Cocrystal Formation in Solution: In Situ Solute Concentration Monitoring of the Two Components and Kinetic Pathways

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Abstract

The purpose of this work was to investigate the kinetic pathways in the phase solubility diagram of a cocrystallization process in solution. A cocrystal model composed of an active pharmaceutical ingredient (carbamazepine, CBZ) and a vitamin (nicotinamide, NCT) was selected. Batch experiments were performed in a stirred vessel. The process monitoring was carried out using in situ ATR−FTIR spectroscopy, which provided estimates of the solute concentrations of both CBZ and NCT at different temperatures. In the working field, it was possible for CBZ/NCT cocrystals and CBZ crystals to develop separately or simultaneously. The concentration profiles plotted in the phase diagram showed the kinetic pathways of the cocrystallization process. Their analysis indicated which solid form was in suspension and what the proportion of each solid phase was. Several experiments were in particular performed in the working domain leading to the invariant composition solution in equilibrium with both CBZ/NCT and CBZ crystals. Temporal information on the kinetic pathways and supersaturation levels is essential for finding the optimal operating conditions of the cocrystallization process.

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