IDENTIFICATION AND CHARACTERIZATION OF A NOVEL POTENTIAL DEGRADANT AND DEVELOPMENT AND VALIDATION OF STABILITY-INDICATING RP-LC METHOD FOR NICARDIPINE IMPURITIES IN INJECTABLE DOSAGE FORM

Abstract

The major degradation product of nicardipine hydrochloride injection that emerged throughout stress stability study have been determined, identified, and characterized. Identification and characterization of unknown degradant in nicardipine hydrochloride injection is an important aspect of product development. The presence of higher levels of impurities can have a significant impact on quality and safety of the drug product. Initially this impurity generated through the forced degradation and has been identified by LC-MS and was not reported in the literature. Then, the isolation of degradant was carried out by preparative HPLC method followed by freeze-drying of the collected fractions. Based on the characterization data, the impurity was named as Methyl 3-methyl-3′-nitro-5-oxo-1,2,5,6-tetrahydro-[1,1′-biphenyl]-2-carboxylate. The isolation, formation, and structural elucidation of this impurity by spectral data [¹H NMR, ¹³C NMR, 2D-NMR (COSY, HSQC, and HMBC), LC-MS, TOF-MS, and elemental composition by HRMS], are discussed in detail. This paper also deals with the development of stability-indicating RP-HPLC method and, developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, precision, linearity, accuracy, limit of detection, limit of quantification, robustness, and system suitability. Supplemental materials are available for this article. Go to the publisher's online edition of the Journal of Liquid Chromatography & Related Technologies to view the supplemental file.

Keywords:

• characterization
• degradation
• development
• impurities
• isolation
• nicardipine

ACKNOWLEDGMENT

The authors wish to thank the management of Dr. Reddy's Laboratories Ltd. for supporting this work. Cooperation from colleagues, especially Nitish Sharma, Y. Ravindra Kumar, and Malleswara Reddy, Analytical Research & Development of Dr. Reddy's Laboratories Ltd. is appreciated.

Notes

^a MUSI = Maximum un-specified impurity.

ND = Not detected.

^a Amount of four impurities spiked with respect to specification level.

^b Mean ±RSD (%) for three determinations.

^a Resolution between Nicardipine and Imp-C.

NA, Not applicable; ND, Not detected.