Developing an Improved UHPLC Method for Efficient Determination of European Pharmacopeia Process-Related Impurities in Ropinirole Hydrochloride Using Analytical Quality by Design Principles

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-06, Vol.25 (11), p.2691
• Main Authors: Tome, Tim, Obreza, Aleš, Časar, Zdenko
• Format: Article
• Language: English
• Subjects: AQbD; Chromatography; Chromatography, High Pressure Liquid - methods; Design; Design analysis; design of experiments; Drug Contamination - statistics & numerical data; Drug development; Elution; Experiments; Impurities; Indoles - analysis; Indoles - chemistry; Limit of Detection; Linearity; Mathematical models; method development; method optimization; Methods; Models, Theoretical; Pharmacology; pharmacopeia; Quality Control; Reproducibility of Results; Restless legs syndrome; Selectivity; Slope gradients; UHPLC
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25112691

This article presents the development of a reversed-phase ultra-high-performance liquid chromatographic method for determining process-related impurities in ropinirole hydrochloride drug substance applying the analytical quality by design approach. The current pharmacopeial method suffers from selectivity issues due to two coelutions of two pairs of impurities. The development of a new method began with preliminary experiments, based on which the Acquity UPLC BEH C8 was selected as the most appropriate column. The effects of six different critical method parameters (CMPs) were then investigated using a fractional factorial screening design. Column temperature, the ratio of methanol in mobile phase B, and gradient slope turned out to be highly significant CMPs in achieving critical resolutions, and they were further evaluated using a central composite face-centered response-surface design. Mathematical models were created by applying a multiple linear regression method. Based on the elution order of an unknown degradation impurity and impurity C, two design spaces were established, and for each design space an optimal combination of CMPs was determined. The method developed was validated for precision, accuracy, linearity, and sensitivity, and it was proven suitable for determining nine process-related impurities of ropinirole.