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

Abstract

The 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 degrees 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 degrees C/min) individual components crystallize, then melt and the stable cocrystalline phase nucleates and grows from the melt. Isothermal studies above the T(g) 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.

Physico-mechanical and Stability Evaluation of Carbamazepine Cocrystal with Nicotinamide

“…A modified melting method was utilized based on previously reported technique (23). Equimolar amounts of CBZ (4.726 g, 0.02 mol) and NCT (2.442 g, 0.02 mol) were melted by heating on a liquid paraffin oil bath at 140°C for 10 min.…”

“…Nicotinamide has been utilized as a coformer for the cocrystallization of celecoxib (15), theophylline (16), ibuprofen (17), CBZ (18,19), and lamotrigine (20). Reported methods of cocrystal preparation are solution cooling crystallization (21), ambient co-milling (18), cryogenic co-grinding (22), melting (23), and solvent evaporation (24).…”

Effect of Adhesive Layer Thickness and Drug Loading on Estradiol Crystallization in a Transdermal Drug Delivery System

“…Also, hydrogen bonding between hydroxyl groups of estradiol and carbonyl groups of the acrylatevinyl acetate copolymer is possible. Hydrogen bonds have been shown to drive molecular associations that lead to crystalline or non-crystalline solids due to their strength and directionality (18). Hydrogen bonding can change the morphology of drug crystals if the degree of polymer adsorption at different crystal sides is different (19).…”

Cocristais: uma estratégia promissora na área farmacêutica

“…5,71 A aplicação de fusão seguida de extrusão parece ser uma alternativa promissora para a formação de cocristais onde a instabilidade química não é um problema. 84 Para confirmação da formação de um cocristal e diferenciação em relação a outros cristais multicomponentes, diversas técnicas de caracterização no estado sólido podem ser empregadas, como difração de raios X (DRX), 85,86 análise térmica (Calorimetria Exploratória Diferencial -DSC e Termogravimetria -TGA), 1,86,87 microscopia, 88,89 espectroscopia vibracional (Raman e Infravermelho), 86,90 espectroscopia do estado sólido (Ressonância magnética nuclear do estado sólido -RMNss) 86,91-93 e análise de sorção de umidade. [94][95][96][97] …”