Crystal form diversity of antiepileptic drug Retigabine - Crystal Growth

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Crystal form diversity of antiepileptic drug Retigabine Raj Gautam, Ramanpreet Kaur, Suryanarayan Cherukuvada, Diptikanta Swain, and Guru Row Tayur N. Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01488 • Publication Date (Web): 11 Jan 2018 Downloaded from http://pubs.acs.org on January 12, 2018

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Crystal Growth & Design

Crystal form diversity of antiepileptic drug Retigabine Raj Gautam, Ramanpreet Kaur, Suryanarayan Cherukuvada, Diptikanta Swain and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India

ABSTRACT: Crystal form screening of antiepileptic drug Retigabine was undertaken to establish the stability order among the known trimorphs and design new cocrystals of the drug. X-ray crystal structures of polymorphs A and B have been determined and the thermodynamic stability among the trimorphs at ambient conditions is found to be in the order B (least stable) < C < A (most stable) from thermal and phase transformation experiments. Two anhydrous cocrystals, an anhydrous salt and a eutectic of Retigabine were successfully designed and characterized. Interestingly, Retigabine forms a cocrystal with 4hydroxybenzoic acid only with a water of crystallization (i.e. as a cocrystal hydrate), else the binary combination manifests as a eutectic. The number of hydroxyl groups and water is implicated in the formation of anhydrous/hydrated cocrystals and eutectic respectively among the combinations explored.

INTRODUCTION Epilepsy is a common neurological disorder with an estimated prevalence of 1% of the world population.1-3 The therapeutic strategy in treating epilepsy involves reducing neuronal excitability. Although neuronal potassium gated channels are implicated in the control of neuronal excitability, until recently most therapies were developed that target sodium gated neuronal channels or gamma-aminobutyric acid (GABA) mediated transmission. In 2009, Retigabine (abbreviated as RTG; Figure 1) has been developed as a first in class, orally active, neuronal potassium channel opener.2,4 The drug is also known as 'Ezogabine' in the US being marketed under the trade name 'Potiga'.3,4 Pharmaceutical form development, which encompasses the development of an optimal drug formulation with desired physicochemical properties (in terms of solubility, flowability, compressibility, stability, bioavailability etc.), is an essential component of drug research and development program.5,6 A pharmaceutical solid formulation contains the drug in the form of a polymorph/polymorphic mixture, amorphous form, salt, hydrate/solvate, complex, cocrystal or eutectic blended with excipients.5-10 Each of these solid forms exhibit varied physicochemical properties and therefore have their own importance in offering tailored solutions for a variety of cases. The better the screening and knowhow of diverse solid forms, the greater will be the scope to achieve the solid form with desired properties. Hence, deciphering the crystal form diversity via co-crystallization studies has emerged as a new component of pharmaceutical form development from the last decade.5,7,9,11-20

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Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Three polymorphs,21 several salts/cocrystals22,23 and an amorphous form1 of Retigabine have been reported in the patent literature. However, stability relationships among the polymorphs and design aspects in particular to generate cocrystals have not been studied to this day. Thermodynamic nature and stability of the polymorphs is an essential step in pharmaceutical form development since each polymorph is an unique crystalline entity with distinct physicochemical properties.5-9,24-27 The energy landscape of Retigabine suggests interconversions between polymorphic forms leading to changes in bulk properties of the drug, which in turn affects drug efficacy. In short, if a metastable polymorph (higher solubility and hence lower stability as compared to its stable counterpart) needs to be marketed, it is essential to understand the conditions that lead to polymorphic transformations.24,25,28,29 Recently, the European Medicines Agency (EMA)30 and the United States Food and Drug Administration (US-FDA)31 recognized cocrystals32-44 as pharmaceutical materials. In addition, organic eutectics with tunable and desirable properties have been proposed as alternates to co-crystalline solids.10,32,33,45-51 In the current study, solid form screening of RTG has been carried out to systematically investigate several aspects viz. (i) characterization of polymorphs, (ii) polymorphic transformation and establishment of relative stability among the polymorphs and (iii) design of cocrystals and eutectics. The presence of the carbamate functional group on RTG allows cocrystal formation with several hydroxybenzoic acids and a eutectic with benzoic acid. Reports on cocrystals based on carbamate group as primary hydrogen bonding motif are very few in literature and the present study provides a systematic evaluation of the interactions. Xray crystal structures of two polymorphs, several cocrystals and a nitrate salt of RTG in this work.

