The co-crystal approach has the potential to improve key pharmaceutical properties,such as dissolution and stability,especially for poorly soluble drug substances[1].Co-crystal powders are typically produced by mechanical grinding or a solvent evaporation method.[2] In this study,high-purity carbamazepine-saccharin (CBZ-SAC) co-crystals were manufactured by 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 2400–2260cm–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 absorption in the range of 1080–1850cm–1,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.