Insight into the Mechanism of Formation of Channel Hydrates via

Article pubs.acs.org/crystal

Insight into the Mechanism of Formation of Channel Hydrates via Templating Stephen P. Stokes,† Colin C. Seaton,*,§ Kevin S. Eccles,† Anita R. Maguire,‡ and Simon E. Lawrence*,† †

Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland § Materials and Surface Science Institute and the Department of Chemical and Environmental Sciences, Synthesis and Solid State Pharmaceutical Centre, University of Limerick, Limerick, Ireland ‡ Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland S Supporting Information *

ABSTRACT: Cocrystallization of modafinil, 1, and 1,4diiodotetrafluorobenzene, 2, in toluene leads to the formation of a metastable modafinil channel hydrate containing an unusual hydrogen bonded dimer motif involving the modafinil molecules that is not seen in anhydrous forms of modafinil. Computational methodologies utilizing bias drift-free differential evolution optimization have been developed and applied to a series of molecular clusters and multicomponent crystals in the modafinil/water and modafinil/water/additive systems for the additive molecules 2 or toluene. These calculations show the channel hydrate is less energetically stable than the anhydrous modafinil but more stable than a cocrystal involving 1 and 2. This provides theoretical evidence for the observed instability of the channel hydrate. The mechanism for formation of the channel hydrate is found to proceed via templating of the modafinil molecules with the planar additive molecules, allowing the formation of the unusual hydrogen-bonded modafinil dimer. It is envisaged that the additive is then replaced by water molecules to form the channel hydrate. The formation of the channel hydrate is more likely in the presence of 2 compared to toluene due to the destabilizing effect of the larger iodine molecules protruding into neighboring modafinil clusters.

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INTRODUCTION The design of functional crystalline materials through control of intermolecular interactions is a key objective of crystal engineering.1 While the construction of multicomponent crystals such as cocrystals,2−5 salts,6,7 hydrates,8−10 and solvates11 as a route to modify physicochemical properties has been repeatedly demonstrated,12−17 understanding how the process can be controlled at the molecular level is still in its infancy. This has become increasingly important as attempts to make new cocrystals can result in the formation of new polymorphs or hydrate phases.18−23 The cause of these occurrences is poorly understood; some forms have been reported to grow without the coformer present, while in other cases the coformer acts as an additive that impacts the solid state form obtained. In one case, the creation of an intermediate cocrystal form was used to isolate a new polymorph that could not be obtained as a pure material using solution crystallization.24 The formation of multicomponent crystals and the additive effect on growing crystal phases both rely on the strength of intermolecular interactions between components; understanding these interactions is key to successfully controlling the outcome of such experiments. Active pharmaceutical ingredients (APIs) frequently exist as hydrates because water molecules are small in size and contain © XXXX American Chemical Society

two hydrogen bond donors and one acceptor, which can interact with a host molecule or with one another.25−27 Hydrate packing motifs have been classified by Motherwell and coworkers.9,10 Many hydrates exist as channel structures with the water packed throughout the crystal lattice and can form in both stoichiometric and nonstoichiometric phases. The level of water can be affected by temperature or humidity,28 and this variability in composition and phase is a common reason for the avoidance of hydrates as the selected solid form for pharmaceutical materials. Channel formation can often be directed by a loosely bound solvate which is subsequently removed; for example, the channels in form II of carbamazepine have been shown to be stabilized by low levels of tetrahydrofuran (THF) or toluene.29,30 Modafinil, 1, is an analeptic drug used in the treatment of various sleep disorders such as narcolepsy, obstructive sleep apnea, and hypopnea (Figure 1).31,32 It contains a chiral sulfoxide functional group and is prescribed clinically as either the racemate, Provigil,33 or the R-enantiomer, Armodafinil, which has a longer half-life.34,35 The racemate has seven known Received: November 6, 2013 Revised: January 10, 2014

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dx.doi.org/10.1021/cg401660h | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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maximum number of generations (Gmax). This methodology has been shown to display an improved optimization performance over the standard DE on a test bed of standard high dimensionality problems,50 while recent studies on the optimization of molecular clusters confirmed its applicability and performance compared to standard DE optimization.51 Here we report on the development of new computational methodologies based on BDFDE for the optimization of molecular clusters and multicomponent crystals, as applied to modafinil/water and modafinil/water/additive systems for the additive molecules 1,4-diiodotetrafluorobenzene (2) or toluene. This is the first reported work utilizing a combination of computational methods with experimental data to develop an understanding of the molecular level processes occurring during the templated growth of hydrate phases.