Figure 1 Molecular structures and acronyms of the compounds in this study. Page 2 of 18 ACS Paragon Plus Environment

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RESULTS AND DISCUSSION I. Screening, crystallization and characterization of RTG trimorphs RTG is known to exist in three polymorphic forms named as 'A', 'B' and 'C'21 and the same designation is employed in this work. Interestingly, the starting material RTG as was procured from the supplier is found to be polymorph C based on the recorded powder X-ray diffraction (PXRD) (Figure S1 of Supporting Information). The sample was subjected to several experiments involving evaporative crystallization and melting techniques24-26 to obtain the single crystals of the polymorphic forms (details in Experimental Section). Polymorph A was harvested from majority of the solvents and in only one case both A and B crystallized concomitantly. Melt crystallization of RTG resulted exclusively in polymorph B. Both A and B could be identified based on their crystal morphology of the resulting single crystals (Figure 2). However, it must be mentioned that no single crystals of C and no new polymorphs were obtained in our crystallization experiments. X-ray crystal structures were determined for A and B and their crystallographic parameters are given in Table 1. In the crystal structure, RTG molecules form dimers through C−H⋅⋅⋅F interactions which extend into chains through alkyl interactions between ethyl groups (Figure 3). Such chains are connected by N−H⋅⋅⋅F, C−H⋅⋅⋅π and π⋅⋅⋅π interactions in the crystal lattice. The calculated diffraction profile obtained from the X-ray crystal structure showed complete match with the reported PXRD profile of A and with the experimental PXRD pattern of methanol crystallized RTG (Figure S2, Supporting Information). Polymorph B is a high Z′ polymorph52 having five independent molecules in the asymmetric unit, which are found to be disordered (disorder treatment is detailed in the Experimental Section). The molecules form catemers through carbamate N−H⋅⋅⋅O interactions along b-axis and such catemers propagate along c-axis through alkyl and C−H⋅⋅⋅F interactions (Figure 4). The calculated diffraction profile from the X-ray crystal structure matches with the reported PXRD profile of B and with the experimental PXRD pattern of melt-crystallized RTG (Figure S3, Supporting Information).

Polymorph A

Polymorph B

Figure 2 Block crystals of RTG A and acicular crystals of RTG B polymorphs.



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Table 1 Crystallographic parameters.a 1:2:1 RTG− −4HBA− −H2O C16H18FN3O2 −(C7H6O3)2−H2O

1:1 RTG− −24DHBA C16H18FN3O2 −C7H6O4

1:1 RTG− −GA C16H18FN3O2 −C7H6O5

1:2 RTG− −HNO3 (C16H20FN3O2)2+ −(NO3−)2

1493.49

597.59

457.45

473.45

429.37

monoclinic

monoclinic

monoclinic

triclinic

monoclinic

triclinic

7.7384(2) 7.7645(2) 25.1303(6) 90 96.900(3) 90 1499.01(7) P21/n

18.0756(12) 24.0282(14) 35.621(2) 90 102.825(7) 90 15085.2(17) I2/a

10.4793(16) 7.7886(7) 35.799(3) 90 91.811(10) 90 2920.4(6) P21/n

4.8460(10) 15.504(4) 15.755(3) 111.877(5) 96.437(5) 95.666(5) 1078.8(4) P1

36.0182(18) 8.2894(3) 14.3276(6) 90 101.373(4) 90 4193.8(3) C2/c

8.4780(6) 8.8890(7) 14.2547(14) 79.788(7) 74.671(7) 67.718(7) 955.09(15) P1

4

8

4

2

8

2

1 4

5 40

4 16

2 4

2 16

3 6

120(1)

120(1)

120(1)

120(1)

120(1)

120(1)

1.344

1.315

1.359

1.408

1.500

1.493

0.099 640

0.097 6216

0.105 1256

0.108 480

0.118 1984

0.127 448

22950

27700

11530

7287

15660

6923

2626

13322

5155

3792

3685

3890

2466

5863

2839

2489

3051

2318

0.2166, 0.1126

0.1519, 0.0799

0.0982, 0.0616

0.3532, 0.2718

0.1478, 0.1225

0.1374, 0.1150

−0.19, 0.17

−0.39, 0.57

−0.28, 0.41

−0.28, 0.24

−0.21, 0.18

−0.43, 0.43

1.090 1547435

1.025 1547386

1.004 1547428

0.985 1547429

1.053 1547437

1.061 1547445

Compound

RTG− −A

RTG− −B

Formula

C16H18FN3O2

(C16H18FN3O2)5

303.33

Formula weight Crystal system a (Å) b (Å) c (Å) α (°) β (°) γ (°) Volume (Å3) Space group No. of independent general positions Z″ Z Temperature (K) Density (g cm−3) µ (mm−1) F (000) No. of measured reflections No. of unique reflections No. of reflections used

