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Exploring Solid State Diversity and Solution Characteristics in a Fluorine-Containing Drug Riluzole Pradip Kumar Mondal,† Varun Rao,† Sudhir Mittapalli,‡ and Deepak Chopra*,† †

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal 462066, India School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500046, India

‡

S Supporting Information *

ABSTRACT: Solvent drop grinding experiments on riluzole, an organofluorine drug, with different carboxylic acids (mono and di) and pyridine derivatives, resulted in the formation of 10 different co-crystals, one polymorph of a co-crystal, and a salt. The crystal packing is primarily stabilized via strong N−H···O, O−H···N, O−H···O, and N−H···N hydrogen bonds, in addition to secondary interactions of the type C− H···F/O and S···F intermolecular contacts. The melting point of the new crystalline phases was observed to be present in the range of 90−140 °C which is closely related to the melting point (118 °C) of the original API. It was observed that the cocrystals depicted enhanced the solubility and dissolution rate in comparison to that of the free drug.

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INTRODUCTION Co-crystals are multimolecular entities, with the incorporation of multiple components within a crystal. This procedure provides the necessary flexibility to modify the composition of a given solid resulting in altered physical and chemical properties of a solid.1,2 Co-crystals have gained significant interest, due to their ability to alter the properties of compounds of importance in pharmaceutical and material sciences.3−6 In drugs, co-crystals have the potential to improve the physicochemical properties such as solubility, chemical stability, compressibility, bioavailability, dissolution rates, melting point, and the hygroscopicity of an active pharmaceutical ingredient (API).7−9 The selection of a right coformer is necessary to achieve the desired physiochemical properties of the API and to avoid any toxic effects. The design strategy for a co-crystal is based on the concept of noncovalent interactions (namely, hydrogen bonding and van der Waals interactions). To obtain a desirable co-crystal of an API, the initial step is to analyze the structure of the target API molecule and identify the functional groups which can have intermolecular interactions with the corresponding coformer.10,11 The solubility and the dissolution rate of a stable API in water is necessary for good oral bioavailability.12 However, the method is applicable only for drugs which are stable in the test medium. Most of the drugs exhibit therapeutic effect for a period of 4−8 h after oral administration, and hence the role of intrinsic dissolution rate (IDR) in the same period becomes an important parameter. The IDR is a very useful guide for dissolution study and for those solid forms which undergo a phase change. The dissolution rate is a kinetic parameter and is different from the equilibrium solubility which is a thermodynamic quantity. © 2017 American Chemical Society

In the current investigation, we report a strategy aimed toward synthesizing pharmaceutical co-crystals of riluzole, a water insoluble drug (0.3 mg/mL at neutral pH) with different coformers in the solid state. Subsequent characterization of these co-crystals in solution may result in concomitant modifications in the solubility and dissolution rates of this drug, and such studies are of extreme interest in the drug industry. This is the only available drug for the treatment of amyotrophic lateral sclerosis (ALS) and is also used to treat several diseases such as Parkinson’s disease, Huntington’s disease, and mood and anxiety disorders.13−17 Riluzole is a benzothiazole derivative (2-amino-6-(trifluoromethoxy)benzothiazole) and consists of an amino group, a nitrogen atom on the ring, and an oxygen atom that are capable of forming strong hydrogen bonding interactions. However, the sulfur atom and the three fluorine atoms present in the molecule can act as hydrogen bond acceptors and can form weak intermolecular interactions. The organic and medicinal chemistry of drugs containing organic fluorine has received considerable attention as these can productively influence the conformation, pKa, membrane permeability, metabolic pathways, and pharmacokinetic properties.18 Due to the presence of multiple hydrogen bond forming sites in riluzole, we have selected different molecular scaffolds (Scheme 1), namely, an aliphatic unsaturated carboxylic acid (SORBA), different dicarboxylic acids (MLA, SA, GA, AA, PA, SBRA, AZA, and SEBA) and some pyridine derivatives (DMAP and NA) as potential coformers for co-crystallization with riluzole using the Received: December 27, 2016 Revised: February 28, 2017 Published: March 8, 2017 1938

