Temozolomide Cocrystals with Carboxamide ... - ACS Publications

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Temozolomide Cocrystals with Carboxamide Coformers Palash Sanphui, N. Jagadeesh Babu, and Ashwini Nangia* School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Gachibowli, Hyderabad 50046, India S Supporting Information *

ABSTRACT: Temozolomide (TMZ) is an antitumor prodrug of broad spectrum antineoplastic activity. TMZ is stable in acidic medium (pH < 4) but starts to decompose at alkaline pH (>7). In continuation of our efforts to design stable cocrystals of TMZ with partners such as organic acids (pKa 2−5) and a salt dihydrate with hydrochloric acid, we report herein TMZ cocrystals with amide coformers, e.g., isonicotinamide, nicotinamide, pyrazinamide, p-hydroxybenzamide, saccharin, and caffeine. TMZ exhibits polymorphs in the p-hydroxybenzamide cocrystal (synthon polymorphism). The occurrence of the stable conformation A of temozolomide and metastable conformation B (energy difference 1.44 kcal mol−1) in amide cocrystals is compared with the overall statistics in temozolomide cocrystal structures and polymorphs. The novel cocrystals were characterized by spectroscopic, X-ray diffraction, and thermal methods.

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Scheme 1. TMZ Conformers A and Ba

INTRODUCTION Active pharmaceutical ingredients (APIs) often exist in crystalline phases, such as polymorphs, cocrystals, solvates/ hydrates, salts, and occasionally in amorphous form.1 The unique physicochemical properties of each state influences its solubility, stability, bioavailability, hygroscopicity, etc. as an oral drug. The most suitable solid form of a particular API is optimized after solid form screening and selection of the best formulation for drug development. A cocrystal is defined as a multicomponent assembly of two or more solids (at ambient conditions) in a fixed stoichiometry which interact through noncovalent interactions (preferably hydrogen bonds). If one of the components is an API (drug) and the second component is a pharmaceutically acceptable or GRAS molecule (coformer),2 then the product is a pharmaceutical cocrystal. Regulatory agencies, notably the United States Food and Drug Administration (US-FDA),3 are taking note of the significance of pharmaceutical cocrystals in drug formulation. Temozolomide (8-carbamoyl-3-methylimidazo[5,1-d]-1,2, 3,5-tetrazin-4(3H)-one, TMZ) is a N-3 substituted carbamoyl imidazo tetrazinone drug. It is active against malignant melanoma for the treatment of brain tumor4 that releases the reactive alkylating agent by a water-assisted tetrazinone ringopening. The intermediate 3-methyl-(triazenyl-1-yl)imidazole4-carboxamide (MTIC), formed by the elimination of H2O and CO2, then rapidly degrades to 5-aminoimidazole-4-carboxamide (AIC) byproduct and the highly reactive methyldiazonium ion (CH3N2+) species, which is the nascent alkylating agent that binds to the major groove of DNA. Because of O6-methylguanine lesion being left intact, thymine is remismatched leading to cell arrests in the G2/M phase and finally apoptosis.5 N-7 of guanine is the major alkylation site in calf thymus DNA studies.6 Akin to other alkylating agents, temozolomide has a greater antitumor effect if a large population of cells is actively © 2013 American Chemical Society

a

Conformer A is More Stable Than B by 1.44 kcal mol−1.

Scheme 2. Chemical Structure of Temozolomide and the Coformers Used to Make TMZ−Amide Cocrystals

replicating.4d The mean elimination half-life of temozolomide in plasma concentrations is about 1.8 h (range 1.7−1.9 h) with maximum concentration between 0.33 and 2 h. In aqueous buffers, TMZ is relatively stable at acidic pH < 4 but rapidly Received: February 27, 2013 Revised: April 2, 2013 Published: April 3, 2013 2208

dx.doi.org/10.1021/cg400322t | Cryst. Growth Des. 2013, 13, 2208−2219

monoclinic P21/c

90 2177.7(3)

510.46

triclinic

P1̅

9.645(3)

10.609(3)

10.925(3)

87.125(5)

75.546(4)

87.003(4)

1080.2(5)

1.569

formula weight

crystal system

space group

a (Å)

b (Å)

c (Å)

α (°)

β (°)

γ (°)

volume (Å3)

Dcalcd (g cm−3)

TMZ−NCT

2209

2875

0.0511

0.1412

1.04

298(2)

observed reflections

R1 [I > 2 σ(I)]

wR2 (all)

goodnessof-fit

T (K)

−13 to +13

range l

4197

−32 to +32

−13 to +13

range k

unique reflections

−8 to +8

−11 to +11

range h

10890

−15 to +14

2

Z

reflections collected

4

2.18 to 26.01

θ range

298(2)

1.03

0.1442

0.0527

2689

4298

15373

2.31 to 24.29

0.121

μ (mm−1) 0.120

1.557

92.190(2)

90

26.504(2)

6.6310(6)

12.4071(11)

510.46

2(C6H6N6O2)·(C6H6N2O)

TMZ−INA

2(C6H6N6O2)·(C6H6N2O)

molecule

empirical formula

Table 1. Crystallographic Parameters of TMZ Cocrystals TMZ−PYZ

TMZ−OHB form I

298(2)

1.03

0.1378

0.0532

1655

2632

7002

−12 to +12

−11 to +11

−10 to +10

2

2.68 to 25.19

0.122

1.576

668.77(15)

63.129(2)

89.951(2)

68.398(2)

10.3924(14)

9.2537(12)

298(2)

1.02

0.1276

0.0457

3259

4393

11757

−14 to +14

−13 to +13

−12 to +12

2

2.20 to 26.0

0.121

1.547

1127.8(5)

101.835(4)

101.419(4)

107.047(4)

11.809(3)

10.797(3)

9.834(3)

P1̅

P1̅ 8.5570(11)

triclinic

525.47

2(C6H6N6O2)·(C7H7NO2)

triclinic

317.29

(C6H6N6O2)·(C5H5N3O)

TMZ−OHB form II

298(2)

1.01

0.2459

0.0854

2236

3839

6909

−16 to +16

−14 to +14

−8 to +8

2

3.00 to 26.31

0.120

1.545

1129.4(4)

100.942(17)

92.948(16)

106.389(13)

14.141(2)

12.3493(19)

6.9091(17)

P1̅

triclinic

525.47

2(C6H6N6O2)·(C7H7NO2)

TMZ−SAC

298(2)

1.01

0.1205

0.0467

1471

2086

5706

−14 to +14

−9 to +9

−7 to +7

1

2.50 to 25.52

0.210

1.601

592.8(5)

