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Sci Pharm. 2017 Jun 27;85(3). pii: E25. doi: 10.3390/scipharm85030025.

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.

Author information

1
Research and Development, Integrated Product Development, Dr. Reddy's Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India. jadhavsb@drreddys.com.
2
Department of Chemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India. jadhavsb@drreddys.com.
3
Research and Development, Integrated Product Development, Dr. Reddy's Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India. sunilrp@drreddys.com.
4
Research and Development, Integrated Product Development, Dr. Reddy's Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India. kalyanaramanl@drreddys.com.
5
Department of Chemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India. p_n_bhosale@rediffmail.com.

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.

KEYWORDS:

HPLC; design of experiments; development and validation; full factorial design; linagliptin and metformin HCl

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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