DOI: 10.1021/acs.cgd.6b01894 Cryst. Growth Des. 2017, 17, 1938−1946

Crystal Growth & Design

Article

atoms bound to carbon and oxygen were placed in the calculated positions. The hydrogen atoms bound to nitrogen were located. The packing diagrams of all co-crystals were generated using Mercury 3.6 software.27 Powder X-ray Diffraction. The experimental powder X-ray diffraction patterns of the API and the co-crystals were recorded on a PANalytical Empyrean X-ray diffractometer with Cu Kα radiation (1.5418 Å). Bulk powder of each sample was placed on a silica sample holder and measured by a continuous scan between 5° and 50° in 2θ with a step size of 0.013103°. Differential Scanning Calorimetry and Hot Stage Microscopy. Analysis of all the DSC data (Figure 2) recorded on co-crystals was conducted using a PerkinElmer DSC 6000 instrument under nitrogen gas atmosphere. A sample of precisely weighed 1.0 mg of each co-crystal was placed in nonhermetically sealed aluminum pan in vacuum. The samples were scanned at a rate of 5 °C/min in the range of 30−150 °C under a dry nitrogen atmosphere at a flow rate of 20 mL/min. Hot stage microscopic (HSM) experiments were performed on a stereomicroscope equipped with a hot stage apparatus (operating at a heating rate of 2 °C/min), and the photographs were taken with a Leica polarizing microscope. The single crystal was placed on a glass slide, and the images of the experiments were recorded (ESI F-6 and F-7). Theoretical Calculations: PIXELC. The extraction of the molecular pairs from the crystal packing and the interaction energy of the selected molecular pairs with its decomposition into Coulombic, polarization, dispersion, and repulsion contributions were calculated for the co-crystals with PIXELC module28−30 in the CLP program. We have not performed the PIXELC calculations for RZ-MLA (salt), RZAZA (six molecules 2:1 in asymmetric unit), and RZ-DMAP (five molecules 3:2 in asymmetric unit). All of the hydrogen atoms (N−H, O−H, and C−H) were shifted to their neutron values, and the electron density of the molecules was calculated at MP2/6-31G** with Gaussian09.31 The total interaction energies of the selected molecular pairs and their different energetic contributions were extracted from the mlc file after PIXELC calculation. Dissolution and Solubility Measurements. Intrinsic dissolution rate (IDR) experiments were performed on a USP-certified Electrolab TDT-08L dissolution tester (Mumbai, India). Dissolution experiments were carried out for a total period of 5 h in a pH 7 buffer medium at 37 °C. A calibration curve was obtained for riluzole and selected cocrystals by plotting the absorbance versus concentration curve using a Thermo-Nicolet EV300 UV−vis spectrometer. The molar extinction coefficients (ϵ) were obtained from the slope of the plot using the Beer−Lambert law. A 250 mg amount of each material was transferred to the intrinsic attachment, and using a hydraulic press, a pressure of 2.5 tons/in.2 was applied for a period of 4 min; these were compressed into 0.5 cm2 disks. The intrinsic attachment was installed in a 500 mL jar in a pH 7 buffer medium at 37 °C and rotated at 100 rpm. At regular intervals, 5 mL of the aliquot was collected and replaced by an equal volume of fresh pH 7 buffer medium to maintain a constant volume. The concentration of the aliquots was determined with appropriate dilutions from molar extinction coefficients of the respective compounds. The equilibrium solubility was also determined for riluzole and selected co-crystals in the same medium at room temperature using the shake-flask method.32 A 50 mg amount of each sample were stirred for 24 h in 3 mL of buffer. The solution was filtered and sufficiently diluted for the measurement of absorbance at the given λmax. The concentration of the supersaturated solution was calculated at 262 nm absorbance. For all these experiments, we have used the wavelength of 262 nm, which does not interfere with the absorbance value for the selected coformer (in our case on aliphatic carboxylic acids). Only minor peak shifting was observed in some cases. The nature of the undissolved material after the dissolution and solubility experiments was confirmed from PXRD.

