Isostructural cocrystals of metaxalone with improved dissolution characteristics

Area of Science:

• Pharmaceutical Science
• Materials Science
• Drug Delivery

Background:

• Metaxalone (MET) is a BCS Class II drug with poor aqueous solubility and high permeability, leading to low bioavailability.
• High doses of MET (800 mg) can cause central nervous system adverse effects, necessitating improved therapeutic strategies.
• The aromatic skeleton and cyclic carboxamate moiety of MET contribute to its decreased aqueous solubility.

Purpose of the Study:

• To enhance the aqueous solubility and dissolution rate of metaxalone (MET) through cocrystallization.
• To investigate the formation and characterization of MET cocrystals with nicotinamide (NAM), salicylamide (SAM), and 4-hydroxybenzoic acid (HBA).
• To evaluate the potential of MET cocrystals for improved bioavailability and reduced adverse effects.

Main Methods:

• Cocrystallization of MET with NAM, SAM, and HBA.
• Characterization of cocrystals using Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and single crystal X-ray diffraction.
• Binding energy calculations to assess intermolecular interactions.
• Powder dissolution experiments in pH 6.8 phosphate buffer.

Main Results:

• Cocrystallization yielded multicomponent solids, including 2D isostructural cocrystals with SAM and NAM, and a differently packed cocrystal hydrate with HBA.
• Cocrystals confirmed the preference for an imide⋯imide homosynthon in MET, with drug-drug homodimers dominating over drug-coformer heterodimers.
• Powder dissolution studies showed a 3-9 fold improvement in apparent solubility for the cocrystals compared to native MET.
• The MET-NAM cocrystal exhibited the highest solubility and dissolution rate among the tested binary solid forms.

Conclusions:

• Cocrystallization is an effective strategy to enhance the solubility and dissolution rate of metaxalone (MET).
• The MET-NAM cocrystal demonstrates significant potential for improving MET bioavailability and enabling lower, safer dosages.
• The enhanced solubility is attributed to factors such as the absence of stronger heterosynthons, lower melting points, and high coformer solubility.