0.0337, 0.0315 0.0777, 0.0763

R_all, R_obs wR2_all, wR2_obs ∆ρmin, max (e Å−3) GOOF CCDC No. a

0.0527, 0.0416 0.0852, 0.0796

0.1154, 0.0673 0.2269, 0.1689

Z″ = no. of crystallographically non-equivalent molecules of any type in the asymmetric unit;53 Z = Z″ × no. of independent general positions of the space group.


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Figure 3 In RTG polymorph A, chains of RTG molecules formed by C−H⋅⋅⋅F and alkyl interactions are connected by N−H⋅⋅⋅F, C−H⋅⋅⋅π and π⋅⋅⋅π interactions.

Figure 4 In RTG polymorph B, catemers of unique RTG molecules formed of carbamate N−H⋅⋅⋅O interactions are connected by alkyl and C−H⋅⋅⋅F interactions. Symmetry independent RTG molecules in the middle are shown in different color.

II. Polymorphic transformation and Relative Stability of RTG trimorphs Although differential scanning calorimetry (DSC) data of RTG polymorphs have been reported21, the actual conditions of transformation and stability order of the polymorphs were not established. In our experiments, RTG trimorphs were obtained in bulk quantities (confirmed by matching PXRD patterns) and were systematically evaluated for their behaviour under the influence of thermal stress, in presence of polymorphic seeds, mechanical stress and extended storage time to establish their stability relationships. The DSC patterns of A and C show endothermic transitions (at 105 °C and 95 °C respectively) before melting (about 140 °C; Figure 5). This observation is in accordance to literature21 indicating that both A and C convert to B after this transition and melt at around 140 °C akin to the form B. Hence it may be inferred that both form A and C are enantiotropically related to B with A and C being stable at room temperature while B is stable at a higher temperature. The form A is Page 5 of 18 ACS Paragon Plus Environment


more stable than C due to its higher heat of transition as per Burger and Ramberger rules54 on thermodynamics of polymorphs (Figure 5). Overall, the increasing stability order among the polymorphs from thermal measurements can be depicted as B < C < A at room temperature. Additionally, seeding experiments were carried out to confirm the stability order among the three polymorphs. Neat grinding of forms B and C with 5% of form A as seeds resulted in a transformation of both B and C to A as monitored by PXRD analysis (Figures S4-5). It is noteworthy that the conversion to form A takes place in 15 mins in case of B while that of Form C to A takes an hour. In summary, Figure 6 depicts the nature of phase transformations among the polymorphs clearly suggesting that Form A is stable at room temperature whereas Form B represents the high temperature form.

Figure 5 DSC patterns of RTG polymorphs A (red), B (green) and C (blue).

Figure 6 Phase transformations among RTG trimorphs: (i) grinding with A seeds and (ii) heating.

III. Design and formation of RTG cocrystals, salts and eutectics. Very few reports of cocrystals involving carbamate molecular fragment (ROCONHR′) as primary a hydrogen bonding motif are found in the literature CSD; version 5.37).55 However, Page 6 of 18 ACS Paragon Plus Environment

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the individual functionalities of amine (NH/NH2) and carboxy (C=O/C−O) groups within the carbamate group are known to hydrogen bond with hydroxyl (OH) and carboxylic acid (COOH) functionalities to form cocrystals and solvates.56-60 Co-crystallization of RTG was carried out with several hydroxybenzoic acids as partner components based on two possibilities: (i) carboxylic acid homodimers of hydroxybenzoic acids can extend via amine/carbonyl(RTG)–hydroxyl(HBA) interactions into tetrameric motifs, (ii) propagation of carbamate–carboxylic acid heterosynthon through amine/carbonyl–hydroxyl interactions (Figure 7). The design component (i) generated the following multi component systems, 1:2:1 RTG−4-hydroxybenzoic acid cocrystal hydrate, 1:1 RTG−2,4-dihydroxybenzoic acid and RTG−gallic acid cocrystals (crystallographic parameters are given in Table 1).

