Stability-Indicating High-Performance Liquid Chromatographic Method Development and Preformulation-Driven Design of Betamethasone Dipropionate Topical Systems

Abstract

Betamethasone dipropionate (BDP) is a potent topical corticosteroid widely used in semisolid formulations; however, its physicochemical instability, particularly its susceptibility to hydrolytic and photolytic degradation, poses significant formulation challenges. The present study aimed to develop a robust stability-indicating high-performance liquid chromatography (HPLC) method and apply it to preformulation-driven excipient compatibility studies to support rational formulation design.

A selective and reproducible HPLC method was developed and validated in accordance with regulatory guidelines, demonstrating excellent specificity, precision (%RSD < 1%), accuracy (recovery 100–102%), and linearity (R² = 0.9957). The method effectively resolved BDP from its related impurities, including structurally similar degradation products, confirming its suitability for stability assessment in complex semisolid matrices.

Forced degradation studies revealed that BDP is highly susceptible to alkaline hydrolysis (14.6%) and photolytic degradation (20.3%), but comparatively less sensitive to acidic and oxidative conditions. Excipient compatibility studies conducted under accelerated conditions (60°C for 7 and 15 days) demonstrated a significant influence of excipient type on impurity generation. Polar solvents and surfactants, including propylene glycol, polyethylene glycol derivatives, and lecithin, significantly increased impurity levels (up to 1.28%). In contrast, carbomer, poloxamer, parabens, and sorbic acid showed improved compatibility with minimal degradation.

Mechanistic analysis indicated that microenvironmental polarity and water activity play critical roles in governing BDP ester hydrolysis. These insights were translated into formulation design strategies, including conventional semisolid systems and pluronic lecithin organogels, aimed at minimizing degradation while maintaining drug release and permeation.

This study demonstrates the value of integrating analytical method development with preformulation studies to enable data-driven optimization of stable and effective topical drug delivery systems.