Anti-solvent co-crystallization of carbamazepine and saccharin

The co-crystal approach has been investigated extensively over the past decade as one of the most promising methods to enhance the dissolution properties of insoluble drug substances. Co-crystal powders are typically produced by mechanical grinding (neat or wet) or a solution method (evaporation or cooling). In this study, high-purity carbamazepine-saccharin (CBZ–SAC) co-crystals were manufactured by a novel method, anti-solvent addition.Among various solvents, methanol was found to perform well with water as the anti-solvent for the co-crystallization 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 co-crystals occurred within 2–3 min. Co-crystallization was complete after 30 min, giving a solid yield as high as 84.5% 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 at-line via 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, an anti-solvent approach can be used to produce highly pure CBZ–SAC co-crystal powders with a high solid yield.

Graphical abstractClose-up of CBZ/SAC phase solubility diagram in methanol with experiment points.Figure optionsDownload full-size imageDownload high-quality image (66 K)Download as PowerPoint slide