Title : Formulation and optimization of self micro emulsifying drug delivery system (SMEDDS) of Clopidogrel Bisulfate by using D-Optimal mixture design
Abstract:
The present work aims to develop a self-micro emulsifying drug delivery system (SMEDDS) to improve in-vitro dissolution of Clopidogrel Bisulfate an Anti-platelet agent, belonging to BCS class II. Initially, solubility studies were performed to identify the solvents showing the highest solubility of API. Then ternary phase diagrams were plotted for selected components of oil, Smix and water to identify the area of micro-emulsion existence. By using D-optimal mixture design liquid SMEDDS were optimized using three independent variables: Oil phase X1 (Oleic acid), Surfactant X2 (Tween 80) and Co-surfactant X3 (PEG 600). Two dependent variables selected were R1: Self emulsification time (sec), R2: Percentage drug release within 90min. FTIR studies confirmed that the drug and excipients were compatible. The liquid SMEDDS were evaluated for thermodynamic stability studies, visual observation, robustness to dilution, drug content, self-emulsification time, dispersibility test and drug release. A stability study was performed at 40°C/75% RH. Contour plots and Response surface plots indicated that with the increase in oil ratio (X1) there is an increase in Self emulsification time and decreased percent drug release. For these formulations predicted vs. Actual responses showed a correlation of 0.963 for self-emulsification time, 0.9177 for %drug release in 90 minutes. Optimized formulation OPF1 Oil (20.25ml), surfactant (39.74ml) and co-surfactant (40ml) obtained from the design (with criteria <40 sec for Self-emulsification time and >85% release in 90 min.) showed self-emulsification time of 33.87 seconds, 101.41±0.21 %drug release in 90min., particle size of 528.6nm and PDI of 0.560, from which it can be inferred that micro range emulsion has been formulated and the particle size possess large interfacial surface area for drug absorption. The surface morphology of the optimized formulation (OPF1) was examined by SEM and was found to be smooth. Zeta potential is useful in knowing the surface charge of the particle which determines its stability. Zeta potential can be either positive or negative, stable formulations may possess +30 to -30 mV charge. The formulation OPF1 showed a Zeta potential of -15.9 mV. Optimized formulation (OPF1) showed best results in terms of self-emulsification time (85% in 45 min) and was stable for 1 month. The results demonstrated the potential of SMEDDS as a means of improving solubility, dissolution and hence bioavailability.
