A simple quantitative FT-IR approach for the study of a polymorphic transformation under crystallization slurry conditions

The pharmaceutical compound (2R.3S)-2-({(1R)-1 -[3,5-bis(trifluoromethyl)ph enyl]ethyl}oxy)-3-(4-fluorophenyl) morpholine hydrochloride (denoted here a s Compound X), has been found to crystallize in at least two polymorphic fo rms. Using only two frequencies (1009 and 1058 cm(-1)) in the infrared, a l inear (R = 0.998) calibration plot, consisting of the ratio of the: peak ab sorbances plotted against polymorph concentration, was constructed. This pl ot allowed the quantification of binary mixtures of polymorphs ranging from < 3 to similar to 100 wt% Form II in Form I. Spectra were acquired in tran smission mode using mineral oil (Nujol) mull sample preparation, for reason s of compatibility with wet cake and slurry samples. The transformation of the less thermodynamically stable polymorph (Form II) to the more stable fo rm (Form I). in stirred methyl isobutyl ketone (MIBK) slurries, was monitor ed spectroscopically as a function of time. performing the experiment at va rious temperatures allowed the energy of activation for the process to be e stimated (42 kJ/mol). (C) 2001 Elsevier Science B.V. All rights reserved.