Anti-solvent co-crystallization of carbamazepine and saccharin

作者：Wang In Chun; Lee Min Jeong; Sim Sang Jun; Kim Woo Sik; Chun Nan Hee; Choi Guang J^*

来源：International Journal of Pharmaceutics, 2013, 450(1-2): 311-322.

DOI：10.1016/.j.ijpharm.2013.04.012

• Co-crystal
• Carbamazepine Saccharin Anti
• solvent crystallization
• ATR
• FTIR
• Hydrogen bonding

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. %26lt;br%26gt;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. Cocrystallization 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. %26lt;br%26gt;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. %26lt;br%26gt;In conclusion, an anti-solvent approach can be used to produce highly pure CBZ-SAC co-crystal powders with a high solid yield.

• 出版日期2013-6-25