87.095(7)

75.856(7)

76.591(7)

11.952(5)

8.064(4)

6.521(3)

P1̅

triclinic

571.52

2(C6H6N6O2)·(C7HNO3S)

TMZ−CAF

298(2)

0.90

0.1633

0.0573

1473

2865

4962

−14 to +14

−10 to +10

−10 to +10

2

2.65 to 29.13

0.118

1.527

844.5(5)

64.52(3)

87.42(2)

73.87(3)

12.231(4)

9.187(3)

8.698(3)

P1̅

triclinic

388.37

(C6H6N6O2)·(C8H9N4O2)

Crystal Growth & Design Article


Crystal Growth & Design

Article

Table 2. Hydrogen Bond Geometrical Parameters of Crystal Structures (O−H, N−H, and C−H Distances Are Neutron Normalized) compound TMZ−INA

TMZ−NCT

TMZ−PYZ

TMZ−OHB form I

TMZ−OHB form II

TMZ−SAC

interaction

H···A/ Å

D···A/ Å

∠D−H···A/ °

symmetry

N1−H1A···O5 N1−H1B···N6 N7−H7A···O3 N7−H7B···N8 N7−H7B···N6 N13−H13A···O1 N13−H13B···O1 C6−H6B···O3 C9−H9···O5 C12−H12B···N11 C15−H15···N2 C18−H18···O4 N1−H1A···O5 N1−H1B···N6 N7−H7A···O3 N7−H7B···N8 N7−H7B···N5 N7−H7B···N6 N13−H13A···O1 N13−H13B···O1 C4−H4···N11 C6−H6A···O3 C10−H10···O5 C17−H17···N2 N1−H1A···N9 N1−H1B···N2 N1−H1B···O3 N7−H7A···N2 N7−H7B···O2 N7−H7B···N8 C4−H4···O2 C9−H9···O3 C10−H10···O1 C11−H11···N6 N1−H1A···O5 N1−H1B···N2 N1−H1B···O3 N7−H7A···N2 N7−H7B···N8 N13−H13A···O6 N13−H13B···N11 O5−H5A···O1 C4−H4···O2 C10−H10···O4 C12−H12B···O6 C18−H18···O1 N1−H1A···O3 N1−H1A···N10 N1−H1B···N4 O5−H5···O1 N7−H7A···O6 N7−H7B···N8 N13−H13A···O3 N13−H13B···N5 C4−H4···N8 C14−H14···O1 N1−H1A···O1 N1−H1B···N6 N1−H1B···O4 N7−H7···O1

1.88 2.29 1.86 2.29 2.47 2.21 2.08 2.29 2.15 2.41 2.34 2.15 1.83 2.30 1.91 2.38 2.47 2.35 2.00 2.05 2.40 2.35 2.15 2.41 2.08 2.38 2.26 2.01 2.52 2.23 2.28 2.26 2.19 2.46 2.07 2.41 2.36 2.05 2.25 1.84 2.21 1.73 2.28 2.17 2.38 2.27 2.50 2.03 2.29 1.76 1.89 2.42 1.97 2.58 2.20 2.33 1.89 2.27 2.47 1.80

2.886(3) 3.018(3) 2.870(3) 2.764(3) 3.338(3) 3.199(3) 2.861(3) 3.368(3) 3.220(3) 3.463(4) 3.289(3) 3.079(3) 2.834(3) 3.027(3) 2.916(3) 2.798(3) 2.970(3) 3.193(3) 2.988(3) 3.003(3) 3.400(3) 3.402(3) 3.194(3) 3.387(3) 3.020(4) 2.785(4) 3.127(3) 3.006(4) 3.179(3) 2.674(4) 3.290(3) 3.292(3) 3.269(4) 3.376(4) 3.068(2) 2.828(3) 3.249(3) 3.057(3) 2.749(3) 2.849(3) 2.998(3) 2.705(2) 3.300(3) 3.244(3) 3.449(3) 3.074(3) 2.862(5) 3.037(6) 3.056(6) 2.736(5) 2.894(5) 2.810(6) 2.945(5) 3.318(6) 3.144(6) 3.120(5) 2.896(4) 3.030(3) 3.287(4) 2.707(6)

171 128 174 107 143 167 132 172 171 165 145 143 172 128 173 104 110 140 167 157 153 163 161 150 154 103 143 169 122 105 154 158 178 141 171 104 146 173 109 176 133 173 156 169 170 129 101 173 132 170 176 102 162 130 145 129 172 131 138 148

x, y, −1 + z intramolecular 1 − x, −y, −z intramolecular −x, 1 − y, −z x, y, 1 + z 1 − x, 1 − y, 1 − z −1 + x, 1 + y, z −x, 1 − y, 1 − z 1 − x, 1 − y, 1 − z 1 − x, 1 − y, 1 − z −x, 1 − y, 1 − z 1 − x, 1/2 + y, 1/2 − z intramolecular −x, 3 − y, −z intramolecular x, 3/2 − y, −1/2 + z x, 3/2 − y, −1/2 + z 1 − x, −1/2 + y, 1/2 − z x, y, z x, −1 + y, z −x, −3/2 + y, 1/2 − z 1 − x, 1 − y, −z x, 1 + y, z 1 + x, −1 + y, z intramolecular 2 − x, −y, −z 2 − x, −y, −z x, −1 + y, z intramolecular 2 − x, 1 − y, −z 1 − x, 1 − y, −z 1 − x, −y, 1 − z 1 − x, −y, 1 − z −x, 1 − y, 1 − z intramolecular −x, 1 − y, 1 − z −x, 1 − y, 1 − z intramolecular 1 − x, 1 − y, −z x, y, z x, 1 + y, z −x, 1 − y, −z 1 − x, −y, 1 − z 1 − x, 1 − y, −z x, 1 + y, z x, 1 + y, 1 + z x, 1 + y, 1 + z intramolecular 1 − x, 1 − y, 2 − z 1 − x, −y, −z intramolecular 1 − x, −y, −z 1 − x, 1 − y, 2 − z −1 + x, y, 1 + z 1 − x, 1 − y, 2 − z 3 − x, 1 − y, 1 − z intramolecular 1 − x, 1 − y, 1 − z −1 + x, y, z

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Table 2. continued compound

TMZ−CAF

interaction N7−H7···N2 C4−H4···O2 N1−H1A···N2 N1−H1B···O1 C3−H3···O2 C14−H14···O1 C6−H6B···N9 C9−H9B···O3

