TY - JOUR
T1 - Anti-solvent co-crystallization of carbamazepine and saccharin
AU - Wang, In Chun
AU - Lee, Min Jeong
AU - Sim, Sang Jun
AU - Kim, Woo Sik
AU - Chun, Nan Hee
AU - Choi, Guang J.
N1 - Funding Information:
This work was supported by the Soon Chun Hyang University Research Fund (No. 20120262 ).
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/6/25
Y1 - 2013/6/25
N2 - 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.
AB - 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.
KW - ATR-FTIR
KW - Anti-solvent crystallization
KW - Carbamazepine
KW - Co-crystal
KW - Hydrogen bonding
KW - Saccharin
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U2 - 10.1016/j.ijpharm.2013.04.012
DO - 10.1016/j.ijpharm.2013.04.012
M3 - Article
C2 - 23598078
AN - SCOPUS:84878371711
VL - 450
SP - 311
EP - 322
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
IS - 1-2
ER -