Crystallization pathways and kinetics of Carbamazepine− nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy and calorimetry studies

ABSTRACT: Thework presented herewasmotivated by the premise that the amorphous state serves as amediumto study cocrystal formation.Themolecularmobility inherent to amorphous phases can lead tomolecular associations betweendifferent 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 (38C/min) a metastable cocrystalline phase initially nucleates and transforms to the more stable cocrystalline phase of CBZ–NCT, and (2) at higher heating rates (108C/min) individual components crystallize, then melt and the stable cocrystalline phase nucleates and grows from the melt. Isothermal studies above theTg of the amorphous equimolar phase also confirm th