Scheme 1. Molecular Structure of Riluzole (API) and All the Coformers Employed in This Study

method of “solvent drop grinding”. The outcome of our cocrystallization experiments was reflected in the formation of new co-crystals, a co-crystal polymorph (RZ-AA), and a salt of the co-crystal (RZ-MLA).19−21 These were identified by differential scanning calorimetry (DSC), confirmed by powder X-ray diffraction analysis (PXRD), and structurally characterized by single crystal X-ray diffraction analysis (SCXRD). Experiments on dissolution and solubility profiles were performed on those co-crystals and salt which contain low molecular weight coformers such as MLA, SA, GA, AA, SORBA, and SBRA along with the free drug.

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EXPERIMENTAL SECTION

Preparation of Co-crystals. Riluzole was obtained from Rallis India Ltd. All coformers were purchased from Sigma-Aldrich Co. and have been used without further purification. The solvent drop grinding (SDG), also known as liquid-assisted grinding, was performed by mechanical grinding of the two components (API and coformer) using agate mortar and pestle. Methanol was used as a solvent for grinding. Initial studies correspond to a 1:1 stoichiometric ratio of the solid API and the co-crystal former. Grinding was usually carried out for ∼30− 45 min with the dropwise addition of solvent, at an interval of 15 min each. The resulting powder was air-dried and crystallized using various solvents of HPLC grade in 5.0 mL beakers and then kept for crystallization at low temperature (5 °C) or room temperature. These crystals obtained were then characterized structurally using SCXRD. Following these experiments, the observed stoichiometric ratio, as obtained via SCXRD, was used to reproduce the formation of all of the as-synthesized (bulk) co-crystals. The resulting powdered material of all the co-crystals, a co-crystal polymorph, and salt with corrected stoichiometric ratio (as obtained from SCXRD) were used for all of the further experiments. Furthermore, the PXRD patterns obtained for all of the powdered samples (with the correct stoichiometric ratio) along with the PXRD patterns collected on the obtained single crystals are in complete agreement with each other. Single Crystal X-ray Diffraction. The single crystal X-ray diffraction measurements for all the obtained co-crystals, salt, and the co-crystal polymorph were carried out on a Bruker APEX II Kappa CCD single crystal diffractometer equipped with a graphite monochromator using Mo Kα radiation (λ = 0.71073 Å) at 100(3) K. Unit cell measurement, data collection, integration, scaling, and absorption corrections for all co-crystals were performed using Bruker APEX II software.22 Multiscan absorption corrections were applied using SADABS.23 The co-crystal structures were solved by direct methods using SHELXS-9724 and refined with full-matrix least-squares method using SHELXL-201425 present in the program suite WinGX.26 All non-hydrogen atoms were refined anisotropically, and all hydrogen

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RESULTS AND DISCUSSION All co-crystals exhibit unique PXRD patterns in comparison to the native form of riluzole, indicating the formation of new 1939



