LC–MS/MS and NMR Characterization of Key Impurities in Linagliptin and Pramipexole

Parsha, Swetha; Kumar, Yogesh; Ravichander, M.

doi:10.1080/10826076.2015.1087861

Cited by 10 publications

(6 citation statements)

References 75 publications

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“…In addition, some bioanalytical methods were reported for LIN ‐ related to its pharmacology, kinetics and drug interactions 13–16 . There have been a few studies on the stability of LIN alone and in combination with other antidiabetic drugs in formulations using HPLC 17–19 and two reports on the impurity analysis of LIN 20,21 . However, there is no information available on the degradation behavior of LIN.…”

Section: Introductionmentioning

confidence: 99%

Application of online liquid chromatography/quadrupole time‐of‐flight electrospray ionization tandem mass spectrometry for structural characterization of linagliptin degradation products and related impurities

Yadav

Dornala

Swain

et al. 2020

Rapid Comm Mass Spectrometry

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Linagliptin is a drug used for the management of type 2 diabetes, which is a leading cause of global ill health and mortality. Impurities can affect the quality and safety of drug products and eventually may affect human health. A robust, sensitive and reliable analytical method is required to detect, characterize, quantify and control the presence of impurities in finished pharmaceutical products such as linagliptin. Methods: Linagliptin was stressed under harsh conditions as in the ICH Q1A (R2) guidelines to generate degradation products. The degradation products and process-related impurities were separated using an InertSustain C8 column (4.6 mm × 150 mm, 5 μm) and characterized by tandem quadrupole time-of-flight mass spectrometry in positive mode electrospray ionization. The developed method was validated according to the ICH Q2 (R1) guidelines. Results: Upon forced degradation, 12 degradation products were obtained (6 in oxidative stress and 3 in each of acid and alkaline hydrolysis). The special finding here was the presence of a pair of isomeric degradation products in acid hydrolysis and the formation of degradation products in base hydrolysis and oxidative degradation caused by the use of acetonitrile as a diluent. The 12 degradation products and 6 process-related substances were successfully identified using liquid chromatography/tandem mass spectrometry. Conclusions: A reversed-phase high-performance liquid chromatography method was developed and validated for the separation of the 12 degradation products and 6 process-related impurities. Structural characterization of all impurities was carried out using fragmentation pathways obtained from tandem mass spectrometry. The method was sufficiently sensitive and reproducible for quality control of linagliptin and for further research studies. 1 | INTRODUCTION Diabetes is an important cause of ill health and mortality and is a risk factor for other diseases. 1 According to the International Diabetes Federation report in 2017, in that year 425 million people were Amrej Singh Yadav and Divya Dornala contributed equally to this work.

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Section: Introductionmentioning

confidence: 99%

Application of online liquid chromatography/quadrupole time‐of‐flight electrospray ionization tandem mass spectrometry for structural characterization of linagliptin degradation products and related impurities

Yadav

Dornala

Swain

et al. 2020

Rapid Comm Mass Spectrometry

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“…Many publications have reported the synthetic routes of LGP ( Figure 1) [5,6] and relevant LC methods [7][8][9][10][11][12][13][14][15][16]. The impurity profile of LGP was disclosed as well [17][18][19]. Jadhav and co-workers revealed degradation products of LGP interacting with metformin or excipients and related RP-HPLC method [20].…”

Section: Introductionmentioning

confidence: 99%

Identification, isolation, characterization, and UHPLC quantification of potential genotoxic impurities in linagliptin

Huang

Lü

Zhang

et al. 2018

J of Separation Science

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During the stress testing of linagliptin, one unknown degradation product (impurity I) on acidic conditions was detected by using high-performance liquid chromatography and subsequently isolated, identified, and characterized by the spectral data (MS, MS/MS, 1D and 2D NMR spectroscopy, and IR spectroscopy) and finally subjected for mechanism analysis. The degradation product (impurity I) and another process-related impurity (impurity II) of linagliptin were found to contain the structural alerts of N-acylated aminoaryl and alkyl halide, respectively, which were both potential genotoxic substances. Hence, a rapid and facile ultra high performance liquid chromatography method was developed for the simultaneous determination of these two potential genotoxic impurities at ppm levels in linagliptin. The factors involved in the method development were discussed and this method was fully validated as per International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, which proved the method sensitive, selective, and robust. The presented method has been successfully applied to the analysis of real samples from multiple batches. This study will help to risk management of possible genotoxic impurities present in linagliptin.

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“…The five predicted and synthesized impurities showed the However, the literature search did not reveal much work on the impurity research of linagliptin. The impurity profile of linagliptin in this synthetic route is different from the earlier reported study [5,6], which makes it more challenging to identify the unknown impurities formed in small quantities in the drug substance. Since most of the time it is very difficult to identify and control impurities within acceptable levels in the process, some advanced purification techniques for an active drug substance may then be taken into account, such as the continuous-flow process [7], organic solvent nanofiltration (OSN) [8], molecularly imprinted membranes for OSN [9] and counter current chromatography (CCC), as a valuable addition to the chromatography toolbox [10].…”

Section: Structures Of Impuritiesmentioning

confidence: 56%

“…The solvents used were DMSO-d 6 or CDCl 3 . The 1 H-NMR chemical shift values were reported as δ ppm relative to tetramethylsilane (TMS) and the 13 C-NMR chemical shift values were reported on δ ppm relative to DMSO-d 6 or CDCl 3 .…”

Section: General Informationmentioning

confidence: 99%

Synthesis and Characterization of Process-Related Impurities of Antidiabetic Drug Linagliptin

Huang

et al. 2016

Molecules

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Linagliptin, a xanthine derivative, is a highly potent, selective, long-acting and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. During the process development of linagliptin, five new process-related impurities were detected by high performance liquid chromatography (HPLC). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, HRMS, 1 H-NMR, 13 C-NMR and IR) as described in this article. The identification of these impurities should be useful for quality control and the validation of the analytical method in the manufacture of linagliptin.

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LC–MS/MS and NMR Characterization of Key Impurities in Linagliptin and Pramipexole

Cited by 10 publications

References 75 publications

Application of online liquid chromatography/quadrupole time‐of‐flight electrospray ionization tandem mass spectrometry for structural characterization of linagliptin degradation products and related impurities

Application of online liquid chromatography/quadrupole time‐of‐flight electrospray ionization tandem mass spectrometry for structural characterization of linagliptin degradation products and related impurities

Identification, isolation, characterization, and UHPLC quantification of potential genotoxic impurities in linagliptin

Synthesis and Characterization of Process-Related Impurities of Antidiabetic Drug Linagliptin

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