Autori: A.Aramini, G.Bianchini, S.Lillini,S.Bordignon, M.Tomassetti, R.Novelli, S.Mattioli, R.Paolesse, M.R. Chierotti, M.Allegretti
Rivista: European Journal of Medicinal Chemistry
Anno di Pubblicazione: 2021
Pagine:    2-18
A salt/co-crystal polymorphism is a rare phenomenon that can occur when a specific pair of molecules is combined with the same stoichiometry. Here, we present a salt/co-crystal polymorphism of the ketoprofen (KET)-lysine (LYS) system obtained as a result of a polymorph screening study of ketoprofen-L-lysine salt (KLS), a widely used non-steroidal anti-inflammatory drug.

Combining conventional techniques with the accuracy of solid-state nuclear magnetic resonance (SSNMR), we were able to deeply characterize the structures of KLS polymorphs, identifying a co-crystal KET-LYS polymorph 1 (P1) and a salt KET-LYS polymorph 2 (P2). Notably, it emerged that co-crystal KET-LYS P1 is representative of commercial KLS, while the salt KET-LYS P2 is a new isoform of KLS. In vivo pharmacokinetic studies revealed that the new isoform KET-LYS P2 has significantly lower AUC and Tmax values compared to commercial KLS (co-crystal KET-LYS P1), implying the intriguing possibility for the development of new, faster release/acting formulations of commercial KLS. In addition, electronic tongue analysis showed that KET-LYS P2 has a more bitter taste and a different sensorial kinetics compared to the co-crystal, suggesting that different coating or flavouring processes should be envisioned based on the new compound’s characteristics.

These results significantly advance our knowledge regarding the solid-state characteristics of KLS as well as the phenomenon of salt/co-crystal polymorphism, describing also a new polymorph of commercial KLS, the further development of which can potentially lead to faster release/acting formulations of KLS for the treatment of acute inflammatory and painful conditions.