title: Anti-solvent co-crystallization of carbamazepine and saccharin.
abstract: 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.
authors.affiliation: Department of Smart Food & Drugs, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea.
authors.forename: In-Chun
authors.initials: IC
authors.lastname: Wang
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Lee
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Sim
authors.forename: Woo-Sik
authors.initials: WS
authors.lastname: Kim
authors.forename: Nan-Hee
authors.initials: NH
authors.lastname: Chun
authors.forename: Guang J
authors.initials: GJ
authors.lastname: Choi
mesh_terms: D002220:Carbamazepine / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D000432:Methanol / Q000737:chemistry; D011208:Powders; D012439:Saccharin / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D011208:Powders; D012997:Solvents; D014867:Water; D002220:Carbamazepine; D012439:Saccharin; D000432:Methanol