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crystalline phases. The unique peaks corresponding to each of the molecular co-crystals are shown in Figure 1. Further evidence was obtained from the experimental PXRD pattern of RZ-AA-form-1 and RZ-AA-form-2, which support our results from SCXRD. We have observed that, in the case of RZ-AAform-1, the intense peaks are observed at 2θ = 9.5°, 19.2°, and 24.8°, respectively. However, the peak for RZ-AA-form-2 is observed at 2θ = 6.3°, 12.6°, 19°, 25.4°, and 32°. Thus, the formation of new solid phases has been confirmed by PXRD analysis. However, the hydrogen bonding patterns and related intermolecular interactions were ascertained by SCXRD studies, and their nature and energetic contributions in these co-crystals were investigated from PIXELC calculations. The nature of the interaction between an API and a coformer, in the molecular structure of co-crystals, is quite different in comparison to the crystal structure of the API. The co-crystals display different melting points, which are one of the most important physiochemical properties in this class of solids. The selection of a coformer with a different melting point (in comparison to the API) can alter the melting point and thermodynamic stability of the API. The melting point, thermodynamic stability, and solubility for both the API and the co-crystal are intricately related to each other, and all these parameters are of significance in the pharmaceutical industry.33 Herein, we have observed that the melting points of all the isolated and characterized co-crystals lie in the range of 90−140 °C (Figure 2) in comparison to that of riluzole (mp 118 °C) (Table 1). The DSC thermograms of RZ-SORBA and RZDMAP showed lower melting endotherms at 91 and 96 °C, respectively, while those of RZ-MLA and RZ-SBRA showed higher melting endotherms at 139 and 136 °C, respectively (Figure 2). The DSC scan of RZ-MLA and RZ-AA-form-1 showed two endothermic peaks, which indicate the presence of a possible phase transition in both of these co-crystals. The second heating−cooling cycle for RZ-MLA shows no endothermic peak whereas in the case of RZ-AA-form-1 the peak temperature for the second heating−cooling cycle was equivalent to that observed in the first heating−cooling cycle. The HSM images of RZ-MLA in the range of 135−142 °C depict the phase transition, and the crystal melts at 148 °C (ESI F-7). Similarly, the HSM images of RZ-AA-form-1 in the range of 111−115 °C showed a phase transition and the crystal melts at 118 °C (ESI F-6). The thermal stability of the polymorphs of RZ-AA was evaluated using DSC, wherein form-1 melts at 118 °C after a phase transition at the onset temperature of 115 °C (possibly form-1 to form-2 phase change), and form-2 melts at the onset temperature of 119 °C (Figure 2b). On subsequent cooling of the melt, form-1 recrystallizes, thereby indicating that this form is a kinetically controlled polymorph. This is further established from the characterization of the co-crystals obtained from grinding experiments (after obtaining the stoichiometric ratio from SCXRD) with MeOH which gave form-1 [RZ-AA bulk compound confirmed by PXRD] whereas on subsequent crystallization at low temperature under slow evaporation in solvent methanol, crystals of form-2 were obtained, thereby confirming that form-2 is a thermodynamically controlled form. Finally, it is evident from the DSC traces that the second and third heating−cooling cycles of form-1 are analogous with the second and third heating−cooling cycles of form-2. All of the co-crystals, polymorphs, and salt (ESI T-1) have been characterized using SCXRD analysis (ESI F-1 and F-2). Riluzole has a nitrogen atom on the ring which functions as an

Figure 1. PXRD overlay diagram of (a) riluzole, RZ-MLA, and RZMLA-simulated; (b) RZ-SA, RZ-SA-simulated, RZ-GA, and RZ-GAsimulated; (c) RZ-AA-form-1, RZ-AA-form-1-simulated, RZ-AA-form2, and RZ-AA-form-2-simulated; (d) RZ-SORBA, RZ-SORBAsimulated, RZ-PA, and RZ-PA-simulated; (e) RZ-SBRA, RZ-SBRAsimulated, RZ-AZA, and RZ-AZA-simulated; (f) RZ-SEBA, RZ-SEBAsimulated, RZ-DMAP, and RZ-DMAP-simulated; and (g) RZ-NA and RZ-NA-simulated. The simulated PXRD pattern was generated from Mercury 3.8. 1940



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Table 1. Melting Points of Coformers, Co-crystals, Polymorph, and Salt no.

sample code

MP of coformer (°C)

0 1

RZ (API) RZ-MLA

118 136

2 3 4

RZ-SA RZ-GA RZ-AA-form-1

184−188 97−100 151−154

5 6 7 8 9 10 11 12

RZ-AA-form-2 RZ-SORBA RZ-PA RZ-SBRA RZ-AZA RZ-SEBA RZ-DMAP RZ-NA

151−154 135 102−106 141−144 103−108 131−135 110−113 236−239

MP of co-crystal (°C) 139 (phase transition) and 141 133 120 115 (phase transition) and 118 119 91 114 136 110 125 96 118