(a)

(b)

Figure 7 Supramolecular schematics for the formation of RTG–hydroxybenzoic acid cocrystals. (a) Amine/carbonyl(RTG)–hydroxyl(HBA) interactions (marked in red) can extend carboxylic acid homodimers. Only one cocrystal is found in the CSD with such supramolecular motif (Refcode: GIDLUB).55 (b) Carbamate–carboxylic acid heterosynthon (not found in the CSD) can propagate through amine/carbonyl(RTG)–hydroxyl(HBA) interactions (marked in red).

Analysis of RTG−4HBA−H2O cocrystal hydrate (1:2:1) and 2:1 RTG−4HBA eutectic: Co-crystallization of 1:1 RTG and 4HBA in methanol (detailed in Experimental Section) yielded a cocrystal with one molecule of RTG, two molecules of 4HBA and a molecule of water in the asymmetric unit. In the crystal structure, water molecules connect independent chains of RTG molecules (formed by C−H⋅⋅⋅F interactions) and 4HBA molecules (formed of carboxylic acid dimers) through O−H⋅⋅⋅N(primary amine) and O−H⋅⋅⋅O(para-hydroxy) interactions (Figure 8). This cocrystal hydrate could also be produced by water-assisted grinding of RTG and 4HBA in 1:2 molar ratio (Figure 9). It is of interest to note that 1:1 RTG−4HBA neat ground material is not distinct from the parent materials based on PXRD analysis (Figure 9). Page 7 of 18 ACS Paragon Plus Environment


In fact, the combination results in a eutectic (2:1 based on molar fraction at the eutectic point) as analyzed by binary phase diagram (Figure 10).

(a)

(b) Figure 8 (a) Hydroxyl−carbamate interactions between 4HBA and RTG molecules in RTG−4HBA cocrystal hydrate. (b) Water molecules connect a chain of RTG molecules formed by C−H⋅⋅⋅F interactions to 4HBA carboxylic acid dimers through O−H⋅⋅⋅N(primary amine) and O−H⋅⋅⋅O(para-hydroxy) interactions. Symmetry independent 4HBA molecules are shown in different color.


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Figure 9 PXRD pattern of 1:1 RTG–4HBA neat ground material (blue) manifests as a mixture of parent components (RTG (red) and 4HBA (green)). However, 1:2 RTG–4HBA water ground material (gray) is distinct from the parent materials and resembles the calculated diffraction profile of 1:2:1 RTG–4HBA cocrystal hydrate (brown).

Figure 10 Binary phase diagram of RTG−4HBA system showing a eutectic composition of 2:1 with melting temperature 115 °C. Solidus points are shown as filled circles and liquidus points as open squares.

Cocrystals of 1:1 RTG−24DHBA and RTG−GA: Based on the above observations, it appears that the presence of additional –OH groups might induce the formation of cocrystals. Indeed, 1:1 RTG−24DHBA and RTG−GA cocrystals were obtained when the combinations in 1:1 molar ratios were crystallized from Page 9 of 18 ACS Paragon Plus Environment


tetrahydrofuran and methanol respectively (detailed in Experimental Section). In both cocrystals, multiple hydroxyl groups of 24DHBA/GA molecule connect anti parallel tapes of RTG molecules (formed by C−H⋅⋅⋅F interactions) through hydroxyl⋅⋅⋅amine/carbonyl (RTG) interactions (Figure 11) akin to the water molecule connecting the independent chains of RTG and 4HBA molecules in 1:2:1 RTG−4HBA cocrystal hydrate. It is to be noted that the combinations do not need additional water molecule to manifest as cocrystals unlike the case of RTG and 4HBA. It is obvious that in the absence of water to balance the hydrogen bonding sites, the combination results in the formation of a eutectic. To check whether donor-acceptor match leads to an anhydrous salt and mismatch to a eutectic, both nitric acid (having three 'O' acceptors) and benzoic acid (no acceptors except for carboxyl 'O') were examined as coformers with RTG.

(a)

(b)

Figure 11 (a) Ortho- and meta-hydroxyl groups of 24DHBA molecules, which form carboxylic acid dimers, connect antiparallel tapes of RTG molecules through O−H⋅⋅⋅N(primary amine) and N−H(secondary amine)⋅⋅⋅O(hydroxy) interactions in RTG−24DHBA cocrystal. (b) Similarly, in RTG−GA cocrystal, GA carboxylic acid dimers connect RTG molecules on either side through meta-hydroxyl O−H⋅⋅⋅N(secondary amine) and O−H⋅⋅⋅O(carbamate) interactions.