Figure 1. Modafinil, 1, and 1,4-diiodotetrafluorobenzene, 2.

polymorphs,36,37 of which only three are present in the Cambridge Structural Database (CSD),38,39 namely, Form I (ETEXIK01 and ETEXIK03),40 Form III (ETEXIK02),40b and Form IV (ETEXIK06).41 To date, the formation of the hydrates of racemic modafinil has not been reported; however, many cocrystals and solvates of modafinil are known.42 Computational methods offer a complementary perspective on the intermolecular interactions that determine the various crystal forms obtained during cocrystallization. Location of the lowest energy interactions between constituent phases requires the application of suitable optimization algorithms. Many such algorithms have been developed and all offer differing strengths and weakness. Differential evolution (DE)43 is an easy to implement evolutionary algorithm that displays rapid, robust convergence which has been applied to a range of problems within science and engineering44 including structure solution from powder diffraction data,45,46 reaction engineering,47 X-ray absorption fine structure analysis48 and protein crystallography.49 As with other evolutionary algorithms, DE optimizes a population of trial solutions through recombination and mutation operations. The trial solutions are encoded as realvalues vectors (xi), and for each cycle of the algorithm, a new set of trials is generated using eq 1 for each existing member of the population. Ci = Pi + K (Pr3 − Pi) + F(Pr2 + Pr1)

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(±)-Modafinil was synthesized by a literature route,52 using toluene instead of benzene as solvent during the conversion of the carboxylic acid to the amide (Supporting Information, Scheme S1). Modafinil Hydrate. (±)-Modafinil, 1 (0.73 g, 2.66 mmol), and 1,4-diiodotetrafluorobenzene, 2 (1.07 g, 2.66 mmol), were added to a mixture of toluene and water (99:1) (200 mL). The solution was heated to 90 °C with stirring until all solids were dissolved, ca. 0.5 h. The solution was removed from the hot plate and allowed cool to room temperature. Crystals formed were collected by filtration and washed with toluene (30 mL) and dried in air to afford the channel hydrate as white needle crystals (0.68 g, 83%), DSC mp 166−167 °C. Additive Effect of 2. The same crystallization procedure outlined above was used with varying ratios of 1 and 2. The mole ratios examined were 100:0, 91:9, 80:20, 67:33, and 50:50 of 1 and 2 respectively. Grinding. Mechanical grinding experiments were conducted in a Retsch MM400 Mixer mill, equipped with two stainless steel 5 mL grinding jars and one 2.5 mm stainless steel grinding ball per jar. The mill was operated at a rate of 30 Hz for 30 min. Grinding experiments for attempted cocrystallization of 1 and 2 were performed on a 0.2 mmol scale using both neat and liquid-assisted grinding. In all cases, there was no evidence of successful cocrystallization. Infrared Spectroscopy. Infrared spectra were recorded on a Perkin-Elmer 1000 spectrometer in the range of 4000 to 500 cm−1. Samples were prepared as KBr disks. Differential Scanning Calorimetry (DSC). Thermal analysis was recorded on a DSC Q1000 instrument. Samples (2−6 mg) were crimped in nonhermetic aluminum pan with a pinhole in the lid and scanned from 30 to 180 °C at a heating rate of 4 °C min−1 under a continuously purged dry nitrogen atmosphere. Elemental Analysis. Elemental analysis was performed by the Microanalysis Laboratory, University College Cork, on a Perkin-Elmer 240 or an Exeter Analytical CE440 elemental analyzer. Powder Diffraction. PXRD data were collected using a Stoe Stadi MP diffractometer with Cu Kα1 radiation (λ = 1.5406 Å) at 40 kV and 40 mA using a linear PSD over the 2θ range of 3.5−45° with a step size equal to 0.5° and step time of 60 s. Single Crystal Diffraction. Single crystal data for the channel hydrate were collected on a Bruker APEX II DUO diffractometer, as previously described.53 All calculations and refinement were made using the APEX2 software,54,55 and diagrams were prepared using Mercury56 or CrystalMaker.57 The detailed crystallographic data and structure refinement parameters for the hydrate are summarized in Table 1. An initial model including the hydrogen atoms of the waters of crystallization was used as a basis for the computational studies. These hydrogen atoms were excluded from the finalized crystallographic model. Computational Methodology. Lattice energy calculations, using code developed in-house, were performed using the Dreiding forcefield58 with the electrostatic component calculated by the interaction of atomic point charges generated from the fit to the

