Unexpected Salt/Cocrystal Polymorphism of the Ketoprofen–Lysine System: Discovery of a New Ketoprofen–l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties

Abstract

Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt/cocrystal polymorphism of the ketoprofen (KET)–lysine (LYS) system, with the cocrystal, KET–LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET–LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a different sensorial kinetics compared to the cocrystal, suggesting that different coating/flavoring processes should be envisioned for the new compound. Thus, the new KLS polymorphic form with its different physicochemical and pharmacokinetic characteristics can open the way to the development of a new KET–LYS polymorph drug that can emphasize the properties of commercial KLS for the treatment of acute inflammatory and painful conditions.

Polymorphs with Remarkably Distinct Physical and/or Chemical Properties

“…Very recently Aramini et al ., [154] synthesized a new polymorphic Form II (P2) of the commercially available non‐steroidal anti‐inflammatory drug, Ketoprofen‐L‐lysine salt (KET‐LYS) (Scheme 11). They performed more than 230 experiments in order to explore possible polymorphisms of the commercially available Ketoprofen salt.…”

Polymorphism and photoluminescence seen in (2-amino-5-chloropyridine)·(9-anthracenecarboxylic acid)·(trinitrobenzene): a further example of the salt-cocrystal continuum observed by virtue of isolating multiple crystal forms

“…A smaller ∆pK a (less than 1) indicates a greater chance of obtaining a cocrystal, whilst a larger ∆pK a (around 2 or 3) leads to a greater chance of obtaining a salt. 21,22 Accordingly, there exists a region of uncertainty around ∆pK a = 1 where the extent of proton transfer is not predictable and the possibility of obtaining a cocrystal or a salt is very similar. 22 Acid-base adduct with similar pK a values will fall into this region.…”

“…21,22 Accordingly, there exists a region of uncertainty around ∆pK a = 1 where the extent of proton transfer is not predictable and the possibility of obtaining a cocrystal or a salt is very similar. 22 Acid-base adduct with similar pK a values will fall into this region. For these adduct, both ∆pK a values and the crystalline environment will determine the extent of proton transfer and hence cocrystal or salt formation.…”

Exploration of the Safety and Solubilization, Dissolution, Analgesic Effects of Common Basic Excipients on the NSAID Drug Ketoprofen

“…Ketoprofen-L-lysine can exist in salt or cocrystal forms, depending on the preparation method. Both forms have enhanced dissolution characteristics, but the bitterness scores for these two forms of ketoprofen-L-lysine were higher than that of the parent drug [ 13 ]. In another study, ketoprofen–tromethamine was prepared by a coprecipitation method, resulting in a new crystalline state with significantly enhanced solubility and dissolution rates [ 14 ].…”