Mechanistic enhancement of oral bioavailability through a coamorphous apremilast-aceclofenac systems: integrated LC-MS/MS Bioanalysis, in vivo pharmacokinetics, and PBPK modeling.

Poor aqueous solubility and dissolution-limited absorption remain major challenges in the oral delivery of apremilast (APR) and aceclofenac (ACF). In this study, coamorphous systems (CAMS) of APR-ACF were systematically evaluated to enhance biopharmaceutical and pharmacokinetic performance using an integrated experimental-computational approach. Three CAMS with different stoichiometric ratios (AA11, AA12, and AA21) were prepared and assessed. Solid-state analysis confirmed the formation of single-phase homogeneous CAMS stabilized by intermolecular interactions. CAMS showed significant improvements in solubility and dissolution compared to crystalline and physical mixtures, with AA12 exhibiting the greatest enhancement. A fully validated LC-MS/MS method was developed for simultaneous quantification of APR and ACF in rat plasma. In vivo pharmacokinetic studies revealed formulation-dependent increases in systemic exposure. AA12 enhanced APR's AUC (∼2.6-fold) and Cmax (∼1.5-fold) compared to crystalline drug, while ACF showed more moderate improvements (∼1.5-fold AUC, ∼1.3-fold Cmax). Tmax remained unchanged across formulations, indicating improved absorption extent. Physiologically based pharmacokinetic (PBPK) modeling incorporating the Advanced Compartmental Absorption and Transit (ACAT) framework, along with formulation-specific dissolution inputs, accurately predicted plasma concentration-time profiles and regional gastrointestinal absorption, confirming dissolution-driven absorption enhancement. This integrated in vitro-in vivo-in silico investigation establishes coamorphization as a validated strategy to overcome dissolution-limited absorption, identifying AA12 as the optimized CAMS for combined APR-ACF delivery.