H···A/ Å

D···A/ Å

∠D−H···A/ °

2.45 2.24 2.39 1.88 2.22 2.38 2.51 2.30

3.208(6) 3.299(3) 2.771(5) 2.889(5) 3.152(5) 3.196(5) 3.483(5) 2.737(6)

131 166 101 179 142 131 146 102

symmetry −1 + x, y, z 1 − x, −y, 1 − z intramolecular 1 − x, 1 − y, −z 2 − x, 2 − y, −z 1 + x, y, z 2 − x, −y, −z intramolecular

Figure 1. (a) The cluster of four molecules as encircled is planar in TMZ−isonicotinamide cocrystal (b) The layered motif in the cocrystal structure.

dropwise addition of acetonitrile in solvent-assisted grinding experiments.9a,10

hydrolyzes to MTIC at pH > 7. In contrast, MTIC is stable at alkaline pH but rapidly breaks down to AIC at pH < 7.7 TMZ has in vitro half-life of 1.9 h in phosphate buffer at 37 °C and pH 7.5 (physiological pH 7.4), whereas MTIC has a half-life of ∼2 min. In time-dependent experiments, TMZ starts to decompose in 5 min at neutral and alkaline pH solutions, whereas 90% of TMZ was intact in acidic medium for 60 min.7b TMZ is stable in acidified human plasma (pH < 4) for at least 24 h at 25 °C and for at least 30 days at −20 °C. Ten polymorphs of TMZ were disclosed in a US patent (2005) based on their distinctive powder X-ray diffraction line patterns.8a Nangia et al.8b reported X-ray crystal structures of three crystalline polymorphs (with 3D coordinates determined) which were analyzed to contain one or both of temozolomide conformers A and B. An intramolecular hydrogen bond of the amide NH to the imidazole N in a five-member ring defines conformer A, whereas flipping of the amide group to bond with the tetrazinone ring N in a six-member ring motif gives conformer B (see Scheme 1). We recently showed that cocrystals of TMZ with pharmaceutically acceptable carboxylic acids9a exhibited superior stability compared to the pure drug. TMZ− succinic acid and TMZ−oxalic acid were found to be the best cocrystals in a stability study to solve the discoloration (decomposition) problem of temozolomide due to hydrolysis during long-term storage. The crystal structure of temozolomide hydrochloride dihydrate is the first crystallographic evidence of a protonated form of TMZ.9b This report complements the above publications with amide coformers selected from the GRAS list,2 e.g., isonicotinamide, nicotinamide, pyrazinamide, 4-hydroxybenzamide, saccharin, and caffeine (Scheme 2). TMZ cocrystals with these amide partners were prepared by the

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RESULTS AND DISCUSSION Temozolomide was cocrystallized with isonicotinamide (INA), nicotinamide (NCT), pyrazinamide (PYZ), 4-hydroxybenzamide (OHB), caffeine (CAF), and saccharin (SAC). Polymorphs of TMZ−OHB cocrystal were obtained by crystallization from acetone (form I) and CH3CN (form II). All the new cocrystal structures were confirmed by single crystal X-ray diffraction. Out of six cocrystals, TMZ−PYZ and TMZ−CAF are of 1:1 stoichiometry, and TMZ−INA, TMZ−NCT, TMZ− OHB, and TMZ−SAC are 2:1 cocrystals. Crystallographic parameters are summarized in Table 1. TMZ−INA (2:1) Cocrystal, 1. It crystallized in the triclinic space group P1̅ with two molecules of TMZ (conformer A and conformer B) and one molecule of isonicotinamide in the asymmetric unit. The crystal structure contains two distinct amide dimer synthons,11 a centrosymmetric homo amide dimer formed between inversion-related TMZ conformer A molecules (N7−H7A···O3: 1.86, 174°) and an amide heterodimer between conformer B and isonicotinamide (N1−H1A···O5: 1.88 Å, 171°; N13−H13A···O1: 2.21 Å, 167°). Hydrogen bond distances (normalized to the neutron D−H value) are summarized in Table 2. These amide heterodimer motifs are connected to their inversion related partners by N13−H13B···O1 hydrogen bond (2.08 Å, 132°) and C15−H15···N2 (2.34 Å, 145°). The distance between two such heterodimers is 5.1 Å (Figure 1a), the characteristic repeat distance in primary amides. N7− H7B···N6 (2.47 Å, 143°), C9−H9···O5 (2.15 Å, 171°), C6− H6B···O3 (2.29 Å, 172°), C18−H18···O4 (2.15 Å, 143°), and C12−H12B···N11 dimer (2.41 Å, 165°) hydrogen bonds connect 2211



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of a (2:1) cocrystal were obtained from acetone and CH3CN solvent in separate experiments. Form I (crystallized from acetone) was solved in the triclinic space group P1̅ with two molecules of TMZ in the asymmetric unit (both are conformer ) and one 4-hydroxybenzamide. TMZ molecule A forms a centrosymmetric amide dimer interrupted by the hydroxyl group (N1− H1A···O5: 2.07 Å, 171°; O5−H5A···O1: 1.73 Å, 173°). Such dimers extend as a tape via a C4−H4···O2 dimer (2.28 Å, 156°, Figure 4a). The amide group of 4-hydroxybenzamide forms a

these hetero- and homodimer molecules in a layered structure (Figure 1b). TMZ−NCT (2:1) Cocrystal, 2. It crystallized in the monoclinic space group P21/c with two molecules of TMZ (conformer A and B) and one molecule of nicotinamide in the asymmetric unit. Although the cocrystal stoichiometry is same in 1 and 2, the crystal packing is entirely different. Isonicotinamide structure is layered, whereas nicotinamide is helical.12 Like cocrystal 1, here also two types of amide dimers are present in the structure. A centrosymmetric amide homodimer is formed between two TMZ conformer A molecules (N7−H7A···O3: 1.91 Å, 173°) and an amide heterodimer between conformer B and nicotinamide (N1−H1A···O5: 1.83 Å, 172°; N13−H13A···O1: 2.00 Å, 167°). Comparison of these two crystal structures shows that the heterodimer is connected to its inversion-related partner of four molecules by hydrogen bonds (N13−H13A···O1: 2.00 Å, 167°; N13−H13B···O1: 2.05 Å, 157°) in a helical array in nicotinamide cocrystal 2 (Figure 2).