(1)

where K and F are user-defined parameters that control the level of recombination and mutation respectively, Pi is the ith member of the population, and r1, r2, and r3 are random selected indexes between 0 and the size of the population such that i ≠ r1 ≠ r2 ≠ r3. The new solution then replaces the existing population member if it is a better solution; otherwise, the parent is retained. This process is repeated until the population converges on a final answer. This search mechanism can suffer from a drift bias leading to incomplete searching in high dimensional systems. Bias driftfree differential evolution (BDFDE) has been proposed that eliminates this bias resulting in improved optimization.50 This modification of DE introduces a new form for the creation of trial structures (eq 2). ⎧ F ·mr , r if R and (0, 1) ≤ P ⎪ 1 2 ci = xi + ⎨ ⎪ D ·(mr , r ·er , r ) ·er , r otherwise ⎩ 1 2 1 2 1 2

(2)

where mr1, r2 = (xr1 − xr2) er1, r2 =

EXPERIMENTAL METHODOLOGY

xr3 + xr4 − 2xi || xr3 + xr4 − 2xi ||

As with the traditional DE, a limited number of user-defined parameters are required: P, F, population size (Np), and B



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molecular cluster was held fixed during optimization, while in cases with two additive molecules, these were treated as separate species and were optimized individually. The optimization of 2 into the crystal structure was carried out using further code developed in house. The additive molecules were positioned within the channel of the crystal structure, and their position and orientation were optimized through minimization of the lattice energy. The energy was calculated using the Dreiding force field and atomic point charges and the bias drift-free differential evolution global optimization algorithm used as the optimizer (search parameters P, F, Gmax, Np = 0.5, 0.98, 500, 120). The lattice energy was calculated on a 3 × 3 × 3 lattice. The calculation required conversion of the known crystal structure from P21/n to P1 as the presence of an inversion center in the hydrate channel would generate a disordered system, preventing calculation of the lattice energy. This reduction in symmetry leads to creation of a unit cell containing four modafinil molecules and two sites for the additive molecule. This optimization was carried out in two stages; first a single molecule of 2 was optimized into a selected void in the crystal structure; this structure was then fixed, and the second molecules were optimized in the second void. During the optimization, the unit cell parameters as well as the position and orientation of the modafinil molecules were held fixed. Inspection of this second solution indicated close contacts between 1 and an aromatic ring of two symmetrygenerated cells in the structure. As the lattice energy only calculates the interactions between the asymmetric unit and the rest of the crystal, these repulsive interactions were not included in the optimization. Thus, the optimization was repeated using the total interaction energy between all molecules in a generated crystal block (2 × 3 × 2 lattice). During this optimization the lattice parameters were allowed to adjust and were included as parameters (variation allowed ±5% of input values). For comparison with the previous lattice energies, subsequent to optimization, the lattice energy of the final solution was calculated with a 9 × 9 × 9 lattice.

