synthons (dashed green lines)

d(D−H···A) N(1)−H(1B)···O(1)#1 N(1)−H(1A)···O(1)#2

(±)-modafinil chloroform solvate

(±)-modafinil acetonitrile solvate

2.20 Å

d(D−H···A) N(1)−H(1B)···O(1)#3

2.18 Å

d(D−H···A) N(1)−H(1B)···O(1)#5

2.19 Å

2.72 Å

N(1)−H(1A)···O(1)#4

2.50 Å

N(1)−H(1A)···O(1)#6

2.53 Å

Symmetry transformation used to generate equivalent atoms #1 [−x, −y, −z]; #2 [−x, 1 − y, −z]; #3 [2 − x, −y, 2 − z]; #4 [3 − x, −y, 2 − z]; #5 [1 − x, 1 − y, −z]; #6 [1 − x, −y, −z]. a

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Figure 9. Representations of the T-shaped π interactions in the crystal packing of (±)-modafinil monohydrate (a), (±)-modafinil chloroform solvate (b), (±)-modafinil acetonitrile solvate (c). Two different colors are used to depict columns in order to improve the representation of the T-shaped π interactions between these columns.

Figure 10. Projection along the b axis of the crystal packing of (±)-modafinil monohydrate. The hydrogen bonds are depicted by dashed green or blue lines and the π−π interactions by dashed black, purple or orange lines. prior the measurement. Furthermore, the mass spectroscopy confirms the nature of the solvent (m/z = 41). The TGA−DSC analysis performed on the chloroform solvate (Figure 6) highlighted the presence of chloroform molecules with a 1−1 stoichiometry. The first event (gray zone) corresponds to the drying of the sample. The sample is supposed to be dry at ca. 65 °C, so that the mass at this temperature have to be revaluated as 100% of solvate; consequently the mass loss measured between 65 and 110 °C is attributed to the desolvation of the solvate. Therefore, after re-evaluation of the difference measured, the variation is in agreement with one

Figure 11. Projection along the a axis. The hydrogen bonds are depicted by dashed green or blue lines, the π in T-shaped interactions by dashed purple lines and the Cl−π interactions by dashed black lines. chloroform molecule. Furthermore, the mass spectroscopy confirms the nature of the solvent (m/z = 83). 400



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For the three new solvates, the molecules of modafinil generate the same molecular arrangement through two types of hydrogen bonds (Figure 7). These interactions involve the sulfoxide and the amide moieties, unlike the ones observed in the anhydrous forms where the acceptor of hydrogen bonds also involved the carbonyl function. As detailed in Table 2, the two hydrogen atoms of the amide moiety establish two types of hydrogen bonds with the sulfoxide moiety of neighboring molecules. The first type connects two heterochiral molecules together generating a supramolecular synthon (dashed blue lines on Figure 8). Then, the second type (dashed green lines on Figure 8) connects the supramolecular synthons together in order to create a molecular column along a crystallographic axis (a or b depending on the solvate) (Figure 8). The same molecular periodic bond chains (PBCs) are also encountered in (±)-modafinil dihydrate.18 Depending on the solvate, the cohesion between these columns is ensured by means of one up to three types of T-shaped π interactions (Table 3 and Figure 9). The intermolecular interactions between adjacent molecular columns lead to the formation of channels where the solvent molecules are located. In the case of (±)-modafinil monohydrate, the channels are oriented along the b axis (Figure 10). In these channels, the last refinement of the crystal structure led to an SOF (statistical occupancy factor) of 0.5 of two oxygen atoms of the water

Figure 12. Projection along the b axis. The hydrogen bonds are depicted by dashed green or blue lines and the π−π interactions by dashed purple, black or orange lines. The distance between adjacent acetonitrile molecules within a channel is 3.4 Å.

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RESULTS AND DISCUSSION The crystal structures of the solvated phases were determined by using single crystal X-ray diffraction at room temperature. Table 1 presents the crystallographic data of these three new solvated phases, and for the sake of comparisons the crystallographic data of the dihydrate. Structural Description of (±)-Modafinil Solvates. The asymmetric units of each (±)-modafinil solvates are composed of one molecule of modafinil and one molecule of solvent.

Figure 13. Comparison between the crystal packings of solvates. The heterochiral columns are framed with blue rectangles.

Figure 14. DSC curve of the amorphous phase of (±)-modafinil. 401



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Figure 15. XRPD patterns of the powder obtained after complete desolvation under ambient conditions: (±)-Form IV in black, dehydrated (±)-modafinil monohydrate in blue, desolvated (±)-modafinil chloroform solvate in red and desolvated (±)-modafinil acetonitrile solvate in green.