Figure 4. (a) Centrosymmetric amide dimer interrupted by hydroxyl group of OHB in form I. (b) Layered structure of TMZ−OHB cocrystal form I contains a square network of molecules. Both TMZ have the A conformation.

centrosymmetric dimer (N13−H13A···O6: 1.84 Å, 176°) between inversion-related molecules and connects to the next layer of tapes leading to the formation of a square network (Figure 4b). The cavities in the square networks are occupied by the second symmetry-independent TMZ molecule B, which is connected to A molecule via the amide−imidazole synthon (N7−H7A···N2: 2.05 Å, 173°; N1−H1B···O3: 2.36 Å, 146°). Polymorph II of TMZ−OHB was obtained by crystallization from CH3CN. The structure was solved and refined in P1̅ space group with two TMZ (conformer A and B) and one 4-hydroxybenzamide in the asymmetric unit. TMZ conformer A forms amide heterodimer with p-hydroxybenzamide (N13− H13A···O3: 1.97 Å, 162°; N7−H7A···O6: 1.89 Å, 176°). The A and B molecules interact with each other through N−H···N (N1−H1A···N10: 2.03 Å, 173°) hydrogen bond. The anti N−H of 4-hydroxybenzamide forms hydrogen bond with conformer B through N−H···N hydrogen bond (N13−H13B···N5: 2.58 Å, 130°). A hydrogen-bonded trimer motif of two TMZ and one OHB molecules are connected to another motif through O−H···O hydrogen bond (O5−H5···O1: 1.76 Å, 170°) forming 1D motif (Figure 5a). These 1D chains are extended

Figure 2. (a) Amide−amide heterosynthon in TMZ−NCT cocrystal. (b) The arrangement of molecules is helical in cocrystal 2.

TMZ−PYZ (1:1) Cocrystal, 3. It crystallized in the triclinic space group P1̅ with one molecule each of TMZ (conformer A) and pyrazinamide in the asymmetric unit. Surprisingly, the stronger amide dimer synthon is not present in this crystal structure. Instead, the weaker amide−pyrazine hydrogen bond between the syn-NH of TMZ and pyrazine N atom (N1− H1A···N9: 2.08 Å, 154°) is present. Pyrazinamide donates its syn-NH to imidazole N and accepts a hydrogen bond from antiNH of TMZ and forms another weak amide−imidazole motif (N7−H7A···N2: 2.01 Å, 169°; N1−H1B···O3: 2.26 Å, 143°). Inversion-related molecules are connected by auxiliary C9− H9···O3 (2.26 Å, 158°) and C10−H10···O1 (2.19 Å, 178°) interactions (Figure 3a). These hydrogen bond motifs repeat in

Figure 3. (a) The TMZ amide−pyrazine and PYZ amide−imidazole hydrogen bond synthons. (b) Extended layer structure in TMZ−PYZ cocrystal.

Figure 5. (a) Carboxamide heterodimer between TMZ (conformer A) and p-hydroxybenzamide. Both conformer A and B of TMZ are present in this structure. (b) 2D layered structure of form II.

the layered crystal structure (Figure 3b). This example adds to the category of drug−drug cocrystals,13 pyrazinamide being an antituberculosis drug. TMZ−OHB (2:1) Cocrystal Polymorphs, 4. During cocrystallization of TMZ with 4-hydroxybenzamide, polymorphs

to the next layer through C4−H8···N8 auxiliary hydrogen bond (2.20 Å, 145°) forming 2D layer motif (Figure 5b). The difference between the two cocrystal polymorphs is hydrogen 2212



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bond synthons: Form I has hydroxyl interrupted amide homodimer synthon of TMZ, whereas form II contains amide heterodimer of TMZ and OHB (see Figures 4a and 5a). Examples of synthon polymorphs of cocrystals are less common in the literature.14 The calculated X-ray diffraction patterns of the two polymorphs exhibit considerable differences in the line pattern between 5−20° 2θ region (Figure S1, Supporting Information). The crystal structures have a similar calculated density (1.547 vs 1.545 g cm−3) and packing fraction (71.5% vs 71.3%). Because form I was difficult to reproduce for further experiments (except the single crystal data), a conclusion about the stability relationship of polymorphs is postponed. TMZ−SAC (2:1) Cocrystal, 5. Slow evaporation of TMZ and SAC in methanol gave two types of crystals. The needle to blocklike crystals matched with TMZ polymorph II,8b and the diamondoid morphology turned out to be a cocrystal of TMZ and saccharin. It crystallized in the triclinic space group P1̅ with TMZ conformer B. The saccharin molecule resides on the inversion center in a disordered orientation with 50% site occupancy (Figure 6a). TMZ molecules form a one-dimen-

Figure 7. (a) TMZ molecules form centrosymmetric carboxamide dimer and extend in a 1D chain through N−H···O and C−H···O interactions. Caffeine molecules interact with TMZ through auxiliary C−H···O and C−H···N interactions. (b) π-stacking along the c-axis at a distance of 3.37 Å between adjacent TMZ molecules and at 3.38 Å between TMZ and caffeine molecules.

Scheme 3. Three Different Hydrogen Bond Synthons Observed in Crystal Structures 1−6

bond synthons in TMZ−amide structures (Scheme 3) are summarized in Table 3. The predominant synthon for the Table 3. Synthon and Conformer in TMZ Cocrystals 1−6 S. no

Figure 6. (a) ORTEP diagram of TMZ−SAC cocrystal (2:1). Saccharin molecule is disordered over two sites with 50% occupancy of atoms. (b) A layer structure of saccharin connecting TMZ tapes. Only one orientation of the disordered SAC molecules is shown.

stoichiometry predominant synthon conformer

TMZ−INA TMZ−NCT TMZ−PYZ

2:1 2:1 1:1

4

TMZ−OHB form I TMZ−OHB form II TMZ−SAC TMZ−CAF

2:1 2:1 1:0.5 1:1

5 6

sional tape via centrosymmetric amide dimer (N1−H1A···O1: 1.89 Å, 172°) and a C4−H4···O2 dimer (2.24 Å, 166°). Such parallel 1D tapes are connected by the disordered saccharin via N7−H7···O1 hydrogen bond (1.80 Å, 148°; C4−H4···O1: 2.24 Å, 166°). It is easy to see from Figure 6b that the disorder of saccharin molecules is due to an interchange of the N−H···O with a C−H···O hydrogen bond of saccharin to the TMZ zigzag tapes. TMZ−CAF (1:1) Cocrystal, 6. TMZ−caffeine was crystallized from acetonitrile solvent and solved in the triclinic space group P1̅ with one TMZ (conformer A) and one caffeine molecule. Two TMZ molecules form centrosymmetric amide dimer (N1−H1B···O1: 1.88 Å, 179°) and C3−H3···O2 hydrogen bond (2.22 Å, 142°) assemble the 1D chain motif. There is no strong hydrogen bond between the API and caffeine coformer. TMZ and caffeine interact through auxiliary C−H···O and C−H···N interactions (Figure 7a) and connect to the next layer through π-stacking (Figure 7b). This is yet another example of a drug−drug cocrystal,13 caffeine being a CNS stimulant. TMZ−amide cocrystals were not stable enough (compared to cocrystals with carboxylic acids based on visual color change to pink brown tan)9a to store at ambient conditions for more than a month, but were in general more stable than pure TMZ. Because of the conformational flexibility of temozolomide (A and B conformers) one or more of the drug molecules cocrystallized with a GRAS amide in the solid-state. The hydrogen

crystal structure

1 2 3

amide−amide (I) amide−amide (I) amide−pyrazine (II) amide−imadazole (III) amide−amide (I) amide−amide (I) amide−amide (I) amide−amide (I)

