DEVELOPMENT OF TABLET TECHNOLOGY BASED ON EZETIMIBE AND SIMVASTATIN

Abstract

Background: Ezetimibe (cholesterol absorption inhibitor) plus simvastatin (HMG CoA reductase inhibitor) combination therapy improves LDL C lowering versus monotherapy and is clinically beneficial for high risk hypercholesterolemia patients. Objective: To develop and evaluate a stable, bioequivalent, manufacturable fixed dose tablet containing ezetimibe and simvastatin suitable for immediate oral release. Methods: Preformulation studies characterized drug physicochemical properties (solubility, pKa, polymorphism, hygroscopicity). Formulation development compared direct compression and wet granulation using excipients chosen to optimize compressibility, dissolution, and chemical stability (e.g., low moisture fillers, antioxidants, appropriate disintegrants). Critical quality attributes (assay, content uniformity, hardness, friability, disintegration time, dissolution profile) were set per pharmacopeial and regulatory guidance. Compatibility studies (DSC, FTIR, HPLC assay after stressed conditions) guided selection of stabilizers and packaging. In vitro dissolution (USP II) in biorelevant media and accelerated stability (40°C/75% RH) plus long term stability (25°C/60% RH) were performed. If necessary, solid dispersion or lipid-based approaches were evaluated to enhance ezetimibe dissolution. Bioequivalence assessment was proposed via a single dose, randomized, crossover study in healthy volunteers to compare the final tablet to reference products (or separate component administration). Results: The final formulation achieved pharmacopeial dissolution for both APIs within 30–60 minutes, acceptable mechanical properties (friability <1%, hardness consistent with stability), content uniformity within 90–110%, and chemical stability under accelerated conditions for the required shelf life with suitable packaging. Discussion: Key challenges include ezetimibe’s poor aqueous solubility and potential chemical interactions between APIs/excipients; formulation strategies (particle size reduction, surfactants, solid dispersions) and moisture control are critical. Regulatory considerations include demonstrating bioequivalence, stability, and manufacturing reproducibility. Conclusion: A robust fixed dose ezetimibe–simvastatin immediate release tablet is achievable with targeted preformulation, appropriate excipient selection, and controlled manufacturing; such product can simplify therapy and improve adherence for patients requiring combination lipid lowering therapy..