Carvedilol Precipitation Inhibition by the Incorporation of Polymeric Precipitation Inhibitors Using a Stable Amorphous Solid Dispersion Approach: Formulation, Characterization, and In Vitro In Vivo Evaluation

Abstract

An amorphous solid dispersion (ASD) of carvedilol (CVL) was prepared via the solvent evaporation method, using cellulose derivatives as polymeric precipitation inhibitors (PPIs). The prepared ASDs existed in the amorphous phase, as revealed by X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM). The Fourier-transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) results confirmed the compatibility between CVL and the polymers used. The ASDs characteristics were evaluated, with no change in viscosity, a pH of 6.8, a polydispersity index of 0.169, a particle size of 423–450 nm, and a zeta potential of 3.80 mV. Crystal growth inhibition was assessed for 180 min via an infusion precipitation study in simulated intestinal fluid (SIF). The interactions between the drug and polymers were established in great detail, using nuclear magnetic resonance (NMR) spectroscopy, nuclear Overhauser effect spectroscopy (NOESY), and Raman spectroscopy studies. Dielectric analysis was employed to determine the drug-polymer interactions between ion pairs and to understand ion transport behavior. In vivo oral kinetics and irritation studies performed on Wistar rats have demonstrated promising biocompatibility, stability, and the enhanced bioavailability of CVL. Collectively, the stable ASDs of CVL were developed using cellulose polymers as PPIs that would inhibit drug precipitation in the gastrointestinal tract and would aid in achieving higher in vivo drug stability and bioavailability.