A+B A+B A A A+B B A

amide functional group, in the absence of any other interfering functional moieties, is undoubtedly the dimer synthon (84%) followed by the catemer or infinite chain motif of N−H···O hydrogen bonds (14%).15 However, when other hydrogen bond acceptors are present (such as OH, pyridine N, etc.), there is a possibility of other motifs. The competition between the stronger and weaker synthons could be evaluated in the multifunctional milieu of carboxamide, imidazole, tetrazine, pyridine, and pyrazine groups. The amide dimer synthon is present in all the cocrystals, except TMZ−pyrazinamide wherein amide−pyrazine and amide−imidazole motifs are present (Scheme 3). The crystal structures of 1−6 suggest that when different stoichiometries between the API and the coformer are present, there is a tendency of TMZ to adopt conformer B, which is present in cocrystals 1, 2, 4 (form II), and 5, whereas the same stoichiometry cocrystals 3, 4 (form I), and 6 have the lower energy conformer A of TMZ. Though cocrystals 1 and 2 have the same stoichiometry (2:1) and contain both conformers A and B, their crystal packing is totally different. TMZ−isonicotinamide 1 contains a layered structure, whereas TMZ−nicotinamide 2 is helical. In TMZ−4-hydroxybenzamide cocrystal form I, the hydroxyl group interrupts the amide dimer synthon, whereas form II with amide heterodimer is an example of synthon polymorphism.8a,14 Overall the synthons are weaker 2213



Article

Table 4. Summary of Hydrogen Bond Motif and Temozolomide Conformation in Crystal Structures S. no.

crystal structure

stoichiometry

1

TMZ polymorph 1a

2

2

TMZ polymorph 2a

1

3

TMZ polymorph 3a

2

4

TMZ−H2Oa

1:1

5

TMZ−methanolyzed TMZb

1:1

6

TMZ−4,4′-bipyridine-N,N′-dioxidea

1:0.5

7


2:1

8


1:1

9

TMZ−formic acid−H2Ob

2:1:1

10

TMZ−acetic acidb

1:1

11

TMZ−acetic acid−H2Ob

1:1:1

12

TMZ−oxalic acidb

1:0.5

13

TMZ−succinic acidb

1:0.5

14

TMZ−DL-malic acid

1:0.5

2214

intermolecular hydrogen bond Molecule 1 (imidazole)C−H···N(tetrazine N) imidazole N free amide N−H···O dimer Molecule 2 (imidazole) C−H···N(tetrazine N) imidazole N free amide N−H···O dimer tetrazine N free (methyl)C−H···N(imidazole N) amide N−H···O dimer Molecule 1 (methyl)C−H···N(tetrazine N) imidazole N free amide N−H···O dimer Molecule 2 tetrazine N free (amide anti) N−H···N(imidazole N) amide N−H···O dimer tetrazine N free (water)O−H···N(imidazole N) (amide) N−H···O (tetrazinone CO) tetrazine N free (amide)N−H···N(imidazole N) amide N−H···O catemer (phenyl)C−H···N(tetrazine N) (amide)N−H···N(imidazole N) (Amide) N−H···O (tetrazinone CO) Molecule 1 (phenyl)C−H···N(tetrazine N) imidazole N free (amide) N−H···O (N-oxide) Molecule 2 (phenyl)C−H···N(tetrazine N) imidazole N free (amide) N−H···O (N-oxide) tetrazine N free imidazole N free (amide) N−H···O (N-oxide) Molecule 1 (phenyl)C−H···N(tetrazine N) (methyl) C−H···N(imidazole N) (amide) N−H···O (formate) Molecule 2 tetrazine N free (water)O−H···N(imidazole N) amide N−H···O dimer (phenyl)C−H···N(tetrazine N) imidazole N free (amide) N−H···O (acid) (water)O−H···N(tetrazine N) (amide)N−H···N(imidazole N) (amide) N−H···O (acid) (imidazole)C−H···N(tetrazine N) imidazole N free (amide) N−H···O (acid) (imidazole)C−H···N(tetrazine N) imidazole N free (amide) N−H···O (acid) (imidazole)C−H···N(tetrazine N) imidazole N free

TMZ conformer A+A

A

A+B

A

A

A

A+A

A

A+B

A

A

A

A

A



Article

Table 4. continued S. no.

