Isostructural cocrystals of metaxalone with improved dissolution characteristics

Muscle relaxant and pain reliever metaxalone (MET) is a biopharmaceutical classification systems (BCS) class II drug with poor aqueous solubility and high permeability. The presence of an aromatic skeleton and cyclic carboxamate moiety are the probable reasons for the decreased aqueous solubility, which impacts on its low bioavailability. A high dose (800 mg) of the drug often creates adverse side effects on the central nervous system that needs urgent remedy. Cocrystallization of MET with nicotinamide (NAM), salicylamide (SAM), and 4-hydroxybenzoic acid (HBA) resulted in multicomponent solids that were characterized by PXRD, DSC and single crystal X-ray diffraction. Cocrystals with SAM and NAM form 2D isostructural cocrystals, whereas with HBA the result is a differently packed cocrystal hydrate (or anisole hemisolvate) depending upon the crystallization medium. Similar to the reported MET cocrystals, these cocrystals also confirm the preference for an imide⋯imide homosynthon in the drug. The dominance of the drug–drug homodimer over drug-coformer heterodimers was demonstrated based on binding energy calculations. Further, powder dissolution experiments in pH 6.8 phosphate buffer indicate that the cocrystals improved the apparent solubility compared to the native drug by 3–9 fold. The absence of stronger heterosynthons between MET and the coformers, their lower melting points and the high solubility of the coformers are the probable reasons for the enhanced solubility of the bioactive component. The MET–NAM cocrystal exhibited the highest solubility/dissolution rate among the three binary solid forms, which may offer improved bioavailability and a lower dose with minimal side effects.

Metaxalone forms isostructural cocrystals with nicotinamide and salicylamide that offer a solubility advantage compared to the native drug. A drug–drug homosynthon is retained in all the cocrystal structures.