Crystal chemistry of sibutramine: Thermal, diffractometric and spectroscopic characterization

Abstract

Monohydrated sibutramine hydrochloride is a widely used active ingredient for the treatment of obesity. An anhydrous form of sibutramine hydrochloride was prepared starting from its monohydrate form upon heating it at 140°C for 15 min. This dehydration process was monitored using conventional TG/DSC methods. Heated above 190°C, sibutramine hydrochloride sublimes and recrystallizes on the cold walls of the test tube, giving platelet shaped crystals suitable for single crystal X-ray diffraction analysis: monoclinic, P21/na = 7.321(2) Å, b = 25.456(5) Å, c = 9.750(3) Å, β = 101.60(2)°, V = 1779.9(8) Å3Z = 4. At variance, sibutramine free base was typically recovered as a viscous oily material, upon treatment of its hydrochloride salt in ethyl acetate solution. Recrystallization from hexane yielded a white polycrystalline powder, the structure of which was determined by unconventional ab initio X-ray powder diffraction analysis: triclinic, P-1, a = 8.6578(3) Å, b = 9.3318(3) Å, c = 11.1224(4) Å, α = 110.434(3)°, β = 100.159(3)°, γ = 89.201(2)°, V = 827.76(5) Å3Z = 2. Sibutramine, in its different crystalline environments, was also fully characterized by solid state 13C NMR analyses. Additional spectral information was obtained by collecting spectra of a metastable, oily sample, before it slowly recrystallizes (within hours). © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5229–5239, 2008