COPOVIDONE-BASED HOT-MELT EXTRUDED INDOMETHACIN CAPSULES: OPTIMIZED AMORPHOUS FORMULATION ACHIEVING ENHANCED DISSOLUTION AND IMPROVED ORAL BIOAVAILABILITY

Objective: Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) classified asa biopharmaceutics classification system (BCS) Class II drug, characterized by low aqueous solubility and high permeability. Its poor solubility results in dissolution rate-limited and variable oral absorption. To overcome this limitation, the present study aimed to develop and optimize a copovidone-based capsule formulation using hot-melt extrusion (HME) to enhance dissolution and oral absorption. Methods: Copovidone was selected as the polymer of choice following an initial screening. A two-factorial experimental design was employed to optimize the critical HME process parameters. The prepared extrudates were characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR) to assess the solid-state characteristics of indomethacin and potential drug–polymer interactions. The optimized extrudate was filled into capsules and evaluated for mechanical strength, in vitro dissolution performance, and accelerated stability (40 ± 2 °C and 75 ± 5% relative humidity for 3 months) in accordance with International Council for Harmonization (ICH) guidelines. Pharmacokinetic studies were conducted in male Sprague–Dawley (SD) rats, and plasma drug concentrations were quantified using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. Results: The optimized formulation demonstrated a significant improvement in aqueous solubility and a faster dissolution rate compared to the pure drug and marketed tablet (p < 0.05). PXRD and DSC analyses confirmed the complete conversion of indomethacin into an amorphous form within the copovidone matrix, whereas FTIR analysis indicated the absence of detrimental drug–polymer interactions. Pharmacokinetic evaluation revealed a faster absorption rate, characterized by a 1.16-fold increase in maximum plasma concentration (Cmax) and a markedly reduced time to reach (Tmax), indicating rapid early systemic exposure. Stability studies confirmed the maintenance of the amorphous state and dissolution performance throughout the storage period. Conclusion: The findings demonstrate that copovidone-based hot-melt extrusion is an effective strategy for improving solubility, dissolution, and the rate of oral absorption of poorly water-soluble indomethacin, leading to enhanced early systemic exposure.The optimized amorphous capsule formulation shows strong potential for further pharmaceutical development and commercialization in the future.