crystal structure

stoichiometry

15

TMZ−p-aminobenzoic acid−H2Ob

3:1:1

16

TMZ−fumaric acid−H2Ob

1:0.5:1

17

TMZ−salicylic acidb

1:1

18

TMZ−hydrolyzed TMZ−cinnamic acid−H2Ob

3:1:1:1

19

TMZ−D,L-tartaric acidb

1:1

20

TMZ−p-hydroxybenzoic acid−H2Ob

1:1:1

21

TMZ−anthranilic acidb

2:1

22

TMZ−hydrochloride salt−dihydratec

2:2:4

23

TMZ−isonicotinamided

2:1

2215

intermolecular hydrogen bond (amide) N−H···O (acid) Molecule 1 (imidazole)C−H···N(tetrazine N) imidazole N free amide N−H···O dimer Molecule 2 (imidazole)C−H···N(tetrazine N) imidazole N free (amide) N−H···O (acid) Molecule 3 (imidazole)C−H···N(tetrazine N) (methyl) C−H···N(imidazole N) amide N−H···O dimer tetrazine N free (amide)N−H···N(imidazole N) amide N−H···O dimer tetrazine N free (methyl)C−H···N(imidazole N) (amide) N−H···O (acid) Molecule 1 tetrazine N free (methyl)C−H···N(imidazole N) (amide) N−H···O (amide) Molecule 2 (amide)N−H···N(tetrazine N) (amide)N−H···N(imidazole N) (amide) N−H···O (tetrazinone) Molecule 3 tetrazine N free (amide)N−H···N(imidazole N) (amide) N−H···O (amide) (acid)O−H···N(tetrazine N) imidazole N free (amide) N−H···O (acid) tetrazine N free (water) O−H···N(imidazole N) (amide) N−H···O (acid) Molecule 1 (phenyl)C−H···N(tetrazine N) (amide)N−H···N(imidazole N) (amide)N−H···O (tetrazinone) Molecule 2 (amine)N−H···N(tetrazine N) (amide)N−H···N(imidazole N) (amide)N−H···O (tetrazinone) Molecule 1 (water)O−H···N(tetrazine N) imidazole N free (amide)N−H···O (amide) Molecule 2 tetrazine N free (protonated imidazole)N−H···O(water) (amide)N−H···O (amide) Molecule 1 tetrazine N free imidazole N free amide N−H···O dimer Molecule 2 (amide)N−H···N(tetrazine N) (methyl)C−H···N(imidazole N) amide N−H···O dimer

TMZ conformer A+A+A

A

B

A+A+B

A

B

A+A

A+B

A+B



Article

Table 4. continued S. no.

a

crystal structure

stoichiometry

24

TMZ−nicotinamided

2:1

25

TMZ−pyrazinamided

1:1

26

TMZ−4-hydroxybenzamide form Id

2:1

27

TMZ−4-hydroxybenzamide form IId

2:1

28

TMZ−saccharind

1:0.5

29

TMZ−caffeined

1:1

intermolecular hydrogen bond Molecule 1 tetrazine N free (amide)N−H···N(imidazole N) amide N−H···O dimer Molecule 2 (amide)N−H···N(tetrazine N) (methyl)C−H···N(imidazole N) amide N−H···O dimer (phenyl)C−H···N(tetrazine N) (amide)N−H···N(imidazole N) (amide)N−H···N (pyrazine N) Molecule 1 (phenyl)C−H···N(tetrazine N) (amide)N−H···N(imidazole N) hydroxyl interrupted amide dimer Molecule 2 (phenyl)C−H···N(tetrazine N) imidazole N free (amide) N−H···N (imidazole N) Molecule 1 (amide)N−H···N(tetrazine N) (imidazole)C−H···N(imidazole N) amide N−H···O dimer Molecule 2 (amide)N−H···N(tetrazine N) (hydroxl)O−H···N(imidazole N) (amide)N−H···N (tetrazine N) tetrazine N free (amide)N−H···N(imidazole N) amide N−H···O dimer tetrazine N free imidazole N free amide N−H···O dimer

TMZ conformer A+B

A

A+A

A+B

B

A

Ref 8b. bRef 9a. cRef 9b. dThis paper.

balance analysis in crystal structures of conformational polymorphs,16 it is difficult to rationalize why a particular conformer is present in a given crystal structure. Cocrystals with acid and amide coformers contain conformation A and B and also as their mixture, as well as temozolomide polymorph 3. To understand the role of cocrystal stoichiometry on the TMZ conformation, we note that 14 structures contain a single molecule of temozolomide as conformer A, 3 structures contain one temozolomide as conformer B, 5 structures contain more than one temozolomide as conformer A, 7 structures contain conformers A and B, but no structure has multiple occurrence of conformer B. The stoichiometry of the cocrystal is an indicator of more than one TMZ conformation, but whether conformational equilibrium of A and B played in a role in the crystallization of multiple conformers is difficult to say from the crystal structure analysis. The hydrogen bond synthons with the N acceptors on either side of the carboxamide donor group of temozolomide may shed some light on the conformation. When the tetrazine N participates in an intermolecular C−H···N or N−H···N or O− H···N hydrogen bond (motifs A1 to A5, see Figure S2, Supporting Information), the molecule prefers to crystallize as conformer A. The acceptor strength of tetrazine N will be greater in conformation A (since it is not intramolecularly bonded). Conformation A can also occur even when the imidazole N

and of the less common type in form I, which we were unable to reproduce later, compared to form II which is the robust polymorph. The chances of polymorphism are likely to be more especially for crystal structures with unexpected weaker synthons. The cocrystal of pyrazinamide (3) with TMZ is an example of weaker amide−pyrazine and amide−imidazole synthons. Since the expected amide dimer synthon is absent in cocrystal 3, a thorough polymorphic screening is underway to screen for a strongly hydrogen bonded cocrystal similar to TMZ−4-hydroxybenzamide cocrystal. Indeed, such a polymorph screening resulted in two strongly hydrogen bonded cocrystals. We conclude the section on crystal structure analysis with a summary of temozolomide conformation in carboxamide cocrystals (this study), as well as carboxylic acid cocrystals,9a and temozolomide polymorphs.8b Out of 29 structures reported so far from our group, 19 structures have conformer A exclusively, 3 structures have conformer B exclusively, and 7 structures contain both conformers A and B (Table 4) Thus, the stable conformer A was observed 33 times (77%) and conformer B 10 times (23%). The fact that both conformers are present in seven structures means that their conformational energy difference can be overcome by intermolecular hydrogen bonds and crystal packing energies. Yet, beyond this simplistic energy 2216



Article

Figure 8. The exotherm in the DSC thermogram of TMZ cocrystals indicates decomposition of the drug during heating. The melting point of pure TMZ is 210 °C (dec.).

TMZ is the least stable, TMZ−amide cocrystals are slightly more stable among which TMZ−saccharin/caffeine cocrystals are better, and finally TMZ−succcinic/oxalic acid cocrystals are the most stable. Vibrational Spectroscopy. FT-IR spectroscopy18 is a valuable supplementary tool for the identification of new solid forms. TMZ and amide coformers were ground in a definite stoichiometric ratio in a mortar pestle for 15 min after adding a few drops of acetonitrile. New solid forms were confirmed by IR by comparing the spectrum with that of TMZ and the coformer. Temozolomide exhibits both N−H asymmetric and symmetric stretching at 3421.8 and 3388.6 cm−1. There are two carbonyl sites in TMZ, one in amide and second of six member tetrazinone ring which resonate at 1679.2 and 1758.3, 1733.8 cm−1. The C−N stretching frequency of TMZ is at 1354.5 cm−1. A shift in the stretching frequencies of the cocrystal compared to the individual components in the carbonyl and amide functional group regions is confirmatory for cocrystal formation. The coformer exhibited a different amide group vibrational frequency. FT-IR spectral frequencies of TMZ−amide cocrystals 1−6 are summarized in Table 5.

