LC and LC-MS/MS Studies for Identification and Characterisation of Related Substances and Degradation Products of Abrocitinib

Jump To References Section

Authors

  • Department of Chemistry, Gandhi Institute of Technology and Management (GITAM), Institute of Science (Deemed to be University), Visakhapatnam - 530045 ,IN
  • Department of Mathematics, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur (D.T) - 522302, Andhra Pradesh ,IN
  • Department of Chemistry, Tagore Government Arts and Science College (Affiliated to Pondicherry University), Puducherry - 605008 ,IN
  • Dr.V.S Krishna Government Degree College, Visakhapatnam - 530013, Andhra Pradesh ,IN
  • Department of Chemistry, Hindu College, Guntur - 522003, Andhra Pradesh ,IN

DOI:

https://doi.org/10.18311/ti/2024/v31i2/36370

Keywords:

Abrocitinib, HPLC Analysis, LCMS Characterisation, Related Compounds, Stress Degradation Compounds

Abstract

In the pharmaceutical industry, Related Substances (RCs), impurities or Degradation Products (DPs) are associated with the Active Pharmaceutical Ingredient (API) in the final drug product. These compounds must be within permissible limits for safe therapeutic use for consumers. Hence there is a need to quantify these compounds using an appropriate analytical method. No method is reported in the literature for quantification of these compounds in abrocitinib which is a medical drug prescribed to treat severe atopic dermatitis in adults. This study includes the optimisation of stability indicating the HPLC method for resolution and subsequent quantification of abrocitinib RCs and structural characterisation of stressinduced DPs of abrocitinib. The method was optimised by varying mobile phase solvents, pH, flow rate and wavelength of the detector. The finalised conditions were validated and applied for the resolution and evaluation of stress-induced DPs. The stress was induced in abrocitinib pure drug HCl (0.1M), NaOH (0.1M), hydrogen peroxide (3%), 80°C in an air oven and 254nm in a UV chamber. The generated DPs were structurally characterised with the LCMS experiment. Abrocitinib and DPs along with known RCs were resolved on ACE Ultra Core Super C18 250mm column using 0.9mL/min gradient flow of methanol (Solvent A), acetonitrile and buffer (Solvent B). The resolved compounds were detected through a UV detector at 295nm and a mass detector at NMR positive mode. The method identifies 5.85min, 3.13min, 6.60min and 4.38min respectively for abrocitinib, related compounds 1 to 3 respectively with acceptable system suitability. A very high correlate (< 0.999) linear graph was achieved within 5 to 30 μg/mL concentration level for abrocitinib and 0.05 to 0.3μg/ mL for related compounds. Three DPs with molecular mass and formula of C10H13N5 (203.2 g/mol), C11H14N4 (202.2 g/mol) and C13H19N5O2S (309.3 g/mol) in acid-induced stress study and two DPs of C12H21N5O2S (299.3 g/mol) and C11H19N5O2S (285.3 g/mol) in peroxide-induced stress study and one DP of C10H14N4 (190.2 g/mol) in base induced stress study were successfully characterised. The method proposed in this study can effectively resolve unknown degradation products, and known related compounds along with abrocitinib and is hence applicable for quality control analysis of abrocitinib.

Downloads

Download data is not yet available.

Published

2024-04-25

How to Cite

Bhupatiraju, R. V., Kumar, B. S., Tangeti, V. S., Rekha, K., & Sayed, F. (2024). LC and LC-MS/MS Studies for Identification and Characterisation of Related Substances and Degradation Products of Abrocitinib. Toxicology International, 31(2), 321–334. https://doi.org/10.18311/ti/2024/v31i2/36370
Received 2024-01-26
Accepted 2024-04-12
Published 2024-04-25

 

References

Singh D, Isharani R. A detailed review on analytical methods to manage the impurities in drug substances. Open Access Libr. 2023; 10:1-18. https://doi.org/10.4236/oalib.1110223. DOI: https://doi.org/10.4236/oalib.1110223

Zelesky T, Baertschi SW, Foti C, Jansen PJ, Kotoni D, Laue C. Pharmaceutical forced degradation (Stress testing) endpoints: A scientific rationale and industry perspective. Special Topic Commentary. 2023; 112(12):2948-64. https:// doi.org/10.1016/j.xphs.2023.09.003. PMid:37690775. DOI: https://doi.org/10.1016/j.xphs.2023.09.003

Bhupatiraju RV, Kumar BS, Peddi P, Tangeti VS. An effective HPLC method for evaluation of process-related impurities of Letermovir and LC-MS/MS characterisation of forced degradation compounds. J Chem Metrol. 2023; 17(2):181- 98. https://doi.org/10.25135/jcm.98.2311.2975. DOI: https://doi.org/10.25135/jcm.98.2311.2975

Gabric A, Hodnik Z, Pajk S. Oxidation of drugs during drug product development: Problems and Solutions. Pharmaceutics. 2022; 14(2):325. https://doi.org/10.3390/ pharmaceutics14020325. PMid:35214057 PMCid: PMC8 876153 DOI: https://doi.org/10.3390/pharmaceutics14020325

Auclair J, Rathore AS. Analytical methods to determine the stability of biopharmaceutical products. LCGC North America. 2023; 41(1):23-7. https://doi.org/10.56530/lcgc. na.qc1477t9. DOI: https://doi.org/10.56530/lcgc.na.qc1477t9

Varma BHR, Rao BS. Gas chromatography- head spacemass spectrometry sensor based quality control of Dobutamine Hydrochloride bulk material for a mutagenic impurity. 2-bromopropane. Res J Chem Environ. 2023; 27:54-61. https://doi.org/10.25303/2702rjce054061. DOI: https://doi.org/10.25303/2702rjce054061

