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

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.

Characterization and Quality Control of Pharmaceutical Cocrystals

“…92) Some approaches have reduced inorganic solvent use during cocrystal production. Specifically, carbon dioxide gas addition effectively induces itraconazolesuccinic acid cocrystal formation and precipitation from aqueous solution (e.g., gas antisolvent (GAS) method).…”

PAT-based design of agrochemical co-crystallization processes: A case-study for the selective crystallization of 1:1 and 3:2 co-crystals of p-toluenesulfonamide/triphenylphosphine oxide

“…However, many of the current methods used to isolate co-crystal forms such as neat and liquid assisted grinding [10], [11], slurry conversion [12], [13], supercritical fluid enhanced atomization [14], and evaporative co-crystallization [13], [15], [16] cannot be scaled to industrial production capacity. Cooling crystallization is perhaps the most viable route to scale-up, yet there are only a few studies that have explored this method to isolate co-crystals [17]- [19]. There are even fewer studies that are carried out using large scale laboratory crystallizers (that is, 500 -1L capacity) [17], [18].…”

“…Cooling crystallization is perhaps the most viable route to scale-up, yet there are only a few studies that have explored this method to isolate co-crystals [17]- [19]. There are even fewer studies that are carried out using large scale laboratory crystallizers (that is, 500 -1L capacity) [17], [18]. In addition, there is limited use of process analytical technologies (PAT) to monitor, control and characterize cocrystallization processes [16], [18].…”

ATR‐FTIR Spectroscopy

“…ATR-FTIR spectroscopy can be used to identify the concentrations of the two co-crystal forming substances independently. In the case of carbamazepine and nicotinamide, it was found that the formation of the co-crystals of carbamazepine/nicotinamide (1 : 1) is in competition with the formation of pure carbamazepine crystals (Gagniere et al, 2009). Since the stoichiometric ratio of the co-crystal is known, the formation of co-crystals should change the concentrations of the two compounds in that ratio.…”