participates in the strong hydrogen bonding (motifs A6 to A10, Figure S2). Conformation B is associated with hydrogen bond motifs B1 to B5, (Figure S2). Thus it appears that certain intermolecular hydrogen bonds and molecular environment around the temozolomide molecules in the crystal structure guides the conformation preference. Powder X-ray Diffraction. Powder X-ray diffraction is a preliminary characterization tool to differentiate a new solid phase from the API and coformer after solvent-assisted grinding of the components.17 The product of temozolomide ground with the amide coformer was characterized by powder X-ray diffraction to confirm a novel solid phase. Except form I of TMZ−4-hydroxybenzamide cocrystal which we are unable to reproduce after the early experiment of single crystal diffraction, all the other cocrystals were matched with the calculated X-ray lines of the crystal structure to confirm the identity of the solid phases (Figure S3, Supporting Information). Thermal Stability of TMZ Cocrystals. Thermal stability and phase transition of drugs are important to study physicochemical and pharmacokinetic properties. The exact melting/decomposition temperature is measured by differential scanning calorimetry (DSC) which is an accurate method to differentiate new solid phases from the starting components. Temozolomide decomposes at 210 °C as indicated by a sharp exotherm.8b Similar to TMZ acid cocrystals and HCl salt,9a,b the amide cocrystals also exhibited decomposition on heating. Apart from TMZ−saccharin cocrystal (Tdec = 224.5 °C), the other cocrystals decomposed prior to the API Tdec (Figure 8). The TMZ−amide cocrystals were found to be stable at ambient conditions for up to 1 month, after which time isonicotinamide, nicotinamide, pyrazinamide, and 4-hydroxybenzamide cocrystals started showing decomposition, indicated by the change to pink color. Comparatively, the saccharin cocrystal was stable for 2 months at ambient conditions because of the acidic nature of the coformer (saccharin pKa 2.3) among the amide partners. TMZ−caffeine was also found to be relatively stable. The cocrystals were stable for 6 months without any degradation in a freezer (−20 °C). The qualitative stability trend is that pure

Table 5. FT-IR Vibrational Frequency of Temozolomide Cocrystals (in cm−1) compound TMZ TMZ−INA TMZ−NCT TMZ−PYZ TMZ−OHB form II TMZ−SAC TMZ−CAF 2217

N−H stretch 3421.8, 3388.6, 3287.0 3427.3, 3346.4, 3284.7 3455.9, 3415.5, 3384.5, 3285.7 3457.3, 3407.6, 3311.6, 3323.0 3462.5, 3376.6, 3278.2, 3206.9 3435.1, 3403.4, 3289.4, 3180.3 3427.3, 3345.8, 3284.7

N−H bend

C−N stretch

1758.3, 1733.8, 1679.2 1744.0, 1702.6, 1679.5, 1655.5 1736.6, 1667.2

1601.5

1354.5

1601.6

1357.5

1588.8

1357.3

1732.2, 1670.4,

1583.6

1356.7

1750.3, 1730.8, 1683.0, 1665.5 1744.2, 1674.1

1590.6

1362.1

1606.6

1364.0

1744.0, 1702.6, 1679.5

1601.6

1357.5

CO stretch



Article

Similarly Raman spectroscopy17b,c is equally informative in new solid form characterization. Whereas IR is an absorption phenomenon, Raman resonance is based on a scattering phenomenon. The more symmetric bonds gives higher Raman intensities, while less symmetric ones exhibit higher IR intensities. FT-Raman vibrational frequency comparison of TMZ−amide cocrystals is listed in Table 6.

other cocrystals were obtained in bulk quantity in CH3CN solvent assisted-grinding of stoichiometric amount (initially 1:1) of TMZ and coformers. Crystallization conditions for representative cocrystals are given in Table S1 (Supporting Information). X-ray Crystallography. A single crystal obtained from the crystallization solvent(s) was mounted on the goniometer of Bruker Smart (Bruker-AXS, Karlsruhe, Germany) or Oxford Gemini (Oxford Diffraction, Yarnton, Oxford, UK) X-ray diffractometer equipped with Mo−Kα radiation (λ = 0.71073 Å) source and reflections were collected at 298(2) K. Data reduction was performed using SAINTPLUS (Bruker) CrysAlisPro 171.33.55 software (OXFORD).19 Crystal structures were solved and refined using SHELXL-97 and Olex2−1.020 with anisotropic displacement parameters for non-H atoms. Hydrogen atoms were experimentally located through the Fourier difference electron density maps in all crystal structures. All O−H and N−H atoms were located in difference Fourier maps and C−H atoms were geometrically fixed using HFIX command in SHELX-TL program of Bruker-AXS.21 The disorder of saccharin molecule in TMZ−SAC structure was fixed by DFIX and ISOR instructions in SHELX-TL refinement. A check of the final cif file with PLATON22 did not show any missed symmetry. Crystallographic parameters are summarized in Table 1. Hydrogen bond distances in Table 2 are neutron-normalized to fix the D−H distance to its accurate neutron value in the X-ray crystal structures (N−H 0.983 Å, C−H 1.083 Å). Crystallographic .cif files (CCDC Nos. 926516−926522) are available at www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting Information. Powder X-ray Diffraction. Bulk samples were analyzed by powder X-ray diffraction on a Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany). Experimental conditions: Cu−Kα radiation (λ = 1.54056 Å); 40 kV; 30 mA; scanning interval 5−50° 2θ at a scan rate of 1° min−1; time per step 0.5 s. The experimental PXRD patterns and calculated X-ray lines from the single crystal structure were compared to confirm the purity of the bulk phase using Powder Cell.23 Thermal Analysis. DSC was performed on a Mettler Toledo DSC 822e module. Samples were placed in crimped but vented aluminum sample pans for DSC. A typical sample size is 4−6 mg and the temperature range was 30−250 °C at 5 K min−1 for DSC. Samples were purged with a stream of dry N2 flowing at 150 mL min−1. Vibrational Spectroscopy. A Thermo-Nicolet 6700 FT-IR spectrometer (Waltham, MA, USA) with a NXR FT-Raman Module (Nd:YAG laser source, 1064 nm wavelength) was used to record IR and Raman spectra. IR spectra were recorded on samples dispersed in KBr pellets. Raman spectra were recorded on samples contained in standard NMR tubes or on compressed samples contained in a goldcoated sample holder.

