(536f) NIR-Based Process Understanding of Anti-Solvent Cocrystallization Between Carbamazepine and Saccharin

Over the last decade, the cocrystal approach has been studied extensively as one of the most promising methods to improve the dissolution properties of insoluble drug substances. Cocrystal powders are typically screened or produced by mechanical grinding (wet or neat) or a solution method (evaporation or cooling). In this work, high-purity carbamazepine-saccharin (CBZ-SAC) cocrystals were produced by a novel method, anti-solvent addition. Among several solvents, methanol was found to perform well with water as the anti-solvent for the cocrystallization of CBZ and SAC. When water was added to the methanol solution of CBZ and SAC at room temperature under agitation, nucleation of CBZ-SAC cocrystals initiated within 2-3 min. Cocrystallization was complete after 30 min, giving a solid yield as high as 85% on a CBZ basis. The effects of initial concentrations, focusing on the SAC/CBZ ratio, were examined to establish optimal conditions.
The whole anti-solvent co-crystallization process was monitored via in-line NIR measurements as well as at-line ATR-FTIR analysis of regularly sampled solutions. The nucleation and crystal growth of CBZ-SAC co crystals were detected by a significant increase in absorption in the range of 2400-2260 cm-1, associated with the formation of hydrogen bonds between the carbonyl group in CBZ and the N-H of SAC. When CBZ hydrates were formed as impurities during anti solvent co-crystallization, the hydrogen bonding between methanol and water was reduced greatly, primarily due to the incorporation of water molecules into the CBZ crystal lattice.
In conclusion, the whole anti-solvent cocrystallization process can be monitored for a comprehensive understanding with highly pure CBZ-SAC cocrystal powders as final products.