Crystallization Pathways and Kinetics of Carbamazepine–Nicotinamide Cocrystals from the Amorphous State by In Situ Thermomicroscopy, Spectroscopy, and Calorimetry Studies

ABSTRACTThe work presented here was motivated by the premise that the amorphous state serves as a medium to study cocrystal formation. The molecular mobility inherent to amorphous phases can lead to molecular associations between different components such that a single crystalline phase of multiple components or cocrystal is formed. Cocrystallization pathways and kinetics were investigated from amorphous equimolar phases of carbamazepine and nicotinamide using hot-stage polarized microscopy (HSPM), hot-stage Raman microscopy (HSRM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). Nonisothermal studies revealed that amorphous phases generate cocrystals and that thermal history affects crystallization pathways in significant ways. Two different pathways to cocrystal formation from the amorphous phase were identified: (1) at low heating rates (3°C/min) a metastable cocrystalline phase initially nucleates and transforms to the more stable cocrystalline phase of CBZ–NCT, and (2) at higher heating rates (10°C/min) individual components crystallize, then melt and the stable cocrystalline phase nucleates and grows from the melt. Isothermal studies above the Tg of the amorphous equimolar phase also confirm the nucleation of a metastable cocrystalline phase from the amorphous state followed by a solid phase mediated transformation to the stable cocrystalline phase. Cocrystallization kinetics were measured by image analysis and by thermal analysis from small samples and are described by the Avrami–Erofeev model. These findings have important implications for the use of amorphous phases in the discovery of cocrystals and to determine the propensity of cocrystallization from process-induced amorphization. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1147–1158, 2007