Development of the NSAID-L-Proline Amino Acid Zwitterionic Cocrystals

Non-steroidal anti-inflammatory drugs (NSAID) belong to class II of the Biopharmaceutics Classification System (BCS) which exhibit low aqueous solubility. The crystal engineering technique such as cocrystallization is an effective strategy to improve the solubility of drugs. Recently, exploration of the zwitterionic cocrystals involved amino acid, has been started and gained a lot of interest in the pharmaceutically active substance development. Under the guidance of the crystal engineering concept, cocrystal formation of some NSAID was investigated. The drugs are: mefenamic acid, ketoprofen, and diclofenac acid meanwhile L-proline was used as a co-former. Cocrystal screening was conducted by liquid assisted grinding (LAG) with ethanol using the equimolar ratio of drug and L-proline. The dynamic formation of the new phase was monitored by FT-IR of both LAG and neat grinding (NG) crystallization method. Beyond the three of drugs, only diclofenac acid and L-proline interaction showed hydrogen bond that was initially identified by the FT-IR method. This result was supported by the melting point change on the thermogram and the significant differences in diffractogram pattern. Furthermore, the hydrogen bond formation is clearly observed by using the FT-IR method. Next, the formation of the crystalline phase by LAG occurred faster than NG method. Finally, this study found the new phase arrangement between diclofenac acid and L-proline, which strongly indicate a cocrystal. The dynamic of the cocrystal arrangement also was shown influenced by the method, in which LAG was faster than NG method.