Quantification of Drospirenone- and Ethinyl Estradiol-Related Impurities in a Combined Pharmaceutical Dosage Form by a Chromatography Method With a QbD Robustness Study.

Abstract

Background: The estimation of drugs containing drospirenone (DRSP) and ethinyl estradiol (EE), and their related impurities, in low-dose oral contraceptive drug products is an extremely challenging target. The proposed research sought to develop and validate a stability-indicating method for quantifying drug substances and their related impurities in tablet formulation.

Objective: To develop and validate a simple, specific, accurate, precise, and stability-indicating reverse-phase (RP)-HPLC method for quantification of DRSP, EE, and their impurities in accordance with International Conference on Harmonisation (ICH) guidelines.

Method: The separation was achieved using an Agilent Zorbax SB C18 column (4.6 mm × 250 mm, 5 µm) with a detection wavelength of 215 nm and mobile phases A (100% acetonitrile) and B (acetonitrile-water, 1 + 3, v/v) at a flow rate of 1.3 mL/min and a column temperature of 40°C.

Results: The recovery study of each impurity was conducted in the range of 24 to 72 µg/mL for DRSP-related impurities and 0.2 to 0.6 µg/mL for EE-related impurities with respect to the specification limit. A linearity study was conducted over a range of 1.5 to 90 µg/mL for DRSP and DRSP-related impurities, and 0.125 to 0.75 µg/mL for EE-related impurities. A Quality by Design (QbD) study demonstrated the method's robustness.

Conclusions: As per current guidelines, a stability-indicating method has been developed for the determination of impurities in DRSP/EE film-coated tablets. A QbD-based robustness test was performed and the method was found to be robust.

Highlights: An accurate, precise, stability-indicating, gradient RP-HPLC method has been developed and validated to determine DRSP, EE, and nine related impurities in tablet formulation. A QbD technique was used to establish a robustness study.