Table 1. Crystal and Refinement Data for Modafinil dihydrate formula MW crystal system space group, Z a, Å b, Å c, Å β, ° V, Å3 Dc g·cm−3 μ, mm−1 2θ range, ° T, K total ref unique ref obs ref, I > 2σ(I) # parameters R1 [I > 2σ(I)] wR2 [all data] S

C15H15NO4S 305.34 monoclinic P21/n, 4 12.8980(6) 5.6734(3) 22.5802(12) 104.0000(10) 1603.24(14) 1.265 0.216 1.67−26.36 100.(2) 9610 3262 0.0848 208 0.0419 0.1142 0.882

MP2 electrostatic potential calculated for the individual molecules in the program ORCA59 (RI-MP2/def2-TZVPP).60,61 The molecular structures were extracted from the known crystal structures, and the positions of the hydrogen atoms were optimized; however, the remaining atoms were retained in the conformation present in the crystal structure. In all cases, a lattice of size 9 × 9 × 9 unit cells was used. Optimization of the crystal structure was performed using a steepest descent local optimization algorithm, treating the molecules as rigid bodies but allowing the position, orientation, and lattice parameters to adjust. For the channel hydrate, all calculations were performed with full occupancy of the water molecules. Calculation of the lattice energy of the channel hydrate initially utilized the geometry of the water molecules as located in the initial model of the crystal structure. However, given the significant geometric distortions in this case, a new model was constructed. The geometry of a water dimer extracted from the crystal structure was fully optimized in a gas phase MP2 calculation (RI-MP2/def2-TZVPP), reducing the HOH angles from 117/136° to 104/104°. The optimized dimer was positioned in the channel hydrate crystal structure such that the oxygen atoms were in the same sites as the original water molecules. The position and orientations of all three molecules in this new crystal structure, along with the unit cell parameters, were optimized to minimize the lattice energy using the Nelder-Mead downhill simplex algorithm.62 Optimization of the interactions between molecular clusters of 1 (4 or 8 molecules) and either 2 or toluene (1 or 2 molecules) was undertaken using the program mol_dimer developed within the group. This program optimizes relative geometry of a molecular cluster through minimization of the gas phase interaction energy of the component molecules. The energy of interaction was calculated using the Dreiding forcefield with the electrostatic contribution calculated using atomic point charges as for the lattice energy. The molecular clusters were extracted from the crystal structure, and the location of the hydrogen atoms was normalized. The molecular structure of 2 and toluene were optimized in ORCA at the DFT level of calculation using the QuickOpt option (PBE-D3/TZVP). 63 The position and orientation of the second component within the molecular cluster were optimized using a local implementation of the BDFDE global optimization algorithm.50 The user control parameters were set to P, F, Gmax, Np = 0.5, 0.98, 20000, 120, and convergence was signaled when the difference between the lowest energy solution and the mean energy of the population was less than 1 × 10−5. All optimized parameters were constrained to the following value ranges: −3 ≤ x, y, z ≤ 3 Å and 0 ≤ θ, ϕ, γ ≤ 360°. The relative geometry of the

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RESULTS AND DISCUSSION Attempted Cocrystallization of 1 and 2. Modafinil contains sulfoxide and amide functional groups, both of which have previously been utilized in cocrystallization.64,65 Therefore, as part of an investigation into the cocrystallization of racemic modafinil, we examined cocrystallization with 2 via I··· OS halogen-bonding, which has been developed for compounds containing the sulfoxide functional group.53 A number of cocrystallization attempts of 1 and 2 were carried out using both neat and liquid-assisted grinding, all of which were unsuccessful. However, dissolution of the solids in hot toluene (which had not been recently dried) and allowing the solution to cool to room temperature led to the formation of needles of a new crystalline form (Figure S1, Supporting Information). Single crystal analysis revealed the formation of a channel hydrate of modafinil, in which the water molecules are loosely bound in the channel (as evidenced by their large thermal ellipsoids) and are not interacting with the modafinil molecules (Figure 2). Significantly, the modafinil molecules are hydrogen bonded in pairs through two SO···H−N interactions to form R22(12) dimers (Figure 3). This key interaction is different from that seen in the known anhydrous forms, which both contain the well-known amide R22(8) dimer, with the second amide hydrogen capped by a neighboring sulfoxide.40,41 The overall packing of this dihydrate looks similar to that reported in an acetone channel solvate of modafinil.66 The single crystal analysis indicated that the needles are aligned along the b-axis, corresponding to the solvent channel (Figure S2a,b, Supporting Information). The theoretical PXRD pattern generated from the single crystal data matches the experimental PXRD pattern, indicating that the C



