Stability-Indicating HPLC Method for Quantifying Process-Related Impurities in Fedratinib and Identification of Its Forced Degradation Products Using LC-MS/MS

DOI:

https://doi.org/10.37285/ijpsn.2024.17.4.2

Authors

  • Gowtham Panchadi Department of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur - 522302, A.P., India.
  • Naga Babu Uppu 2Department of Engineering Chemistry, S.R.K.R. Engineering College, Chinna Amiram, Bhimavaram, A.P., India - 534204
  • Bhagya Kumar Tatavarti Department of Chemistry, K.B.N. College (Autonomous), Kothapeta, Vijayawada, Andhra Pradesh, India-520001
  • Prasad V.B.V.N. Department of Engineering Mathematics, College of Engineering, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur - 522302, A.P., India.
  • Venkateswara Rao Anna Department of Chemistry, Koneru Lakshmaiah Education Foundation

Abstract

Background: Pharmaceutical industry is characterized by rigorous quality standards to ensure the safety and efficacy of drugs. Despite stringent manufacturing processes, the presence of impurities or generation of degradation products (DPs) in pharmaceutical products remains a concern. This necessitates a comprehensive and systematic approach to analysis impurities and DPs.

Objectives: This study deals with the optimization of the stable HPLC method for quantification of fedratinib impurities and its DPs characterization through LC-MS/MS. 

Method: Method optimization studies were conducted by analyzing standard solutions in various method parameters. The results noticed in every varied method condition were tabulated for finalizing the appropriate conditions for analyzing fedratinib. The mass spectral response of DPs was interpreted carefully for structural conformation of DPs. 

Results: The method is optimized as HIQSIL C18 (250mm×4.6mm;5µ) column employing 1.0 mL/min flow of phosphate buffer (pH 5.2) and acetonitrile in 45:65 (v/v) and 257 nm. This method elutes 5.4, 2.6, 9.2 and 3.5 min for fedratinib, impurity 1, 2 and 3 respectively. Method sensitivity was verified to be very sensitive that can evaluate up to 0.003, 0.015 and 0.004 µg/mL for impurity 1, 2 and 3 respectively. Well correlated calibration curve achieved in 50-200 µg/mL for fedratinib and 0.05-0.20 µg/mL for impurities. Various stress studies produce four stress DPs and were identified using LC-MS/MS. The molecular mass (g/mol) and formula of DPs were identified as 426 and C21H25N5O3S, 312 and C17H22N5O, 354 and C17H14N4O3S, 215 and C11H11N4O respectively for DP 1 to 4. 

Conclusion: The method proposed can successfully be helpful for quantifying the pharmaceutical impurities and DPs of fedratinib in bulk batch samples and formulations. 

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Keywords:

Fedratinib, process related impurities, HPLC method, LCMS analysis, degradation products, characterization

Published

2024-08-15

How to Cite

1.
Panchadi G, Uppu NB, Tatavarti BK, V.B.V.N. P, Anna VR. Stability-Indicating HPLC Method for Quantifying Process-Related Impurities in Fedratinib and Identification of Its Forced Degradation Products Using LC-MS/MS. Scopus Indexed [Internet]. 2024 Aug. 15 [cited 2024 Oct. 4];17(4):7446-58. Available from: https://ijpsnonline.com/index.php/ijpsn/article/view/4373

Issue

Section

Research Articles

References

Szekely G, Amores de Sousa MC, Gil M, Castelo Ferreira F, Heggie W. Genotoxic impurities in pharmaceutical manufacturing: sources, regulations, and mitigation. Chemical reviews. 2015;115(16):8182-229.

Reddy AV, Jaafar J, Umar K, Majid ZA, Aris AB, Talib J, Madhavi G. Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review. Journal of Separation Science. 2015; 38(5):764-79.

Wang T, Yang H, Yang J, Guo N, Wu G, Xu X, An M. Quantitative Determination of Four Potential Genotoxic Impurities in the Active Pharmaceutical Ingredients in TSD-1 Using UPLC-MS/MS. Molecules. 2022;27(13):4129.

Pokar D, Rajput N, Sengupta P. Industrial approaches and consideration of clinical relevance in setting impurity level specification for drug substances and drug products. International Journal of Pharmaceutics. 2020;576:119018.

Rajesh Varma Bhupatiraju, Srinivasa Kumar B, Pavani Peddi, Venkata Swamy Tangeti. An effective HPLC method for evaluation of process related impurities of Letermovir and LC-MS/MS characterization of forced degradation compounds. Journal of Chemical Metrology. 2023;2(2):181-198

Zhang K, Pellett JD, Narang AS, Wang YJ, Zhang YT. Reactive impurities in large and small molecule pharmaceutical excipients–A review. TrAC Trends in Analytical Chemistry. 2018;101:34-42.

