Improvement of Physico-mechanical and pharmacokinetic attributes of naproxen by cocrystallization with l-alanine

Abstract

The current research investigates the improvement in key physico-mechanical and pharmacokinetic properties of naproxen by cocrystallizing it with L & β-alanine which were used as coformers. Naproxen belonging to BCS class II, suffers low oral bioavailability due to extremely low solubility. It also manifests poor mechanical properties due to its inability to undergo plastic deformation on applying stress. In this study, naproxen and coformers were ground together in three different ratios (1:1, 1:2 &2:1) by mechanochemical method and characterized by PXRD, DSC, intrinsic dissolution rate and tabletability analysis. Naproxen/l-alanine cocrystal in 1:1 ratio showed improved physicochemical and mechanical properties. Within the whole range of compaction pressure used, the tablet tensile strength of naproxen was low and lamination and sticking occurred in some tablets. On the contrary, cocrystal acquired a desirable tensile strength ~3 MPa making it a suitable candidate for tablet formulation. Cocrystal exhibited 4 and 2 fold higher intrinsic dissolution rate than naproxen in 0.1 M HCl and phosphate buffer pH 7.4. Furthermore cocrystal was easily formulated into tablets by direct compression with adequate hardness and showed better dissolution profiles (~38% and ~85%) in 0.1 M HCl and phosphate buffer pH 7.4 respectively when compared to a commercial formulation, Neoprox® (~25% and ~80%) after 60 min. In a single dose sheep model study cocrystal showed ~1.4 times enhanced total area under the curve and peak concentration. To conclude with, cocrystal of naproxen with l-alanine modified the physico-mechanical and pharmacokinetic profile of pure drug.