Mechanistic modeling and characterization of amorphous solid dispersions for nimodipine: preparation methods, physicochemical properties, and in vitro-in vivo exposures

초록

Purpose To overcome the poor aqueous solubility and low oral bioavailability, an amorphous solid dispersion (ASD) system was developed and mechanistically evaluated using various polymeric carriers which stabilized the drug through intermolecular interactions. Methods ASDs of a weakly basic drug, nimodipine were prepared using acidic/non-ionic polymers (HPC, HPMCAS, HPMCP, and PVP K25) via spray-drying and melt-quenching techniques. The solid-state was evaluated using glass transition temperature (T- g) and morphological assessment to optimize the formulation and suppress recrystallization. Predictive miscibility was established using Hansen solubility parameters (delta) and Gordon-Taylor equation. Thermodynamic phase equilibria and molecular interactions were analyzed using the Flory-Huggins parameter () and PC-SAFT modeling. Dissolution kinetics were modeled using the Korsmeyer-Peppas equation. Results Theoretical miscibility was confirmed, as all drug-polymer interactions exhibited Delta(delta) < 7 MPa0.5. Experimental T galigned closely with Gordon-Taylor predictions, and <0.5 indicated strong, favorable micro-level interactions. PC-SAFT-derived ternary phase diagrams demonstrated that ethanol-based processing broadened the thermodynamic stability window compared to aqueous systems. The optimized spray-dried HPMCP formulation exhibited a superior dissolution profile with a dissolution efficiency (DE) of 0.901 at pH 6.0 achieving rapid supersaturation (85.51%) and a saturation solubility of 2.387 mg/mL. In vivo exposure revealed a 33-fold increase in C-max and a 14-fold increase in AUC(0-t) compared to the reference. Conclusion Integrating predictive thermodynamic modeling with experimental validation confirms that spray-dried using HPMCP suppresses recrystallization, resulting in a robust ASD with enhanced bioavailability.

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