Jamieson C, Hasserjian R, Gotlib J, Cortes J, Stone R, Talpaz M, Thiele J, Rodig S, Pozdnyakova O. Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis. Journal of translational medicine. 2015; 13(1):1-8.

Zhang M, Xu CR, Shamiyeh E, Liu F, Yin JY, von Moltke LL, Smith WB. A randomized, placebo‐controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK 2 inhibitor fedratinib (SAR 302503) in healthy volunteers. The Journal of Clinical Pharmacology. 2014;54(4):415-21.

Pardanani A, Tefferi A, Jamieson C, Gabrail NY, Lebedinsky C, Gao G, Liu F, Xu C, Cao H, Talpaz M. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood cancer journal. 2015; 5(8):e335.

Srujani Ch. Krishnamanjari Pawar Amgoth, Nataraj KS, Roshini K. Implementing Quality by Design Approach in Analytical RP-HPLC Method Development and Validation for the Determination of Fedratinib. International Journal of Pharmaceutical Sciences and Drug Research. 2021; 13(3): 253-262.

Yarra Raviteja, Suresh G. Method Development And Validation Of An Lc–Esi-Ms/Ms Technique For The Quantitation Of Fedratinib In Biological Matrices. Natural Volatiles & Essential Oils. 2021; 8(4): 16728-16739.

Ayesha Begum Khadernaick, Gubbiyappa Shiva Kumar, Pamu Sandhya, Darna Bhikshapathi. A Highly Sensitive LC–MS/MS Method Development and Validation of Fedratinib in Human Plasma and Pharmacokinetic Evaluation in Healthy Rabbits. Current Pharmaceutical Analysis. 2021; 17(6): 782 – 791.

Tang C, Niu X. Shi L, Zhu H, Lin G, Xu RA. In vivo Pharmacokinetic Drug-Drug Interaction Studies Between Fedratinib and Antifungal Agents Based on a Newly Developed and Validated UPLC/MS-MS Method. Frontiers in Pharmacology. 2021; 11: 626897.

Zahra Khorsandi, Abdol RH, Mohamad Reza Sarfjooa, Rajender SV. A Pd/Cu-Free magnetic cobalt catalyst for C–N cross coupling reactions: synthesis of abemaciclib and fedratinib. Green Chemistry. 2021; 23: 5222-5229.

Bikshal BK, Useni RM, Venkateswara RA, Maheshwara RL. Intended high-performance liquid chromatography procedure for the quantification of norfloxacin and its potential impurities in active pharmaceutical ingredient and tablet dosage forms. Thai Journal of Pharmaceutical Sciences. 2018; 42(1): 27-36.

Mallu UR, Anna VR, Kasimala BB. Rapid Stability Indicating HPLC Method for the Analysis of Leflunomide and Its Related Impurities in Bulk Drug and Formulations. Turkish Journal of Pharmaceutical Sciences. 2019; 16: 457-465.

Bikshal Babu Kasimala, Venkateswara Rao Anna, Useni Reddy Mallu. Stability-Indicating Reversed-Phase HPLC Method for the Separation and Estimation of Related Impurities of Cilnidipine in Pharmaceutical Formulations. Indian Drugs. 2018; 55(12): 41-49.

Sri Girija K, Bikshal Babu Kasimala, Venkateswara Rao Anna. A new high-performance liquid chromatography method for the separation and simultaneous quantification of eptifibatide and its impurities in pharmaceutical injection formulation. International Journal of Applied Pharmaceutics. 2021; 13(2): 165-172.

ICH. Validation of Analytical Procedures: Text and Methodology Q2(R1), 1994; 1-13.

Varma BHR, Rao BS. Gas Chromatography-Head Space-Mass Spectrometry Sensor based Quality Control of Dobutamine Hydrochloride Bulk Material for a mutagenic impurity, 2-bromopropane. Research Journal of Chemistry and Environment. 2023; 27: 54-61.

Rajesh VB, Battula SR, Kapavarapu MVNR, Mandapati VR. A novel Rivaroxaban degradation impurity detection by RP-HPLC extraction by preparative chromatography, and characterization by LC-MS, NMR and FT-IR: Analysis of novel impurity in batch samples and tablets of Rivaroxaban. RASĀYAN Journal of Chemistry. 2022; 15: 2373-2381.

Rajesh VB, Sreenivasa RB, Maruthi VNRK, Varaprasad RM. Assessment of gas chromatography methodology approach for the trace evaluation of carcinogenic impurity. methyl chloride, in trimetazidine dihydrochloride. Annales pharmaceutiques françaises. 2023; 81: 64-73.

Varma RB, Rao BS. Gas Chromatography-Head Space-Flame Ionization Sensor based assessment of four residuary solvents in rivaroxaban bulk medication. Research Journal of Pharmacy and Technology. 2022; 15: 5158-5163.