Structural and Thermal Characterization of Zolpidem Hemitartrate Hemihydrate (Form E) and Its Decomposition Products by Laboratory X-Ray Powder Diffraction

The crystal structure of zolpidem hemitartrate hemihydrate (I, Form E) has been solved from high-resolution laboratory powder diffraction data. It crystallizes in the orthorhombic P2(1)2(1)2(1) space group with a = 22.4664(6) angstrom, b = 26.0420(7) angstrom, and c = 7.4391(1) angstrom. Protonation of zolpidem molecules could not be unambiguously determined. Thermal stability of Form E has been investigated by TG-DTA and in situ by temperature resolved X-ray powder diffraction. Water loss occurs between 50 degrees C <= t <= 100 degrees C while structure decomposition commences at approximately 120 degrees C yielding zolpidem tartrate (II) and pure zolpidem base (III) in approximately equimolar amounts. Crystal structures of II and III have been solved simultaneously from a single powder pattern of thermally decomposed I. Zolpidem tartrate crystallizes in the orthorhombic P2(1)2(1)2(1) space group with a = 19.9278(8) angstrom, b = 15.1345(8) angstrom, and c = 7.6246(2) angstrom (at 140 degrees C). Zolpidem base crystallizes in the orthorhombic Pcab space group with a = 9.9296(4) angstrom, b = 18.4412(9) angstrom, and c = 18.6807(9) angstrom (at 140 degrees C). In the reported crystal structures zolpidem molecules form stacks through pi-pi interaction or dipole-dipole interactions while tartrate moieties, if present, form hydrogen bonded chains. Water molecule in I forms a hydrogen bond to the imidazole nitrogen atom of the zolpidem molecule. Free space in the crystal structure of I could allow for the additional water molecules and thus a variable water content. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:871-878, 2010