Rajesh VB, Battula SR, Kapavarapu MVNR, Mandapati VR. A novel Rivaroxaban degradation impurity detection by RP-HPLC extraction by preparative chromatography, and characterisation by LC-MS, NMR and FT-IR: Analysis of novel impurity in batch samples and tablets of Rivaroxaban. Rasayan J Chem. 2022; 15: 2373-81. https:// doi.org/10.31788/RJC.2022.1547008 DOI: https://doi.org/10.31788/RJC.2022.1547008

Varma RB, Rao BS. Gas chromatography-head spaceflame Ionisation sensor-based assessment of four residuary solvents in rivaroxaban bulk medication. Res J Pharm Technol. 2022; 15(11):5158-63. https://doi. org/10.52711/0974-360X.2022.00868 DOI: https://doi.org/10.52711/0974-360X.2022.00868

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. 2023; 81(1):64-73. https://doi.org/10.1016/j. pharma.2022.06.012. PMid:35803334. DOI: https://doi.org/10.1016/j.pharma.2022.06.012

Welsch K, Holstein J, Laurence A, Ghoreschi K. Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors. Eur J Immunol. 2017; 47(7):1096-107. https://doi.org/10.1002/eji.201646680. PMid:28555727. DOI: https://doi.org/10.1002/eji.201646680

Deckers IAG, McLean S, Linssen S, Mommers M, van Schayck CP, Sheikh A. Investigating international time trends in the incidence and prevalence of Atopic Eczema 1990-2010, A systematic review of epidemiological studies. PLoS ONE. 2012; 7(7):e39803. https://doi.org/10.1371/ journal.pone.0039803. PMid:22808063 PMCid:PMC 3394782. DOI: https://doi.org/10.1371/journal.pone.0039803

Tripathy S, Wentzel D, Wan XK, Kavetska O. Validation of enantioseparation and quantitation of an active metabolite of abrocitinib in human plasma. Bioanalysis. 2021; 13(19):1477-86. https://doi.org/10.4155/bio-2021-0128 PMid:34601943.

Fathima H, Yakhoob M, Khaleel M. Estimation and validation of abrocitinib dosage form and in bulk drug by spectrophotometric method. AJRC. 2023; 16(3):230-44. https://doi.org/10.52711/0974-4150.2023.00037 DOI: https://doi.org/10.52711/0974-4150.2023.00037

Limbad D, Sarkar S, Tarai DK. Development and validation of RP-HPLC method for estimation of abrocitinib in tablet dosage form. Int J All Res Educ Sci Methods. 2023; 11(5):1605-12.

Khan S, Thakker S, Mali P, Munipalli VK, Kumar A, Palekar S. Development and validation of a RP-HPLC method for the estimation of abrocitinib in tablet dosage form. World J Pharm Res. 202; 12(15):736-48.

Tripathy S, Wentzel D, Wan XK, Kavetska O. Validation of enantioseparation and quantitation of an active metabolite of abrocitinib in human plasma. Bioanalysis. 2021; 13(19):1477-86. https://doi.org/10.4155/bio-2021-0128 PMid:34601943. DOI: https://doi.org/10.4155/bio-2021-0128

Wang X, Gupta BP, Malhotra IK, Farooqui SA, Le VH, Wojciechowski J, Mukherjee A, Nicholas T. Population pharmacokinetic/pharmacodynamic modelling of the effect of abrocitinib on QTIntervals in healthy volunteers. Clin Pharmacol Drug Dev. 2022; 11(9):1036-45. https:// doi.org/10.1002/cpdd.1111 PMid:35532896 PMCid: PMC9835371. DOI: https://doi.org/10.1002/cpdd.1111

Bauman JN, Doran AC, King-Ahmad A, Sharma R, Walker G, Lin J, Lin TH, Telliez J-B, Tripathy S, Goosen TC, Banfield C, Malhotra BK, Dowty ME. The pharmacokinetics, metabolism and clearance mechanisms of abrocitinib, a selective Janus Kinase inhibitor, in humans. Drug Metab Dispos. 2022; 50:1106-18. https://doi.org/10.1124/ dmd.122.000829 PMid:35701182. DOI: https://doi.org/10.1124/dmd.122.000829

Wang WQ, Melissa O’Gorman V, Tripathy S, Dowty ME, Wang L, Malhotra BK. Effects of hepatic impairment on the pharmacokinetics of abrocitinib and Its metabolites. J Clin Pharmacol. 2021; 61(10):1311-23. https://doi.org/10.1002/ jcph.1858. PMid:33749838 PMCid: PMC8518898. DOI: https://doi.org/10.1002/jcph.1858

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

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. 2018; 42(1):27-36. DOI: https://doi.org/10.56808/3027-7922.2392

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. 2019; 16(4):457-65. https://doi.org/10.4274/tjps. galenos.2018.34635 PMid:32454750 PMCid: PMC7227885. DOI: https://doi.org/10.4274/tjps.galenos.2018.34635

Kasimala BB, Anna VR, Mallu UR. Stability-indicating reversed-phase HPLC method for the separation and estimation of related impurities of cilnidipine in pharmaceutical formulation. Indian Drugs. 2018; 55(12):41-9. https://doi.org/10.53879/id.55.12.11185 DOI: https://doi.org/10.53879/id.55.12.11185

Sri Girija K, Kasimala BB, Anna VR. A new highperformance liquid chromatography method for the separation and simultaneous quantification of eptifibatide and its impurities in pharmaceutical injection formulation. Int J App Pharm. 2021; 13(2):165-72. https://doi. org/10.22159/ijap.2021v13i2.39895 DOI: https://doi.org/10.22159/ijap.2021v13i2.39895