(3) These columns pack regarding the nature of solvent. Therefore, the size of the channel and the packing of the molecular columns are solvent dependent (Figure 13). (±)-Modafinil dihydrate described by Stokes et al.18 and (±)-modafinil acetonitrile solvate present very close crystallographic parameters (Table 1), and the two structures present the same space group and packing (Figure 13); thus they are isomorphous. Study of the Amorphous State of (±)-Modafinil. The amorphous phase of (±)-modafinil was obtained by using spray drying from a methanolic solution. The DSC analysis shows that the glass transition occurred at ca. 30 °C (Figure 14). Desolvation of Solvates below Tg . (±)-Modafinil monohydrate, (±)-modafinil chloroform solvate, and (±)-modafinil acetonitrile solvate exhibit an efflorescent character under ambient conditions. The XRPD analyses of the powders obtained after complete desolvation show the formation of (±)-Form IV for these three solvates (Figure 15). The crystal structure of (±)-Form IV was described in a previous work22 and presents a rather unusual non-centrosymmetric and nonchiral space group: Fdd2. The comparison between the molecular conformations of the modafinil molecules in (±)-Form IV and in the solvates shows that the main difference is the value of the torsion angle N1−C15−C14-S (Figure 16, Table 4, and Figure 17). Desolvation of Solvates above Tg . (±)-Modafinil Monohydrate. As shown on Figure 2, a thermal event occurs above 60 °C. According to the thermogravimetry analysis, this event is related to the dehydration. The XRPD analysis of the powder obtained after complete dehydration by heating above 60 °C shows the formation of (±)-Form III (Figure 18). The crystal structure of (±)-Form III was described in previous works, and the asymmetric unit presents two similar independent molecules. The comparison between the molecular conformations of the modafinil molecules in (±)-Form III and in (±)-modafinil monohydrate exhibits large conformational modifications (mainly the torsion angles N1−C15−C14-S, SC1−C2−C3 and S-C1−C8−C9) (Table 5 and Figure 19) and a redistribution of the H-bonds: the 5.70 ± 0.05 Å periodic bond chain (PBC) has disappeared and has been replaced by a 9.7 Å PBC. (±)-Modafinil Chloroform Solvate. The DSC analysis of (±)-modafinil chloroform solvate performed at 5 K/min shows that the desolvation phenomenon begins at ca. 70 °C (Figure 6).

Figure 16. Heteromolecular layers of Form IV, view along c.

Table 4. Torsion Angle N1−C15−C14−S N1−C15−C14-S (°) (±)-modafinil monohydrate (±)-modafinil chloroform solvate (±)-modafinil acetonitrile solvate (±)-Form IV

119 124 136 −144

molecules. The distance between these two oxygen atoms being ca. 1 Å means that these water molecules are disordered. The closest atoms convenient for hydrogen bond (i.e., oxygen atoms of the sulfoxide or the nitrogen atoms of the amine) are approximately 3 Å apart. The weak interactions with the molecular network of modafinil column are consistent with the efflorescent character of this phase. In the case of (±)-modafinil chloroform solvate, the channels are spreading along the a axis. The solvent molecules exhibit a statistical disorder, but also present some interactions with the molecular column (Figure 11). For (±)-modafinil acetonitrile solvate, the channels are spreading along the b axis. Each one contains two antiparallel rows of solvent molecules; the molecules from one row establish π interactions with the molecules of the neighboring rows by means of their sp carbon atoms (Figure 12). A common feature, between these three solvates, is the heterochiral column whose periodicity is 5.70 ± 0.05 Å. The build up of these solvates can also be described as (1) Homochiral rows; two consecutive molecules are 5.70 ± 0.05 Å apart; they have no direct interaction (bold molecules in Figure 8). (2) Two interdigitated antipodal rows generate a heterochiral column of H-bonded molecules through centers of symmetries (Figure 8). 402



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Figure 17. Comparison between the modafinil molecules in (±)-Form IV (in standard colors) and (±)-modafinil monohydrate (in orange), (±)-modafinil chloroform solvate (in green), and (±)-modafinil acetonitrile solvate (in blue).

Figure 18. XRPD patterns of the powder obtained after complete dehydration by heating of (±)-modafinil monohydrate (in black) and (±)-Form III (in blue).

Figure 19. Comparison between the modafinil molecules in (±)-Form III (in standard colors) and (±)-modafinil monohydrate (in orange).