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Retigabine dinitrate salt: RTG has both primary and secondary amine groups and therefore can be protonated at both sites by strong acids. Thus, nitric acid with multiple oxygen acceptors can form hydrogen bonds with RTG. Indeed, retigabine dinitrate salt (anhydrous) (Figure 12) displays hydrogen bonding patterns similar to those observed in RTG−multihydroxybenzoic acid anhydrous cocrystals.

(a)

(b)

Figure 12 (a) Carbamate−nitrate interactions between RTG and nitrate moieties in RTG dinitrate salt. (b) Parallel tapes formed of RTG C−H⋅⋅⋅F dimers are connected by nitrate ions through protonated primary and secondary amine groups. Symmetry independent nitrate ions are shown in different color.

1:2 RTG−BA eutectic: It has been hypothesized that a supramolecular combination forms a eutectic when heteromeric motifs cannot propagate in a continuous manner in the crystal lattice.10,30 It has been shown earlier that RTG−4HBA combination forms a eutectic due to the lack of additional hydroxyl groups that can extend carbamate(RTG)−hydroxyl(4HBA) heterodimers into tetramers to form a cocrystal. RTG−benzoic acid combination likewise cannot form a cocrystal and prefers to form a eutectic (Figure 13). The lack of formation of a hydrated complex is confirmed experimentally as shown in Figure 14.



Figure 13 Binary phase diagram of RTG−BA system showing a eutectic composition of 1:2 with melting temperature 82 °C. Solidus points are shown as filled circles and liquidus points as open squares.

Figure 14 PXRD patterns of 1:1 RTG–BA neat ground (blue) and water ground (red) materials respectively suggest a mixture of parent components (RTG (brown) and BA (green)).

CONCLUSIONS Polymorph characterization and design of new cocrystals and eutectics of RTG provides the following inputs. The stability order among RTG trimorphs at ambient conditions as B (least stable) < C < A (most stable) is established unequivocally through an analysis of phase transformations. Single crystal X-ray diffraction studies of polymorphs A and B as well as three cocrystals and a salt brings out the importance of the participation of the carbamate functionality and the requirement of water of hydration to control and generate cocrystals and /or eutectics. Though water is implicated as a design element in crystal engineering, this study suggests the possibility to selectively design cocrystals (as cocrystal hydrates) of otherwise eutectic-forming combinations.

EXPERIMENTAL SECTION Materials: Retigabine is a gift sample from Zydus Cadila, Ahmedabad, India. All other compounds were purchased from commercial suppliers (Sigma-Aldrich and Alfa Aesar, Bengaluru, India) and were used without further purification. Solvents used were of analytical or chromatographic grade and water used for experiments was purified from a Siemens Ultra Clear water purification system. Page 12 of 18 ACS Paragon Plus Environment

