Solvent-free engineering of a co-amorphous efavirenz-ritonavir system by hot-melt extrusion: Solid-state...

Combination antiretroviral therapy remains the most successful approach for effective HIV management, as the simultaneous targeting of multiple stages of the viral replication cycle improves therapeutic efficacy and limits the emergence of drug resistance. Efavirenz (EFV) and ritonavir (RTV) form a mechanistically complementary drug pair; however, both exhibit poor aqueous solubility, leading to dissolution-limited oral absorption. In this work, a dose- and mechanism-informed co-amorphous formulation strategy was developed using hot-melt extrusion (HME) to improve the biopharmaceutical performance of EFV and RTV. Three EFV:RTV molar ratios were designed to preserve EFV-dominant dosing while sufficient RTV content to facilitate intermolecular stabilisation and amorphous phase formation. Molecular docking served as a pre-formulation screening tool and revealed favourable drug-drug compatibility. Among the investigated compositions, the 1:0.5 (EFV:RTV) system (CM3) achieved complete amorphisation, whereas other ratios retained residual crystallinity. Solid-state characterisation using PXRD, DSC, TGA, FT-IR, and ¹H NMR confirmed the formation of a single-phase amorphous system with enhanced thermal stability, while SEM demonstrated pronounced morphological changes, supporting the HME-induced transformation. CM3 exhibited substantially improved solubility and accelerated dissolution, alongside short-term physical and chemical stability. In rat in-vivo pharmacokinetic study, the co-amorphous system produced 8.7-fold higher C_max and 10.1-fold greater systemic exposure (AUC_∞) for EFV compared with the pure drug suspension, indicating improved absorption and bioavailability. RTV exhibited sustained plasma exposure, enhanced overall systemic availability, and modulated absorption behaviour from the CM3 system. The improved pharmacokinetic performance was attributed to the amorphous conversion, improved molecular dispersion, and dissolution enhancement achieved through HME processing.