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mixtures of the channel hydrate and the anhydrous form III were observed (Figure 4, panels c and b respectively). The channel hydrate was observed exclusively with 50% of 2, confirming the initial result (Figure 4a). Modafinil Dihydrate Stability. DSC analysis carried out on the channel hydrate indicates loss of water close to 100 °C, a melting event at ∼167 °C followed almost immediately by decomposition (Figure S4, Supporting Information). Separately, heating to 130 °C, cooling back to room temperature, and PXRD analysis indicated the formation of the anhydrous form III (Figure S5, Supporting Information). The stability of the channel hydrate was investigated by recording the time required for it to dehydrate at ambient conditions. A sample held at 21 °C completely converted to the anhydrous form III within 21 days (Figure S6b, Supporting Information). Because of the lability of the channel hydrate, obtaining accurate elemental analysis proved challenging with partial or complete loss of water during sample preparation. Furthermore, the IR spectrum of a KBr disc made from the channel hydrate was essentially the same as that of the KBr disc obtained from the anhydrous form, again indicating loss of water during disc formation. Energetics of Known Crystal Forms. The anhydrous forms I and III of 1 are reported to be similar in energy and are often obtained concomitantly.67 Lattice energy calculations (Table 2) of these structures agree with these experimental

Figure 2. Packing of modafinil channel hydrate viewed along the b-axis as an ORTEP style plot (one orientation of the disordered water molecule omitted for clarity).

Table 2. Lattice Energies for the Optimized Crystal Structures Figure 3. Hydrogen bonding between modafinil neighbors in the channel hydrate.

bulk material obtained from the recrystallization procedure was the channel hydrate (Figure S3, Supporting Information). Investigation into the Additive Effect of 2. The role of 2 on the crystallization outcomes was investigated by undertaking a variety of cooling crystallizations of 1 and 2 from a toluene/water mixture (99:1). PXRD analysis indicated that the anhydrous form III of 1 was formed with 0 and 9% of 2 present (Figure 4, panels e and d respectively), the former being consistent with the literature.37 At 20 and 33% of 2,

system

lattice energy/kJ mol−1

Form I Form III anhydrous structure channel hydrate (expt geometry) channel hydrate (opt geometry)

−221.57 −220.14 −127.70 −157.45 −164.46

studies, showing form I as the lower energy structure and so more stable, although both structures are close in energy (ΔE = 1.43 kJ mol−1). The stability of the channel hydrate with respect to dehydration was investigated through optimization of the water-free crystal structure. This showed that the channel structure is energetically stable but significantly higher in energy than the known structures and therefore would not be expected to form following removal of the water, which is in agreement with the experimental studies. The lattice energy of the channel hydrate structure was initially calculated using the experimental crystal structure [channel hydrate (expt geometry) in Table 2] with only the hydrogen positions normalized. The structure has a lower energy than the anhydrous structure but higher than the two known polymorphs; however, as the geometry of the water molecules are distorted, this may limit the interactions between the water molecules and raise the interaction energies. To investigate this, water molecules that had been fully optimized by a MP2 level calculation replaced those in the crystal structure [channel hydrate (opt geometry) in Table 2]. Optimization of the lattice energy by adjusting the location of all three molecules and lattice parameters of the crystal gives a final structure with a lower energy than that derived from the experimental structure. However, there is little change in the

Figure 4. PXRD patterns obtained after crystallizing 1 with varying amounts of 2 present in solution. The percentage mole ratios of 1 and 2 are (a) 50:50, (b) 67:33, (c) 80:20, (d) 91:9, and (e) 100:0, respectively, along with (f) the theoretical PXRD pattern of 1 form III. D



