Formulation, Optimization and Evaluation of Self-Microemulsifying Drug Delivery System (SMEDDS) for Solubility Enhancement of Metolazone

Abstract

Background: Metolazone (MTZ), a quinazoline-sulphonamide thiazide-like diuretic, is a Biopharmaceutical Classification System (BCS) class II drug with poor aqueous solubility, which results in its low oral bioavailability (65%). The purpose of this study was to develop and optimize a Self Micro-Emulsifying Drug Delivery System (SMEDDS) of Metolazone for enhanced solubility and dissolution.
Method: Pre-formulation studies like Fourier Transform Infrared Spectroscopy (FTIR), identification of λmax and melting point determination were performed to confirm drug identity. Ultraviolet (UV) spectrophotometric was developed for the quantification of MTZ. Equilibrium solubility studies revealed Capmul MCM PG-8-NF, Tween 80 and Transcutol P as oil, surfactant and co-surfactant. A pseudo-ternary phase diagram was constructed to identify the self-micro emulsification region, followed by optimization by simplex lattice mixture design. Quadratic models were developed for droplet size, equilibrium solubility, self-emulsification time and percentage transmittance. The optimized SMEDDS was evaluated for physicochemical characteristics, thermodynamic stability and in-vitro studies and was compared with marketed tablet.
Results: The optimized SMEDDS exhibited 95.3 ± 0.31% transmittance, no phase separation, globule size of 46.05 ± 0.34 nm, and an emulsification time of 42 ± 0.76s. Equilibrium solubility was increased to 74.2 ± 0.87 mg/mL. The formulation was thermodynamically stable with a cloud point of 68.5 ± 0.11°C. The quadratic models were statistically significant (p < 0.05), with R² > 0.92 and adequate precision >4. In vitro drug release demonstrated faster and pH-independent release.The optimized SMEDDS retained its performance after 6 months of accelerated stability testing, indicating its potential for enhancing MTZ solubility and dissolution.