Abstract
This article presents the development of a reversed-phase (RP) high-performance liquid chromatographic (HPLC) method for determination of process-related impurities in a celecoxib drug substance following Analytical Quality by Design (AQbD) principles. The method from European Pharmacopeia (EP) for celecoxib drug substance does not sufficiently separate celecoxib from its EP impurity B because the system suitability criterion is not achieved (resolution NLT 1.8). The same issue was observed with the proposed method from United States Pharmacopeia (USP) for celecoxib capsules, where EP impurity A elutes under the main peak. A new HPLC method was developed that eliminates the disadvantages of the two pharmacopeial methods and is capable of efficiently separating and determining all seven impurities listed in EP and the proposed USP monographs. The development of a new HPLC method started with method scouting, in which various C18 and phenyl stationary phases were tested. Improved selectivity was obtained only with a chiral stationary phase. An immobilized Chiralpak IA-3 column used in RP mode turned out to be the most appropriate for method optimization. The ratio of acetonitrile in the mobile phase, flow rate, and column temperature were recognized as critical method parameters (CMPs) and were further investigated using a central composite face response-surface design. A multiple linear regression (MLR) method was applied to fit the mathematical models on the experimental data to determine factor–response relationships. The models created show adequate fit and good prediction abilities. The Monte Carlo simulation method was used to establish the design space. The method developed was verified in terms of precision, sensitivity, accuracy, and linearity, and the results showed that the new method is suitable for determination of seven process-related impurities of celecoxib.
Highlights
Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) used for the treatment of inflammation, osteoarthritis, rheumatoid arthritis, and pain
Pharmacopeial Forum [25], and Rao’s method [16] to verify whether these methods have the ability to separate all seven process-related impurities of celecoxib that are stated in European Pharmacopeia (EP) and United States Pharmacopeia (USP) according to the criteria set in regulatory guidelines
Analytical Quality by Design (AQbD) principles were successfully applied to the development of a new high-performance liquid chromatographic (HPLC) method for the determination of seven process-related impurities of celecoxib
Summary
Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) used for the treatment of inflammation, osteoarthritis, rheumatoid arthritis, and pain. It is a member of a non-steroidal anti-inflammatory drug (NSAID) class that has significantly less severe side effects in the gastrointestinal tract, such as gastric ulceration, compared to conventional non-selective NSAIDs. long-term treatment may increase the risk of adverse side effects in the cardiovascular system, celecoxib has Molecules 2020, 25, 809; doi:10.3390/molecules25040809 www.mdpi.com/journal/molecules cancer [1,2,3,4,5,6]. A monograph for control of celecoxib drug substance is available in European Pharmacopoeia shown therapeutic effectsanonHPLC colon method polyp formation, decreasing the riskof of celecoxib colorectal and adenoma in (EP), which prescribes for quantitative determination its two patients suffering from familial adenomatous polyposis, which may lead to colorectal cancer [1,2,3,4,5,6]
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