hydrogen bonds, which we have observed in all of our cocrystals. RZ-MLA crystallizes in the monoclinic space group P21/c. The asymmetric unit of RZ-MLA consists of one RZ molecule and one MLA molecule resulting in a salt co-crystal of 1:1 stoichiometric ratio. It is quite evident that a proton transfer has taken place from the carboxylic group of malonic acid to the ring nitrogen of riluzole (Figure 3a, ESI T-3) which creates a negative charge on carboxylic oxygen atom resulting in a salt formation. Now, this negative charge on oxygen atom in [O C−O]- is resonance stabilized. Also, an intramolecular hydrogen bonding O−H···O interaction provides further stability to the molecular conformation (ESI F-2). The formation of the carboxylate anion was confirmed by infrared spectroscopy study as well. The carboxylic acid O−H stretching peak (2500−3200 cm−1) was not observed in the binary system RZ-MLA salt (Figure 5, depicted by orange arrow), whereas all the remaining carboxylic and dicarboxylic acid co-crystals depicted an O−H stretching peak (ESI F-5) corresponding to the presence of a carboxylic acid functional group. For RZMLA salt, only N−H stretching peak was observed at 3330 cm−1. The broad carboxylic acid CO stretching peak was shifted from 1750 to 1700 cm−1 (in malonic acid) to 1650 cm−1 (in RZ-MLA salt, depicted by black arrow), which again proves the formation of the carboxylate anion (Figure 5). A primary heterodimeric motif comprising of N−H···O hydrogen bonds was formed between riluzole and malonic acid. The 1:1 co-crystals RZ-SA, RZ-GA, and RZ-PA crystallized in the monoclinic space group C2/c. The primary heterodimeric motif, formed via N−H···O and O−H···N hydrogen bonds, homodimeric motifs via O−H···O, and strong N−H···O heterosynthon interactions were presented in all three crystal structures. The nature and energetics associated with both strong and weak interactions have been investigated via PIXELC, and the partitioning among the different energy components (namely, electrostatics, polarization, dispersion, and repulsion) provides quantitative indicators toward the role of the various interactions in the overall crystal packing. It is indeed noteworthy that a short and highly directional C−H···F [2.43 Å, 172°] intermolecular contact is present in the crystal packing of the co-crystal RZ-SA; the interaction distance is less than the sum of the van der Waals radii of hydrogen and fluorine atoms, and the nature of this interaction has a

Figure 2. DSC traces of the cocrystals, cocrystal polymorph, and the salt performed at 5 °C/min for a heating-cooling cycle (a) Riluzole, RZ-MLA, RZ-SA, and RZ-GA; (b) RZ-AA-form-1, RZ-AA-form-2, and RZ-SORBA; (c) RZ-PA, RZ-SBRA, and RZ-AZA; (d) RZ-SEBA, RZDMAP, and RZ-NA.

acceptor site and an amine group which acts as a donor for the formation of hydrogen bonding interactions with a carboxylic acid group. In the crystal structure of co-crystals with dicarboxylic acids and sorbic acid, there exists a primary heterodimeric motif between riluzole and the coformer formed by N−H···O and O−H···N hydrogen bonds and a primary homodimeric motif between two dicarboxylic acid molecules formed by O−H···O hydrogen bonds, as are shown in Figure 3 and Figure 4. The presence of these heterodimeric and homodimeric motifs in the crystal structure of co-crystals is due to the stabilization imparted via the presence of strong 1941



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Figure 3. Packing diagrams: (a) RZ−MLA salt via the network of strong N−H···O hydrogen bonds along with other weak interactions, (b) RZ-SA, and (c) RZ-GA co-crystals via the network of strong heterodimeric motifs N−H···O and O−H···N hydrogen bonds, homodimeric motifs O−H···O and N−H···O hydrogen bonds along with other weak interactions. (d) RZ-AA-form-1, (e) RZ-AA-form-2, and (f) RZ-SORBA co-crystals via the network of strong heterodimeric motifs, namely, N−H···O and O−H···N hydrogen bonds, along with other weak interactions. The Roman numerals indicate different molecular motifs in the crystal packing; the quantitative estimates for all these molecular pairs are presented in ESI T-2 and T-3.

