Effect of environmental humidity on the transformation pathway of carbamazepine polymorphic modifications during grinding

Abstract

The effect of humidity on the physicochemical stability of carbamazepine (CBZ) polymorphic forms (form I anhydrate and dihydrate) during grinding was investigated by using powder X-ray diffraction, Fourier transform infrared (FT-IR) spectra and differential scanning calorimetry (DSC) methods. The relative humidity (RH) in the centrifugal ball mill equipment was controlled at 17 or 90% during grinding. The powder X-ray diffraction profiles and DSC curves of the anhydrate after grinding for 1–24 h at 17 and 90% RH did not change significantly. In contrast, the X-ray diffraction peaks of the dihydrate decreased rapidly during grinding at 17% RH. The decrease was gradual at 90% RH. The CBZ dihydrate form first transformed into the amorphous state containing 1–1.5 mol water per CBZ before forming the anhydrate during grinding at both humidity levels. The results of FT-IR spectra of ground CBZ suggested the following: (1) the CBZ dihydrate first transformed into amorphous form after dehydration of the first crystal water which interacted with the carboxyl group of CBZ; (2) the amorphous form then transformed into the anhydrate after dehydration of the second water, which interacted with the amino group; (3) the second water was more strongly bound to CBZ in crystal lattice than the first water.