Received 4 October 2011
Polymorphic form IV of olanzapine
2-Methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine, C17H20N4S, commonly known as olanzapine, is a psychotropic agent that belongs to the thienobenzodiazepine class of drugs. A new polymorph form IV was obtained upon attempted cocrystallization with nicotinamide in a 1:1 ratio from an ethyl acetate solution. Two butterfly-like molecules form centrosymmetric dimers stabilized by weak C-H interactions between the 4-methylpiperazin-1-yl fragment and the benzene/thiophene aromatic system. Form IV consists of a herringbone arrangement of dimers, whereas the previously reported form II has parallel dimers. Both crystal structures are sustained by an N-HN hydrogen bond.
Olanzapine [systematic name: 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine], (I), is a frontline psychotropic drug marketed by Eli Lilly under the brand name Zyprexa. It is one of the top 20 prescription drugs based on a recent survey (Craig & Stitzel, 1997; Lindsley, 2010), and is a yellow crystalline solid that is practically insoluble in water (43 mg l-1), sparingly soluble in acetonitrile and ethyl acetate, and freely soluble in chloroform. According to the Biopharmaceutics Classification System (BCS), olanzapine belongs to the Class II category, namely a drug with low solubility and high permeability. Six solid-state forms of olanzapine have been characterized (Bunnell et al., 1996, 1998; Hamied et al., 2002; Sundaram et al., 2006; Reguri & Chakka, 2005; Wawrzycka-Gorczyca et al., 2004), together with a few solvates and hydrates (Reutzel-Edens et al., 2003; Almarsson et al., 2007; Hickey & Remenar, 2006; Wawrzycka-Gorczyca et al., 2004, 2007; Capuano et al., 2003; Larsen, 1997; Bunnell et al., 1997; Kotar-Zordan et al., 2005; Dalmases Barjoan et al., 2006, 2007) and salts with carboxylic acids (Keltjens, 2005; Simonic et al., 2006; Kozluk, 2007; Bush, 2008; Mesar et al., 2008; Ravikumar et al., 2005; Sridhar & Ravikumar, 2007; Thakuria & Nangia, 2011). Only one X-ray crystal structure of olanzapine has been reported to date (Reutzel-Edens et al., 2003; Wawrzycka-Gorczyca et al., 2004), the powder X-ray diffraction pattern (PXRD) of which matched that of a polymorph designated form II in US patents (Bunnell et al., 1996, 1998). We now report the X-ray crystal structure of a polymorph of olanzapine, designated form IV (Hamied et al., 2002) by PXRD overlay.
The molecule of (I) has a central seven-membered diazepine ring which is fused with a benzene and a thiophene ring, and substituted with a 4-methylpiperazin-1-yl ring (Fig. 1). The boat conformation of the central 1,5-diazepine ring defines the overall butterfly shape of the molecule, but the 4-methylpiperazin-1-yl ring can have conformational variation (Reutzel-Edens et al., 2003).
Cocrystallization of olanzapine with nicotinamide in a 1:1 ratio from ethyl acetate afforded block-shaped pale-yellow crystals of olanzapine form IV in the space group P21/c. The expected cocrystal with nicotinamide was not obtained. Such observations are not unusual (Day et al., 2006; Li et al., 2011; Sanphui et al., 2011; Vishweshwar et al., 2005). The asymmetric unit of olanzapine form IV contains one molecule of olanzapine, having a single hydrogen-bond donor, N2-H2, and two exposed acceptors, imine atom N1 and piperazine atom N4, which are hydrogen bonded in the crystal structure.
Two butterfly-like molecules form centrosymmetric dimers (Reutzel-Edens et al., 2003; Wawrzycka-Gorczyca et al., 2004) in the crystal structures of both forms IV and II, which are stabilized by weak C-H interactions between the 4-methylpiperazin-1-yl fragment (C14-H14A in form IV) and the benzene/thiophene aromatic system. Theoretical calculations estimated that this C-H binding energy is about 8 kcal mol-1 (1 kcal mol-1 = 4.184 kJ mol-1) (Wawrzycka-Gorczyca et al., 2007). The packing of such dimer motifs in the two structures is completely different: form IV consists of a herringbone arrangement of dimers, whereas the dimers are parallel in form II (Fig. 2).
The intermolecular interaction N2-H2N1i [symmetry code: (i) x, -y + , z + ] (Table 1) links the molecules in form IV into extended chains which can be described by the graph-set notation C(5) (Bernstein et al., 1995), and thereby connects the inversion-related dimers to form columns along the c axis. A similar, slightly shorter, interaction [HN = 2.27 (2) Å] leading to similar chains occurs in the form II structure. The chains in form IV are further enhanced by a very weak intermolecular C-HN interaction between piperazine atom N4 and a methyl H atom, H8B, on the thiophene ring of the molecule two links further on in the chain. This C-HN interaction can be described with a graph-set notation of C(10).
| || Figure 1 |
The molecular structure of olanzapine form IV, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
| || Figure 2 |
(a) The parallel stacking of olanzapine dimers in olanzapine form II. (b) The herringbone arrangement of dimers in form IV.
A solution of olanzapine (60 mg, 0.2 mmol) and nicotinamide (24 mg, 0.2 mmol) in a 1:1 ratio in ethyl acetate (approximately 10 ml) was allowed to evaporate slowly at room temperature for 5-10 d. Complete evaporation of the solvent resulted in a mixture of crytalline nicotinamide and olanzapine. Colourless transparent crystals of nicotinamide were manually separated. Olanzapine form IV, as yellow block-shaped crystals, was selected for X-ray diffraction. Because the polymorph was obtained from a cocrystallization experiment, the phase purity of the bulk sample could not be confirmed by powder diffraction.
The N-bonded atom H2 was located from a difference-electron density map, and its positional and isotropic displacement parameters were refined freely. H atoms attached to C atoms were positioned geometrically and treated as riding on their parent C atoms, with C-H = 0.96 Å and Uiso(H) = 1.5Ueq(C) for methyl, C-H = 0.97 Å and Uiso(H) = 1.2Ueq(C) for methylene, and C-H = 0.93 Å and Uiso(H) = 1.2Ueq(C) for aromatic H atoms.
Data collection: SMART (Bruker, 2002); cell refinement: SMART; data reduction: SAINT (Bruker, 2002); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: PLATON (Spek, 2009).
Supplementary data for this paper are available from the IUCr electronic archives (Reference: EG3078 ). Services for accessing these data are described at the back of the journal.
The authors thank the DST for research funding (grant No. SR/S1/OC-67/2006). RT thanks the UGC for a fellowship. The Bruker SMART APEX CCD X-ray diffractometer was funded by the DST (IRPHA) and UGC is thanked for the UPE programme.
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