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the optimization was performed using a double layer of modafinil molecules (Table 3). These results confirmed the previous calculations showing similar energies of binding and the significant intrusion of 2 into the second layer of modafinil molecules (Figure 6a), thus preventing the inclusion of a

structure and bonding patterns displayed, and the structure is still higher in energy than the anhydrous forms. Optimization of Additives in Modafinil Clusters. The formation of the hydrate was only seen when 2 was present in the crystallizing solution, which suggests that 2 acts as an additive directing the formation of the channel hydrate. It was envisaged that the additive 2 may initially direct the formation of the molecular channel in the hydrate structure and subsequently be displaced by the water molecules. While the channel hydrate was only observed with 2 present, and therefore, there was no direct experimental evidence for toluene acting as a template for channel hydrate formation, the computational work explored both 2 and toluene as potential templates. The results of these calculations show a weak stabilizing π···π interaction between modafinil and each of 2 and toluene, which is energetically comparable to the lower end of the range of moderate hydrogen bond strengths68 (Table 3). Modafinil Table 3. Cluster Energies for the Optimized Crystal Structures system toluene, 4 × modafinil toluene, 8 × modafinil 2 × toluene, 8 × modafinil 2, 4 × modafinil 2, 8 × modafinil 2 × 2, 8 × modafinil

total cluster energy/ kJ mol−1

energy per component/ kJ mol−1

−58.49 −88.91 −144.68

−29.25 −29.64 −36.17

−78.55 −111.09 −165.79

−39.28 −37.30 −41.45

Figure 6. Optimization of one molecule of (a) 2 and (b) toluene into an eight-molecule cluster of 1.

forms a stronger interaction with 2 than with toluene (the larger induced charge on the ring carbons by the attached fluorines being the dominant factor in this difference), supporting the experimental observation that only 2 acts as a template for channel hydrate formation, even though both molecules fit within the void formed by the modafinil molecules (Figure 5). As 2 is larger than toluene, the iodine atoms protrude out of the plane of the four modafinil molecules, while toluene is fully encased. Thus, in the case of 2 steric clashes with the next layer in the crystal may occur. To confirm this,

second 2 into the cluster. In contrast, toluene packs freely in the space (Figure 6b). Optimization of two additive molecules into the eight molecule cluster, however, shows that significant space is available for the reorientation of the additives to give a stable cluster of molecules (Figure 7), with an increase in stability due to the electrostatic interactions between the two molecules of 2. Significantly, the cluster with 2 is notably more stable than that with toluene, which is again consistent with the experimental data (Table 3). These results suggest that a 25% molar ratio of 2 to 1 is required to stabilize the molecular cluster. The experimental results indicate that the dihydrate does not form until a molar ratio of 20% of 2 is present, although increased quantities are required to ensure complete conversion. Thus, higher concentration clusters with increased interactions between molecules of 2 may play a strong role in the selective formation of these structures. The flexibility of the additive in the pocket of the cluster was investigated through a systematic rotation of the single additive molecule around its three axes of rotation in steps of 1°. In both cases, a single minima with a stable energy is located for all angles, but broader minima are observed for toluene than 2, suggesting greater flexibility (Figure 8), while 2 displays significantly larger steric clashes (Figure 9) due to the presence of the iodine atoms. The modeling confirms the potential for cluster directing interactions between 2 and modafinil. These interactions are relatively weak and so may be easily displaced. This suggests that the additive molecules of 2 can provide a template around which the modafinil molecules crystallize, with subsequent displacement of 2 by water molecules.