characterized via motif III (−20.4 kJ/mol), motif VIII (−14.9 kJ/mol), and motif IX (−10.3 kJ/mol), respectively (ESI T-2). The co-crystal of riluzole and adipic acid consists of two polymorphic forms, wherein form-1 crystallized in the triclinic space group P1,̅ and form-2 crystallized in the monoclinic space group P21/c. The asymmetric unit of both forms consists of one molecule of RZ and a half-molecule of AA. The primary heterodimeric motif is formed via N−H···O and O−H···N hydrogen bonds and strong N−H···O heterosynthon interactions (Figure 3d,e, ESI T-2), and these constitute the core building blocks for both polymorphic forms. However, the secondary noncovalent interactions present are different. The stabilized energy contribution of form-1 originates from C− H···π (motif III, −24.3 kJ/mol) and O(lp)···π (motif IV, −12.8 kJ/mol) interactions (ESI T-2), whereas form-2 was stabilized

contribution of 25−30% from electrostatics (ESI T-2). The packing in the crystal structure of RZ-SA involves the formation of a molecular layer via π···π interactions, characterized via motif III (−16 kJ/mol) and motif VII (−13.9 kJ/mol), respectively (ESI T-2). A secondary heterodimeric motif (motif IV) was observed between the API and succinic acid via C−H···F and C−H···O interactions with 50−55% electrostatic contribution. Similarly, a secondary heterodimeric motif (motif IV) was also observed in RZ-GA co-crystal via C−H···F and C−H···O interactions with 45−50% electrostatic contribution. Two short C−H···O [2.45 Å, 130°; 2.46 Å, 170°] contacts are present between API and coformer in RZ-PA cocrystal. The RZ-PA crystal packing also involved the formation of a molecular layer via π···π and O(lp)···π interactions 1942



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Figure 4. Packing diagrams: (a) RZ-PA co-crystal via the network of strong heterodimeric motifs, namely, N−H···O and O−H···N hydrogen bonds, homodimeric O−H···O hydrogen bonded motifs, and N−H···O hydrogen bonds along with other weak interactions; (b) RZ-SBRA; (c) RZ-AZA; (d) RZ-SEBA co-crystals via the network of strong heterodimeric motifs N−H···O and O−H···N hydrogen bonds, and N−H···O hydrogen bonds along with other weak interactions; (e) RZ-DMAP co-crystal via the network of strong homodimeric motifs N−H···N and N−H···N hydrogen bonds along with other weak interactions; (f) RZ-NA co-crystal (co-crystallizes with the zwitterion of nicotinic acid) via the network of strong N− H···O hydrogen bonds along with other weak interactions. The Roman numerals indicate molecular motifs, presented in ESI T-2 and T-3.

by π···π (motif III, −16.7 kJ/mol) interactions. A short S···F interaction [3.196(1) Å] is present in the crystal structure of RZ-AA-form-1, and the nature of this interaction has a contribution of 35−40% from electrostatics (ESI T-2). This observation is further confirmed by plotting the electrostatic potential mapped on the Hirshfeld surface of such S···F interactions and may be classified as a “chalcogen bond” (ESI F-3a).34 A short C−H···O [2.46 Å, 141°] contact is present between the API molecules in the co-crystal of form-2 with 35% electrostatic contribution. The packing features of RZ-AA polymorphic form-1 were characterized by the formation of planar sheets, whereas in form-2 the packing was completely different (Figure 3d and 3e). Hence the formation of the different structures of the co-crystal is a case of packing polymorphism.

RZ-SORBA co-crystallizes in the triclinic space group P1̅, where the coformer (sorbic acid) is an unsaturated monocarboxylic acid with 1:1 stoichiometric ratio. The primary heterodimeric motif, formed via N−H···O and O−H···N hydrogen bonds and strong N−H···O heterosynthon interactions, was present in RZ-SORBA crystal structures. A secondary heterodimeric motif (motif V) was observed between the API and sorbic acid via C−H···F and C−H···O interactions with 40% electrostatic contribution. The crystal packing of RZ- SORBA involves the formation of a molecular layer via π···π (motif IV, −14.2 kJ/mol) interaction. RZ-SBRA co-crystallizes in the monoclinic space group P21 with 2:1 stoichiometric ratio. The presence of a short C−H···F [2.43 Å, 145°] in RZ-SBRA is of significance with this interaction having an electrostatic contribution of 25%. A short S···F interaction 1943



