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Open AccessArticle

Development of RP-HPLC, Stability Indicating Method for Degradation Products of Linagliptin in Presence of Metformin HCl by Applying 2 Level Factorial Design; and Identification of Impurity-VII, VIII and IX and Synthesis of Impurity-VII

1
Research and Development, Integrated Product Development, Dr. Reddy’s Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India
2
Department of Chemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India
*
Author to whom correspondence should be addressed.
Academic Editor: Gernot A. Eller
Sci. Pharm. 2017, 85(3), 25; https://doi.org/10.3390/scipharm85030025
Received: 21 May 2017 / Revised: 6 June 2017 / Accepted: 7 June 2017 / Published: 27 June 2017
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Abstract

The novel reverse phase-high performance liquid chromatography (RP-HPLC), stability indicating method was developed for determination of linagliptin (LGP) and its related substances in linagliptin and metformin HCl (MET HCl) tablets by implementing design of experiment to understand the critical method parameters and their relation with critical method attributes; to ensure robustness of the method. The separation of nine specified impurities was achieved with a Zorbax SB-Aq 250 × 4.6 mm, 5 µm column, using gradient elution and a detector wavelength of 225 nm, and validated in accordance with International Conference on Harmonization (ICH) guidelines and found to be accurate, precise, reproducible, robust, and specific. The drug was found to be degrading extensively in heat, humidity, basic, and oxidation conditions and was forming degradation products during stability studies. After slight modification in the buffer and the column, the same method was used for liquid chromatography–mass spectrometry (LC-MS) and ultra-performance liquid chromatography -time-of-flight/mass spectrometry UPLC-TOF/MS analysis, to identify m/z and fragmentation of maximum unspecified degradation products i.e., Impurity-VII (7), Impurity-VIII (8), and Impurity-IX (9) formed during stability studies. Based on the results, a degradation pathway for the drug has been proposed and synthesis of Impurity-VII (7) is also discussed to ensure an in-depth understanding of LGP and its related degradation products and optimum performance during the lifetime of the product. View Full-Text
Keywords: HPLC; design of experiments; full factorial design; development and validation; linagliptin and metformin HCl HPLC; design of experiments; full factorial design; development and validation; linagliptin and metformin HCl
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Jadhav, S.B.; Reddy, P.S.; Narayanan, K.L.; Bhosale, P.N. Development of RP-HPLC, Stability Indicating Method for Degradation Products of Linagliptin in Presence of Metformin HCl by Applying 2 Level Factorial Design; and Identification of Impurity-VII, VIII and IX and Synthesis of Impurity-VII. Sci. Pharm. 2017, 85, 25.

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