Table 6. FT-Raman Vibrational Frequencies of Temozolomide Cocrystals (in cm−1) compound

C−H stretch

CO stretch

TMZ

3115.6, 2966.0 1732.5, 1671.9 TMZ−INA 3115.0, 2961.0 1731.8, 1671.6 TMZ−NCT 3117.0, 3067.6, 1740.3, 2962.6 1666.0, TMZ−PYZ 3115.2, 3062.5, 1730.4, 2952.8 1676.8, TMZ−OHB form II 3123.2, 3069.5, 1746.6, 2960.4 1725.5, 1688.3, TMZ−SAC 3123.9, 3088.9, 1738.9, 2951.9 1698.7, 1663.1 TMZ−CAF 3132.3, 3105.7, 1739.7, 3031.5, 2958.5 1696.0, 1655.1

N−H bend 1576.4 1576.4 1578.9 185.8 1595.1

C−O stretch

C−N stretch

1224.2 1340.9, 1355.7 1224.1 1340.6, 1355.5 1216.8 1361.1 1225.7 1346.1, 1355.5 1226.8 1359.7, 1348.5

1591.1

1225.8 1361.9

1598.7, 1573.2

1229.3 1357.4, 1343.9

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CONCLUSIONS Chemical stability is of special concern for the antitumor prodrug temozolomide. It undergoes degradation to the inactive AIC species by hydrolysis upon prolonged storage. This problem will be more acute in the hot and humid tropical Zone IV of the ICH classification for drug stability, i.e., Asian and Latin American countries and tropical coastal regions. A crystal engineering approach was utilized to design stable cocrystals of temozolomide with carboxamide partner molecules from the GRAS list of safe chemicals. The occurrence of stronger amide dimer synthon was observed in five out of six cocrystals. Weaker hydrogen bond motifs such as amide− pyarazine and amide−imidazole were observed in competition for two cases. The metastable conformer B of TMZ is present in cocrystals 1, 2, 4 (form II), and 5 whereas stable conformer A is present in all structures except TMZ−SAC cocrystal 5 which contains conformer B exclusively. A statistical analysis of about 30 crystal structures suggests a correlation between the hydrogen bonding motifs and the conformation preference of the amide group in Temozolomide. The amide cocrystals of TMZ complement the carboxylic acid cocrystals and HCl salt in the search for a hydrolytically stable temozolomide solid form.

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information (.cif files); crystallization conditions (Table S1), calculated X-ray lines comparison of TMZ− OHB cocrystal polymorphs (Figure S1), hydrogen bond synthons and conformations in crystal structures (Figure S2), and experimental PXRD plots (Figure S3). This material is available free of charge via the Internet at http://pubs.acs.org.

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EXPERIMENTAL SECTION

AUTHOR INFORMATION

Corresponding Author

Temozolomide was purchased from Giovell Healthcare (New Delhi, India) and used directly for experiments. All other chemicals were of analytical or chromatographic grade. Melting points were measured on a Fisher-Johns melting point apparatus. Cocrystallization. Temozolomide and the appropriate amide coformer were taken in a definite stoichiometric ratio and ground in a mortar and pestle for 15 min with a few drops of acetonitrile added. The product was characterized by FT-IR and FT-Raman spectroscopy, as well as powder X-ray diffraction, and then crystallized from methanol, acetone, or acetonitrile. Except form I of TMZ−OHB, all

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS P.S. and N.J.B. thank the UGC for fellowship. We thank the Department of Science and Technology (J.C. Bose fellowship SR/S2/JCB-06/2009) and Council of Scientific and Industrial 2218



Article

Mukherjee, A.; Desiraju, G. R. CrystEngComm 2011, 13, 4358. (d) Lemerrer, A.; Bernstein, J.; Griesser, U. J.; Kahlenberg, V.; Többens, D. M.; Lapidus, S. H.; Stephens, P. W.; Esterhuysen, C. Chem.Eur. J. 2011, 17, 13445. (14) (a) Sreekanth, B. R.; Vishweshwar, P.; Vyas, K. Chem. Commun. 2007, 2375. (b) Mukherjee, A.; Desiraju, G. R. Chem. Commun. 2011, 47, 4090. (c) Schultheiss, N.; Roe, M.; Boerrigter, S. X. M. CrystEngComm 2011, 13, 611. (d) Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Walsh, R. D. B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909. (e) Porter, W. W., III; Elie, S. C.; Matzger, A. J. Cryst. Growth Des. 2008, 8, 14. (15) McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340. (16) Nangia, A. Acc. Chem. Res. 2008, 41, 595. (17) (a) Karki, S.; Frišcǐ ć, T.; Fábián, L.; Jones, W. CrystEngComm 2010, 12, 4038. (b) Thakuria, R.; Nangia, A. CrystEngComm 2011, 13, 1759. (c) Sanphui, P.; Kumar, S. S.; Nangia, A. Cryst. Growth Des. 2012, 12, 4588. (18) (a) Stuart, B. H. Infrared Spectroscopy: Fundamentals and Applications; John-Wiley: U.K., 2004 (b) McCreery, R. L. Raman Spectroscopy for Chemical Analysis; John-Wiley: U. K., 2000. (c) Smith, E.; Dent, G. Modern Raman Spectroscopy − A Practical Approach; JohnWiley: U.K., 2005. (19) (a) SAINT-Plus, version 6.45; Bruker AXS Inc.: Madison, WI, 2003. (b) CrysAlis CCD and CrysAlis RED, versions 1.171.33.55; Oxford Diffraction Ltd: Yarnton, Oxfordshire, U.K., 2008. (20) (a) SMART (Version 5.625) and SHELX-TL (Version 6.12); Bruker AXS Inc.: Madison, WI, U.S.A., 2000. (b) Sheldrick, G. M. SHELXS-97and SHELXL-97; University of Göttingen: Germany, 1997. (c) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339. (21) SMART, version 5.625 and SHELX-TL, version 6.12; Bruker AXS Inc.: Madison, WI, 2000. (22) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherlands, 2002. Spek, A. L. Single crystal Structure Validation with the Program PLATON. J. Appl. Crystallogr. 2003, 36, 7. (23) Kraus, N.; Nolze, G. Powder Cell, version 2.3, A Program for Structure Visualization, Powder Pattern Calculation and Profile Fitting; Federal Institute for Materials Research and Testing: Berlin, Germany, 2000.

Research (Pharmaceutical Cocrystals project 01/2410)/10/ EMR-II) for funding. DST (IRPHA) and University Grants Commission (UGC-PURSE grant) are thanked for providing instrumentation and infrastructure facilities at University of Hyderabad (UOH). We thank a referee for suggestions to improve the discussion on Temozolomide conformations.

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