Development and Validation of a Stability‐Indicating Reversed‐Phase High‐Performance Liquid Chromatographic Method for the Simultaneous Determination of Betamethasone Dipropionate, Chlorocresol, and Related Impurities in Betamethasone 0.05% Cream

ABSTRACT

Topical corticosteroid formulations require rigorous analytical control of the active pharmaceutical ingredient, antimicrobial preservatives, and degradation products. Traditional quality control approaches often employ separate methods for each determination, increasing analysis time and solvent consumption. This study describes the development and comprehensive validation of a unified reversed‐phase high‐performance liquid chromatographic method for the simultaneous quantification of betamethasone dipropionate (BDP), chlorocresol, and BDP‐related impurities in a 0.05% cream formulation, following Analytical Quality by Design principles as described in the International Council for Harmonization (ICH) Q14. Chromatographic separation was achieved on an XBridge Shield RP18 column using gradient elution with water–acetonitrile and dual‐wavelength ultraviolet detection (240 nm for BDP and impurities; 280 nm for chlorocresol). Validation was performed according to ICH Q2(R1) guidelines. Baseline resolution (Rs > 2.5) was achieved for all analytes within 50 min. Excellent linearity was demonstrated ( r ² > 0.999) with y‐intercepts not significantly different from zero. Mean recoveries were 100.1 ± 1.0% for BDP and 100.0 ± 0.9% for chlorocresol. Precision relative standard deviations were below 2.2% for assay and below 4.0% for impurities. Limits of detection and quantification were 0.015% and 0.05%, respectively. Correction factors of 0.83 for betamethasone and 1.09 for beclometasone dipropionate were determined. Nominal operating conditions were selected based on the factorial robustness study as: column temperature 35.0 ± 0.5°C, flow rate 1.50 ± 0.03 mL/min. Solution stability was confirmed for 24 h at 22°C. The proposed unified method replaces three separate analytical procedures with a single chromatographic run, reducing solvent consumption and total analysis time. It is specific, accurate, precise, and robust, offering significant efficiency gains for routine pharmaceutical quality control while maintaining full regulatory compliance.