LC-MS/MS characterization of stress degradation products of Gilteritinib and establishment of HPLC method for analysis of process related impurities of Gilteritinib

Srinivasa Rao Katta; Immani  Ramachandra Rao; P Punitha; Thota  Siva prasad

doi:10.18231/j.joapr.2024.12.2.109.123

Authors

Srinivasa Rao Katta Department of Chemistry, Radha Govind University, Ramgarh, Jharkhand
Immani Ramachandra Rao Department of Chemistry, Annamalai University, Annamalainagar – 608002, Tamil Nadu,
P Punitha Department of Chemistry, Annamalai University, Annamalainagar – 608002, Tamil Nadu
Thota Siva prasad Department of Chemistry, Andhra University, Visakhapatnam-530003, Andhra Pradesh

DOI:

https://doi.org/10.18231/j.joapr.2024.12.2.109.123

Keywords:

Gilteritinib, stress degradation products, characterization, impurity analysis

Abstract

Background: The current investigation entails the characterization of seven degradation products (DPs) formed in different stress conditions of gilteritinib employing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methodology: This study developed a stability-indicating reversed-phase high-performance liquid chromatographic (HPLC) method for precisely determining gilteritinib in the presence of its process-related impurities in bulk drug and formulation samples. To explore the stability profile of gilteritinib, it was exposed to forced degradation experiments conducted under various conditions, including acidic, basic, oxidative, photolytic, and thermal stress. These experiments revealed the degradation of gilteritinib under basic, acidic, and photolytic conditions, forming seven distinct DPs. Result: The chromatographic resolution of gilteritinib and its impurities along with DPs was effectively achieved using a Waters Symmetry C18 (250 mm × 4.6 mm, 5 μm) column using equal volumes of solvent A and B (pH 4.5 phosphate buffer and acetonitrile in 25:75 (v/v) as solvent A, acetonitrile and methanol in 75: 25 (v/v) as solvent B) pumped isocratically at 0.7 mL/min and 230 nm wavelength. The method produces an accurate fit calibration curve in 25-175 μg/mL for gilteritinib and LOQ (0.025 μg/mL) – 0.175 μg/mL for its impurities with acceptable precision, accuracy, and recovery. Conclusion: The efficacy of this method was validated through LC-MS/MS, which allowed for the verification of the chemical structures of newly generated degradation products of gilteritinib. Hence, this method is appropriate for the resolution and evaluation of process-related impurities of gilteritinib and can also be applied for evaluating stress degradation products.

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References

Short NJ, Nguyen D, Ravandi F. Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors. Blood Cancer J. 13, 142 (2023)

Vignal N, Kelly L, Lengline E, Cabannes-Hamy A. Favorable pharmacokinetic and pharmacodynamic properties of gilteritinib in cerebrospinal fluid: a potential effective treatment in relapsing meningeal acute myeloid leukemia FLT3-ITD patients. Haematologica. 108, 2531-2534 (2023)

Pratiksha AK, Pankaj PT, Vijay KM, Raman MS, Bharti F, Vaidhun B. RP-HPLC Method for Determination of Gilteritinib in Tablet Dosage Form. Int J Pharm Sci Rev Res 77, 29-34 (2022).

Yasu T, Sugi T, Momo K, Hagihara M, Yasui H. Determination of the concentration of gilteritinib in human plasma using HPLC. Biomed Chromatogr 35, 5028 (2021).

Kharat PA, Sonawane B, Thakur PP, Munipalli VK, Warde SU, Singh RM, Fegade B. Development and Validation of HPTLC Method for Gilteritinib in Tablet Dosage Form. Int J. Pharm Pharm Res Hum 24, 382-395 (2022).

Zhang M, Tajima S, Suetsugu K, Hirota T, Tsuchiya Y, Yamauchi T, Yoshimoto G, Miyamoto T, Egashira N, Akashi K, Ieiri I. Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients with FLT3 Mutation-Positive Acute Myelogenous Leukemia. Therapeutic drug monitoring 44, 592-596 (2022).

Dominique A, Garrison, Yan Jin, Muhammad Erfan Uddin, Alex Sparreboom, Sharyn D, Baker. Development, validation, and application of an LC-MS/MS method for the determination of the AXL/FLT3 inhibitor gilteritinib in mouse plasma. J Chromatogr B 1179, 122882 (2021).

Attwa MW, AlRabiah H, Alsibaee AM, Abdelhameed AS, Kadi AA. An UPLC–ESI–MS/MS Bioanalytical Methodology for the Quantification of Gilteritinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Evaluation. Separations 10, 278 (2023).

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. Turk J Pharm Sci 16, 457-465 (2019).

Bikshal BK, Venkateswara RA, Useni RM. Stability-Indicating Reversed-Phase HPLC Method for the Separation and Estimation of Related Impurities of Cilnidipine in Pharmaceutical Formulations. Indian Drugs 55, 41-49 (2018).

Sri GK, Bikshal BK, Venkateswara RA. A new high-performance liquid chromatography method for the separation and simultaneous quantification of eptifibatide and its impurities in pharmaceutical injection formulation. Int J Appl Pharm 13, 165-172 (2021).

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 J Pharm Sci 42, 27-36 (2018).

International Conference of Harmonisation. ICH. Q1A(R2), Stability testing of new drug substances and products. Geneva: International Conference on Harmonization; 2003.

Varma RB, Rao BS. Gas Chromatography-Head Space-Flame Ionization Sensor based assessment of four residuary solvents in rivaroxaban bulk medication. Res J Pharm Technol 15, 5158-5163 (2022).

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. Res J Chem Environ 27, 54-61 (2023).

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. Rasayan J Chem 15, 2373-2381 (2022).

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. Ann Pharm Fr 81, 64-73 (2023).

Rajesh VB, Srinivasa Kumar B, Pavani P, Venkata ST. An effective HPLC method for evaluation of process related impurities of Letermovir and LC-MS/MS characterization of forced degradation compounds. J Chem Metrology 2, 181-198 (2023).