Mechanistic investigation of polymorphic transformation and solubilization in piroxicam multicomponent delivery systems via experimental and multiscale simulation approaches.

The solid-state structure of poorly soluble drugs significantly influences their solubility and oral bioavailability. Here, multicomponent delivery systems of Piroxicam (PRX MC-DSs) have been developed by incorporating PVP, Tween, and Na2CO3. The mechanisms underlying polymorphic transformation and solubilization of PRX MC-DSs are investigated by integrating experiments and multiscale simulations. Experimental analyses reveal that sequential additions of excipients induce PRX from thermodynamically stable Form I to metastable Form II crystal, and ultimately to an amorphous state. These transformations result in significant increases in solubility, bioavailability and anti-inflammatory effect. To mimic experimental desolvation, a solvent evaporation simulation has been developed, in which the computed glass transition temperatures show good agreements with experimental data. Results reveal that ethanol evaporation facilitates PVP chains rearrangement to form drug-loading cavities, Tween and Na2CO3 enhanced uniform molecular dispersion, thereby significantly improving water miscibility. RDF and QTAIM analyses indicate that PVP disruptes PRX lattice via H-bonding, Tween weakens PRX-PRX interactions while strengthens PRX-PVP affinity, and Na2CO3 break intramolecular H-bonds within PRX. These interactions synergistically increased PRX conformational flexibility, inhibited crystallization, and promoted amorphization. This study uncovers the molecular mechanisms of excipient-mediated polymorphic transformation and provides theoretical insights for the rational design of multicomponent solubilization systems.