Table 5. Torsion Angles N1−C15−C14-S (±)-modafinil monohydrate (±)-Form III

S-C1−C2−C3 S-C1−C8−C9

119°

−116°

130°

150°

−141°

114°

The XRPD analysis of the powder obtained after complete desolvation by heating above 75 °C shows the formation of (±)-Form V (Figure 20). (±)-Modafinil Acetonitrile Solvate. The DSC analysis of (±)-modafinil acetonitrile solvate performed at 5 K/min shows that the desolvation phenomenon begins at ca. 65 °C (Figure 5). The XRPD analysis of the powder obtained after complete desolvation by heating above 65 °C shows the formation of (±)-Form VI (Figure 21). Discussion on the Desolvation Mechanisms. Scheme 1 below details the preparation and filiation between the different solvates according to the desolvation process. Figure 4 clearly demonstrates that at T < Tg, desolvation occurs through a nucleation−growth mechanism starting from the surface of a single crystal. The description of the structures has also shown that those three solvates have a common crystallographic parameter (5.70 ± 0.05 Å) corresponding to the periodicity along the heterochiral columns. Actually, a view along this translation vector shows that every column is made of two homochiral rows. It is more than anecdotal to find these

Figure 20. XRPD patterns of (±)-Form V (in black), the powder obtained after complete desolvation by heating of (±)-modafinil chloroform solvate (in blue).

homochiral rows in the crystal structure of (±)-Form IV but not in (±)-Form I and (±)-Form III. Therefore, it is likely that the desolvation below Tg proceeds through heteronucleation and growth using a templating effect of the homochiral rows especially those on the surface of the particles. This hypothesis is re-enforced by the greater similarities between the conformations of modafinil molecules in the three solvates and in 403



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molecular crystals below Tg and above Tg, of the corresponding nonsolvated phase is a key point in the evolution of the solid phases and the underlying dominant mechanisms.

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CONCLUSION In this study three new (±)-modafinil solvates were determined by single crystal X-ray diffraction. These crystal structures exhibit a similar supramolecular synthon between modafinil molecules heterochiral columns whose periodicity is 5.70 ± 0.05 Å. The desolvation of these efflorescent solvated phases leads to several possibilities depending on the desolvation temperature: (1) When the desolvations are performed below Tg, they all and always lead to (±)-Form IV. The comparison between the crystal structures of these mother phases and the daughter phase highlights the presence of a common homochiral periodic bond chain (homochiral row) and relative similarities in terms of molecular conformations of the modafinil molecules. There is clear evidence that the desolvation is concomitant to a heteronucleation and growth mechanism of (±)-Form IV. The common homochiral periodic bond chain is likely to serve as template on the surface of the particles. (2) When the desolvations are performed above Tg, the anhydrous phases generated depend on the initial solvated phase. Thus, there are still structural filiations between the mother phases and their respective daughter phases. In the case of (±)-modafinil monohydrate, the anhydrous phase obtained after complete desolvation by heating ((±)-Form III) has already been described, and the comparison between the crystal structures of these phases has highlighted substantial molecular conformation differences between modafinil molecules in the mother phase and in their daughter phase. Among the set of the internal and external parameters that affect the desolvation pathways, the desolvation temperature with regards to Tg of the nonsolvated phase is confirmed to be one of the most important ones governing the fate of the desolvated packing.

Figure 21. XRPD patterns of (±)-Form VI (in black) and the powder obtained after complete desolvation by heating of (±)-modafinil acetonitrile solvate (in blue).

(±)-Form IV rather than in the three solvates and in (±)-Form I or (±)-Form III. When desolvation is performed above Tg the phases obtained are specific of each solvate. Thus, there is very little probability that (±)-Form IV represents a common transient state. It is more likely that a given lattice of a solvate gives a specific nucleation and growth by some kind of co-operative effect. The molecular mobility (T > Tg) and the greater freedom in conformation help. The 5.70 Å homochiral PBC is destroyed at least in the monohydrate. Ongoing efforts are put in the resolution of (±)-Form V and (±)-Form VI. As the dihydrate is an isostructural form of the acetonitrile solvate, it is simply common sense to imagine that the dehydration could proceed with the same scheme (below Tg: (±)-Form IV, above Tg (±)-Form VI). Thus, by comparing the crystal structure of both the monohydrate and the dihydrate, it is rather surprising to see that by dehydration above Tg the former evolves toward the stable (±)-Form I and the latter is more likely to evolve toward a metastable (±)-Form VI before possible subsequent polymorphic transition. This clearly shows that our degree of understanding cooperative movements in the solid state and the corresponding predictability is still weak. Nevertheless, this study confirms former observations6 in which desolvation of

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ASSOCIATED CONTENT

Accession Codes

CCDC 1415719−1415721 contains the supplementary crystallographic data for this paper. These data can be obtained free of

Scheme 1

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charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

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