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Methods RTG polymorph screening: (i) About 100 mg of RTG was dissolved in each of 5−10 mL methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, nitromethane, ethyl acetate and dimethyl sulfoxide and kept for evaporative crystallization at ambient conditions. The powders/crystals harvested were analyzed by X-ray diffraction. Polymorph A was obtained from majority of the solvents as block crystals and C as powder from few solvents. Polymorph B crystallized concomitantly with A from isopropanol as acicular crystals. (ii) 100 mg of RTG was taken in a sublimation tube and heated in an oil bath at 160 °C (i.e. beyond the melting point of RTG) for 5 min. The molten material was kept aside for ambient cooling. The solidified material was found to be polymorph B. Polymorphic transformation experiments:24,25 Pure RTG trimorphs were isolated in bulk quantity (about 500 mg) for phase transformation experiments. Co-grinding experiments were done using a mortar-pestle in 100 mg scale with 5% polymorphic seeds added. Co-crystallization 1:2:1 RTG:4HBA:H2O: 30 mg (0.1 mmol) of RTG and 14 mg (0.1 mmol) of 4HBA were dissolved in 3 mL of methanol and left for slow evaporation at room temperature. Colorless plate crystals of cocrystal hydrate were obtained after a few days upon solvent evaporation. Water-assisted grinding62 (with 0.5 mL quantity) of RTG and 4HBA in 1:2 molar ratio (75 mg (0.25 mmol):70 mg (0.5 mmol)) resulted in the formation of cocrystal hydrate in bulk quantity as analyzed by PXRD of the ground material. 1:1 RTG−24DHBA: 30 mg (0.1 mmol) of RTG and 16 mg (0.1 mmol) of 24DHBA were dissolved in 4 mL of tetrahydrofuran and left for slow evaporation at room temperature. Colorless plate crystals of cocrystal were obtained after a few days upon solvent evaporation. The cocrystal was made in bulk quantity by methanol-assisted grinding (with 1 mL quantity) of RTG and 24DHBA in 1:1 molar ratio (75 mg (0.25 mmol):40 mg (0.25 mmol)) as analyzed by PXRD of the ground material (Figure S6, Supporting Information). 1:1 RTG:GA: 30 mg (0.1 mmol) of RTG and 17 mg (0.1 mmol) of GA were dissolved in 5 mL of methanol and left for slow evaporation at room temperature. Colorless plate crystals of cocrystal were obtained after a few days upon solvent evaporation. The cocrystal was made in bulk quantity by methanol-assisted grinding (with 1 mL quantity) of RTG and GA in 1:1 molar ratio (75 mg (0.25 mmol):40 mg (0.25 mmol)) as analyzed by PXRD of the ground material (Figure S7, Supporting Information). 1:2 RTG−HNO3: 300 mg (1 mmol) of RTG was subjected to grinding with 1 mL dil. nitric acid (taken from solution made of 1mL 68% HNO3 + 14 mL methanol). The ground material (50 mg) dissolved in 5 mL tetrahydrofuran gave colorless block crystals of RTG dinitrate salt which is found to completely match the experimental PXRD of the former (Figure S8, Supporting Information). Single crystal X-ray diffraction: X-ray reflections on suitable single crystals were collected on an Oxford Xcalibur (Mova) diffractometer equipped with an EOS CCD detector and a microfocus sealed tube using Mo Kα radiation (λ = 0.71073 Å). Low temperature data Page 13 of 18 ACS Paragon Plus Environment


collection was performed using an Oxford Cobra open stream non-liquid nitrogen cooling device. Data collection and reduction were performed using CrysAlisPro (version 1.171.36.32)63 and OLEX2 (version 1.2)64 was used to solve and refine the crystal structures. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on heteroatoms were located from difference electron density maps and all C–H atoms were fixed geometrically using HFIX command. The structure of RTG polymorph B has positional disorder and was treated using SHELXL-9765 program in WinGX66 suite. The final refinement and production of CIFs and crystallographic parameter table was done using WinGX. Powder X-ray diffraction: PXRD were recorded on PANalytical diffractometer using CuKα X-radiation (λ = 1.5406 Å) at 40 kV and 30 mA. Diffraction patterns were collected over 2θ range of 5–40° using a step size of 0.06° 2θ and time per step of 1 sec. X'Pert HighScore Plus (version 1.0d)67 was used to collect and plot the diffraction patterns. Thermal analysis: DSC was performed on samples of size 1–3 mg using a Mettler Toledo DSC 822e module. Samples were heated @ 10 °C/min in the temperature range 30–200 °C under ultra high pure nitrogen environment purged at 50 mL/min. Different compositions (1:1, 1:2, 1:3, 1:4, 2:1, 3:1 and 4:1) of eutectic-forming combinations were analyzed for their solidus–liquidus temperatures using a Labindia visual melting range apparatus (MR 13300710) equipped with a camera and an LCD monitor. Based on the merger of solidus and liquidus points, the eutectic composition was determined.68 Packing diagrams: X-Seed free software69 was used to prepare packing diagrams. Molecular and supramolecular schematics: ChemBioDraw Ultra (version 14)70 was used to prepare schematics.

ASSOCIATED CONTENT Supporting Information PXRD patterns and CIFs. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *Email: [email protected]; Tel: +91-080-22932796; Fax: +91-080-23601310. Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS RG and RK thank the Institute for a Promotional Fellowship and a Senior Research Fellowship respectively. SC thanks the SERB for Start-Up Research Grant and DS thanks the


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DST for Fellowship. TNGR thanks the DST for J. C. Bose Fellowship. We thank the Institute for infrastructural facilities.

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For Table of Contents Use Only

Crystal form diversity of antiepileptic drug Retigabine Raj Gautam, Ramanpreet Kaur, Suryanarayan Cherukuvada, Diptikanta Swain and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India

Co-crystallization of antiepileptic drug Retigabine with benzoic acid and its hydroxy analogues resulted in a variety of co-crystalline adducts such as anhydrous/hydrated cocrystals and eutectics.


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Crystal form diversity of antiepileptic drug Retigabine - Crystal Growth

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