Figure 5. Optimized solution for one molecule of (a) 2 and (b) toluene into a four-molecule cluster of 1. E



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the influence of an increased number of neighboring molecules (Figure 10). A final optimization was undertaken to allow relaxation of the unit cell parameters and the positions of 2 for a final lattice energy of −492.23 kJ mol−1 (9 × 9 × 9 lattice). This large change in energy is due to the relaxation of the cell parameters increasing the space between components and reducing the repulsion between components, notably, between the iodine atoms of 2 and the nitrogen atoms of modafinil. However, while the structure is energetically stable, such a cocrystal would only form if the lattice energy was greater than the sum of the lattice energy of the two isolated single components (eq 3).69,70 cc mod afinil 1,4DIFTB ΔE = E latt − (2·E latt + E latt )

(3)

This calculation requires the lattice energy of the 2 single component structures. A search of the CSD reveals that two enantiotropic polymorphs are reported for 2 (ZZZAVM and ZZZAVM01) with a transition temperature of 358 K.71,72 Both polymorphs have the molecules located over inversion centers, and so the lattice energies were calculated for the expanded P21/c system, giving a final energy of −174.15 and −167.52 kJ mol−1 for low and high temperature forms respectively. Comparison with the other lattice energies show that (i) the proposed cocrystal form is unstable relative to the single components (ΔE = +125.06 kJ mol−1 for modafinil form I) and (ii) the hydrate structure is more stable than the additive free channel structure. However, full calculation of the stability of the channel hydrate would require a consideration of water or ice stability.73 Despite this, the results suggest that initial formation of the clusters is possible and that replacement of the additive by water, presumably in a sequential manner during crystal growth, leads to a more stable hydrate phase.

Figure 7. Optimization of two molecules of (a) 2 and (b) toluene in an eight-molecule cluster of 1.

Optimization of 2 into Modafinil Dihydrate Crystal Structure. Optimization of 2 into the channels of the modafinil hydrate crystal structure was undertaken to identify whether a stable crystal structure could form with inclusion of the additive and how this compared to the hydrate energetically. The total interaction energy of the optimized crystal block is −605.80 kJ mol−1. The lattice energy of this structure (9 × 9 × 9 lattice) is −64.89 kJ mol−1. The molecules of 2 pack with a different orientation to the previous isolated cluster runs, due to

Figure 8. Rotational energy surfaces for toluene in a four-molecule cluster of 1 around (a) θ, (b) ϕ, (c) γ axes. Expanded region displays the structure around minima. F



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Figure 9. Rotational Energy surfaces for 2 in a four molecule cluster of 1 around (a) θ, (b) ϕ, (c) γ axes. Expanded region displays the structure around minima.

observations. However, introduction of water into the channels of this structure leads to a more stable structure. Accordingly, formation of the channel hydrate can be rationalized mechanistically by initial formation of clusters of modafinil around the additive, with sequential displacement of 2 by water before an additional layer forms. The computational data support the observation that toluene alone does not template the channel hydrate formation.

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ASSOCIATED CONTENT

S Supporting Information *

Reaction schemes, X-ray crystallographic information in CIF format, DSC and PXRD data and additional figures. This material is available free of charge via the Internet at http:// pubs.acs.org. The crystallographic data for the hydrate has been deposited with the Cambridge Crystallographic Data Centre, CCDC numbers 969516. This data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/ cif.

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Figure 10. View along the b-axis of the optimized 1/2 crystal structure.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel.: +353 61 234 166 (Computational Work). *E-mail: [email protected]. Tel.: +353 21 490 3143 (Experimental Work).

CONCLUSIONS The successful synthesis of a channel hydrate of modafinil has been achieved. The additive 2 was required for the formation of this channel hydrate when crystallized from toluene, with an anhydrous form obtained in the absence of 2. The channel hydrate transforms to the more energetically favorable anhydrous modafinil over time at room temperature. The computational study indicates that the formation of the channel hydrate through templating by 2 is feasible as small clusters of these systems are stable. However, while a cocrystal structure between modafinil and 2 can be constructed computationally, it is energetically less stable than the individual components, in line with the experimental

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This publication has emanated from research conducted with the financial support of IRCSET (PD/2012/2652), Science Foundation Ireland under Grant Numbers 07/SRC/B1158, 05/PICA/B802/EC07, and 12/RC/2275, and UCC 2012 Strategic Research Fund. G



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NOTE ADDED AFTER ASAP PUBLICATION This article was published ASAP on January 22, 2014, with a missing reference. The corrected version containing a modified ref 40 and new ref 41 was published ASAP on January 28, 2014.

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