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systems after a time interval after every 3−4 h. After a period of 6−7 h we have not observed any improvement in solubility. The solubility after stirring for 24 h for all the samples is taken as the equilibrium solubility. The solubility of riluzole is 0.35 g/ L in a pH 7 buffer medium at 25 °C. Our goal was to improve the solubility of the drug through the formation of a riluzole cocrystal and salt. We have performed the dissolution and solubility experiments on those co-crystals and salt which contain low molecular weight coformers such as MLA, SA, GA, AA, SORBA, and SBRA. The RZ-MLA salt and RZ-SORBA cocrystal exhibited the highest solubilities (3.21 and 1.98 g/L) (Table 2). The remaining co-crystals, such as RZ-SA, RZ-GA, Table 2. Dissolution and Solubility Parameters of Riluzole Co-crystals/Salt in pH 7 Buffer Medium at 37°C compd

absorption coeff (mM−1 cm−1)

equilib solubility (g L−1)

RZ (API) RZ-MLA RZ-SA RZ-GA RZ-AA-form-1 RZ-SORBA RZ-SBRA

11.30 11.81 13.37 11.18 11.17 25.07 10.48

0.35 3.21 0.81 0.62 0.43 1.98 0.54

Figure 5. IR overlay diagram of API RZ, RZ-MLA salt, and malonic acid conformer.

[3.109(3) Å] is also present in RZ-SBRA along with C−H···F interactions (ESI F-3b). The stabilized energy contribution of RZ-SBRA co-crystal also originates from the secondary C− H···π (motif III, −21.3 kJ/mol; motif VIII, −21.8 kJ/mol) interactions (ESI T-2). RZ-AZA co-crystal crystallizes in the triclinic space group P1̅ in the stoichiometric ratio of 4:2. The two short C−H···F’s [2.46 Å, 150°; 2.43 Å, 155°] and one short C−H···O [2.41 Å, 169°] are present along with the primary heterodimeric motif and strong N−H···O hydrogen bonds in RZ-AZA co-crystal. RZ-SEBA co-crystallizes in the monoclinic centrosymmetric space group P21/n with a stoichiometric ratio of 1:0.5. The RZSEBA crystal packing is involved in the formation of a molecular layer via π···π (motif III, −16.1 kJ/mol) interaction. The stabilized energy contribution of RZ-SEBA co-crystal also originates from the secondary noncovalent C−H···O [2.54 and 2.70 Å] (motif IV, −10.9 kJ/mol) contact that was present between the API and coformer with 55% electrostatic contribution. RZ-DMAP and RZ-NA crystallize in the space group P1̅ (3:2 stoichiometric ratio) (Figure 4e) and P21/c (1:1 stoichiometric ratio) (Figure 4f) respectively, and both coformers are derivatives of pyridine. In RZ-DMAP co-crystal, the two riluzole molecules were connected via N−H···N homodimeric motif, a unique example among all the co-crystals. However, the primary motif between API and the coformer was the strong N−H···N hydrogen bond along with short C−H···F [2.46 Å, 142°; 2.43 Å, 135°] and C−H···π interactions (ESI T-3). In RZ-NA co-crystal, the riluzole molecule co-crystallizes with the zwitterionic form of nicotinic acid which prevents the formation of the heterodimeric motif consisting of N−H···O and O−H··· N hydrogen bonds. RZ-NA was constructed via strong N−H··· O homosynthon (between two coformers) and heterosynthon (between API and coformer) interactions. The packing in the crystal structure of RZ-NA also involved the formation of a molecular layer via π···π interactions in motif III (−23.3 kJ/ mol) along with motif VIII (−17.9 kJ/mol), motif XIII (−68.7 kJ/mol), and motif XIV (−54.8 kJ/mol), respectively (ESI T2). A short C−H···F [2.38 Å, 137°] contact is present in RZNA with an astonishingly high electrostatic contribution of 60%, which is extremely rare for weak intermolecular interactions. The concentration of a substance in solution with an excess of the undissolved substance at chemical equilibrium is the equilibrium solubility. The solubility was checked for binary

intrinsic dissolution rate (mg cm−2 min−1)a 0.03806 0.06198 0.04399 0.05152 0.08317 0.27184 0.09461

(×1.62) (×1.15) (×1.35) (×2.18) (×7.14) (×2.48)

a

Number in parentheses indicates the number of times the higher solubility of co-crystals/salt is compared to that of the least soluble riluzole.

