Enabling Direct Compression of Paracetamol–Amantadine Hydrochloride Drug Combination via Cocrystal Engineering

Abstract

A drug–drug cocrystal (DDC) is a promising solid-state delivery system for combination therapy. Beyond the pharmacological synergy or complementarity between constituent components, DDCs are expected to offer improved physicochemical or pharmacokinetic properties. The two active pharmaceutical ingredients (APIs) selected in this study are the main components of the compound paracetamol (PAR) and amantadine hydrochloride (AH) tablets, a widely used over-the-counter (OTC) cold medication in China. Guided by the O─H···Cl supramolecular synthon, the PAR-AH DDC was successfully prepared via water-assisted grinding. Structural analysis reveals that PAR-AH DDC has a molar ratio of 1:1:0.75 for PAR, AH, and water molecules, respectively. The lattice water plays a pivotal role in maintaining the cocrystal structure. Both PAR and AH exhibit poor/unsatisfactory tabletability. Unexpectedly, the PAR-AH DDC demonstrates excellent tableting performance, which is reasonably supported by the theoretical elastic modulus calculations. The superior tabletability of the cocrystal enables direct tablet compression without polymeric excipients, thereby offering reduced tablet size, greater patient convenience, and lower manufacturing costs. The successful preparation of PAR-AH DDC with improved physicochemical property offers a reference for cocrystal engineering in developing delivery systems for fixed-dose combinations and combination therapies.