Simultaneously Improving Mechanical, Formulation, and In Vivo Performance of Naproxen by Co-Crystallization

Abstract

Naproxen (NAP), an anti-inflammatory drug belonging to class II of Biopharmaceutic Classification System, has low aqueous solubility and dissolution rate which limit its oral bioavailability. The focus of this investigation was to assess the impact of co-crystallization in improving the physico-mechanical and in vivo performance of NAP. NAP was co-crystallized using nicotinamide as a co-former employing liquid-assisted grinding method and characterized by intrinsic dissolution rate, DSC, and PXRD. Prepared co-crystal exhibited improved physicochemical and mechanical properties. Mechanical behavior of NAP and developed co-crystal was analyzed by drawing tabletability curves. Over the entire range of used compaction pressure, NAP showed poor tensile strength (< 2MPa) which resulted in lamination and capping in some tablets. In contrast, tensile strength of co-crystal gradually increased with pressure and was ~ 1.80 times that of NAP at 5000psi. Intrinsic dissolution profile of co-crystal showed a more than five and twofold faster dissolution than NAP in 0.1M HCl and phosphate buffer pH 7.4 at 37°C. In addition, formulation of co-crystal powder into tablets by direct compression demonstrated enhanced dissolution profiles (~ 43% in 0.1M HCl and ~ 92% in phosphate buffer pH 7.4) in comparison to a marketed product, Neoprox (~ 25 and ~ 80%) after 60min. In a single dose oral exposure study conducted in sheep, co-crystal showed more than 1.5-fold increase in AUC and Cmax. In conclusion, co-crystals of NAP illustrated better tabletability, in vitro and in vivo performance.