Quality by Design Approach for Development and Validation of Stability Indicating RP-HPLC Method for Fosaprepitant Dimeglumine

Jalil K. Shaikh1, Mazahar Farooqui2, and Ummul Khair Asema Syed2,*,

1USP India Private Limited, I.K.P. Knowledge Park, Hyderabad-500101, India

2Department of Chemistry, Maulana Azad College of Art Science and Commerce, Rauza Bagh, Aurangabad-431001, India

*Corresponding author: E-mail: ukasema@gmail.com

Abstract

Quality by design approach has been used to develop simple, rapid, sensitive gradient RP-HPLC stability indicating method for fosaprepitant dimeglumine and its related impurities. The chromatographic method has been developed by using symmetry shield RP-18 (250 mm × 4.6 mm; 5 μm) column maintained at column temperature of 20 ºC. The mobile phase-A consisted of water and acetonitrile (800:200, v/v), added 2 mL of orthophosphoric acid and 0.17 g of tetrabutylammonium hydrogen sulphate. The mobile phase-B consisted of water and acetonitrile (200:800, v/v), added 2 mL of orthophosphoric acid and 0.17 g of tetrabutylammonium hydrogen sulphate. Gradient program was executed as time (min)/% MP-A: 0/80, 3/80, 12/40, 20/20, 24/20, 25/80, and 30/80. The UV detection was carried out at wavelength 210 nm and 20 μL of sample was injected. Sample cooler was maintained at 5 ºC. Stability of fosaprepitant dimeglumine sample was investigated in different stress condition as acid, base, oxidation, thermal, humidity and photolytic. The method was developed in two phases, screening and optimization. During the screening phase, the most suitable stationary phase, organic modifier, and solvent were identified based on the behaviour of each stationary phase with fosaprepitant dimeglumine and its impurities using each buffer and solvent. Total 18 experiments were performed to find out the best experimental condition. The optimization was done for secondary influential parameters like column temperature, gradient program, using six experiments to examine multifactorial effects of system suitability parameters and generated design space representing the robust region. A verification experiment was performed within the working design space and the model was accurate. Drug showed unstable behaviour under acid, base, oxidation, thermal, and humidity conditions. Apripetant was found as major degradation impurity. The method was validated as per ICH guideline for specificity, limit of detection (LOD), limit of quantitation (LOQ), linearity, accuracy, precision, ruggedness and robustness. Correlation coefficient is about 0.999 for all impurities, recovery is between 90% to 103% at all level. LOD value of each impurity is less than 0.01% w/w. DOE statistically based experimental designs proved to be an important approach in optimizing selectivity-controlling parameters for the organic impurities determination in FD API. The method was found to be specific, linear, accurate, precise and robust. The peak purity test results confirmed that the fosaprepitant dimeglumine peak was homogenous in all stress samples and the mass balance was found to be more than 99%, thus proving the stability indicating power of the method. Present method is found to be suitable for routine analysis in quality control laboratory.

Keywords

Quality by Design, Fosaprepitant dimeglumine, Monobenzyl impurity, Aprepitant, HPLC.

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