Systematic QbD- Driven Preparation and Analysis of Naproxen Pharmaceutical Co-Crystals

Abstract

Introduction: Naproxen is a non-steroidal anti-inflammatory drug (NSAID) widely prescribed for the long-term management of chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis. However, its clinical use is limited by gastrointestinal side effects, including gastric ulceration, and poor aqueous solubility. Naproxen belongs to Biopharmaceutics Classification System (BCS) class II, characterized by high permeability and low solubility, which adversely affects its dissolution and bioavailability.

Objectives: The objective of the present study was to develop pharmaceutical co-crystals of naproxen with cinnamic acid in order to improve its physicochemical properties, particularly solubility, dissolution rate, and potential bioavailability.

Methods: Pharmaceutical co-crystals of naproxen and cinnamic acid were prepared using the solvent drop grinding method. The prepared co-crystals were characterized using Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), and X-ray Diffraction (XRD) to confirm the formation of a novel crystalline phase, as well as to assess purity and homogeneity. Further, tablets containing naproxen–cinnamic acid co-crystals were formulated and evaluated for in vitro dissolution performance.

Results: The naproxen–cinnamic acid co-crystals exhibited a significant enhancement in solubility, showing an 8.61-fold increase compared to the pure drug. Characterization studies confirmed the successful formation of a distinct crystalline structure. The formulated co-crystal tablets demonstrated an improved dissolution rate when compared with a marketed naproxen formulation.

Conclusions: The study demonstrates that co-crystallization of naproxen with cinnamic acid is an effective approach to modify and enhance its physicochemical properties. Naproxen–cinnamic acid co-crystals represent a promising alternative for improving solubility and dissolution behavior, which may lead to enhanced bioavailability and improved therapeutic performance.