RZ-AA-form-1, and RZ-SBRA exhibit comparatively lower solubilities of 0.81, 0.62, 0.43, and 0.54 g/L (Table 2). The RZ, RZ-AA-form-1, RZ-SBRA, and RZ-SORBA co-crystals were stable after 24 h of the slurry experiment (ESI F-4). The RZ-SA co-crystal transformed to riluzole during the slurry experiments after 24 h. The RZ-MLA salt and RZ-GA co-crystal were transformed to a new phase (not matching with both the API and the coformers and these new phases are under investigation) during the slurry experiments after 24 h. The dissolution rates are an extremely useful parameter for a drug which undergoes phase transformation during the studies on solubility, and hence a comparison of the actual drug concentrations with different conformers is of importance. IDR measurements were performed in pH 7 buffer medium. The amount of riluzole, co-crystals, and salt dissolved (mg/cm2) were plotted against time (min) (Figure 6). The intrinsic dissolution rates (mg cm−2 min−1) were deliberated from the slope in the linear region of the dissolution curves. The RZSORBA co-crystal and RZ-MLA salt showed faster dissolution rates than the other co-crystals (Table 2). We noted the inverse correlation between the melting point of RZ-SORBA (91 °C) and its solubility. Initially, the RZ-SORBA, RZ-AA-form-1, and RZ-SBRA co-crystals showed higher dissolution rates, but the rates slowly decrease with increasing time; the final concentration reached saturation (ESI T-4). The RZ-MLA salt and RZ-SA and RZ-GA co-crystals showed a better dissolution profile after 90 min (ESI T-4). All of the co-crystals and salt were stable during the period of 5 h of the IDR experiment. This was also confirmed by PXRD (ESI F-4).

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CONCLUSIONS The work discussed and illustrated herein shows that the API riluzole, an important fluorine-containing drug molecule, can 1944



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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: 91-0755-6692392. ORCID

Deepak Chopra: 0000-0002-0018-6007 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS P.K.M. thanks CSIR for the senior research fellowship. We are also very thankful to IISER Bhopal for research facilities and infrastructure. D.C. thanks DST-SERB Scheme for funding. We express our gratitude to Prof. Ashwini Nangia for his support.

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Figure 6. Measurements of the intrinsic dissolution rate of riluzole cocrystals and salt in pH 7 buffer medium.

form a variety of co-crystals with aliphatic dicarboxylic acids and pyridine derivatives via heterodimeric and homodimeric motifs formed by N−H···O, O−H···N, O−H···O, and N−H···N hydrogen bonding interactions. The structural diversity observed in these solids is exemplified by the altered stoichiometric ratio between the conformer and the API in the final co-crystal. This is indeed a noteworthy feature in the present study. The complete structural characterization of all the multicomponent forms of RZ has been identified to be cocrystals of riluzole. All of these co-crystals of RZ were produced using the solvent drop grinding (SDG) method and crystallized at low temperature. Co-crystallization through solvent drop grinding demonstrated in this study offers environmental benefits through a substantial or complete reduction of solvent use which leads to a step toward green chemistry. A large number of crystalline phases discovered (co-crystals, polymorph, and salt) for riluzole in this study shows that the API is a potential host for the development of novel molecular cocrystals. Those co-crystals help to overcome some of the limitations related to this essential drug, particularly in alteration of the solubility profiles related to this drug. This is expected to have benefits for the health of humans who have been diagnosed with amyotrophic lateral sclerosis.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01894. Details on crystallographic refinement, table of intermolecular interactions, crystal images, ORTEP diagrams, Hirshfeld surfaces, data on intrinsic dissolution rates, PXRD diagrams, IR diagrams, and HSM snapshots (PDF) Accession Codes

CCDC 1509354−1509365 contains the supplementary crystallographic data for this paper. These data can be obtained free of 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. 1945



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