Abstract
Objective: A simple, robust, precise, and selective stability-indicating liquid chromatography (LC) method (reverse-phase high-performance LC) was developed for the estimation of simeprevir through quality by design paradigm.
 Methods: The chromatographic separation was performed on Water’s 2695(Alliance) equipped with a photodiode array detector at 300 nm. The method was developed on Discovery C18 column (250×4.6, 5 mm) using orthophosphoric acid and acetonitrile (55:45 % v/v) with the flow rate of 1 ml/min at 30°C. The degradation studies of simeprevir were carried out under the stress conditions of hydrolysis (acid, base, and neutral), oxidation, photolytic, and thermal as per the International Conference on Harmonization (ICH) guidelines. The peroxide hydrolysis shows more critical impurities which were well resolved from pure drug with the application of design of experiment and optimized the method.
 Results: Independent variables (critical analytical attributes) selected for the method optimization were mobile phase ratio, flow rate, and temperature of the column based on the risk assessment. The retention time and resolution were selected as the method response. In response surface method, the central composite design and 23 factorial designs were employed for the optimization of the method. The polynomial equation was derived for the estimation of method response.
 Conclusion: The method was optimized for better resolution among the drug, and impurity peaks were then validated as per the ICH parameters.
Highlights
One of the most crucial steps in the development of pharmaceutical products is to assess the stability of the product
Instrument liquid chromatography (LC) equipment used for the development was WATERS 2695 equipped with a photodiode array (PDA) detector using Empower 2 software (Waters Corporation, Milford, MA, USA)
The mobile phase used for the detection was Orthophosphoric acid (OPA) and ACN in the ratio of 55:45 at the flow rate of 1 ml/min
Summary
One of the most crucial steps in the development of pharmaceutical products is to assess the stability of the product. The convenient method to achieve the goal of stability-indicating method is reversephase (RP) liquid chromatography (LC), but often this method encounters the method failure or method transferability problem. This problem arises due to the lack of understanding of product and process. The success of a LC stability-indicating assay totally depends on its selectivity of the method [1]. The quality by design (QbD) paradigm’s principles have been utilized to develop a successful stability-indicating method. The International Conference on Harmonization (ICH) Q8 (R1) guideline defines QbD as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” [2,12,13]
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