Forced Degradation Studies to Assess the Stability of a Janus Kinase Inhibitor Using RPLC Method

Year 2021, Volume: 25 Issue: 1, 134 - 141, 20.04.2021

Hulya Yilmaz

https://doi.org/10.19113/sdufenbed.826534

Cited By: 2

Abstract

In optimization studies, it is important to study the retention behavior of the compounds containing the ionizable functional groups under the intended chromatographic conditions. In this study, the influence of pH and acetonitrile (ACN) composition in the mobile phase on chromatographic behavior of tofacitinib (TOF), a Janus kinase (JAK) inhibitor, was thoroughly investigated. First, the chromatographic conditions were optimized using retention factors and pKa values. Then, the developed method was used for the stability studies under various stress conditions, and for the estimation of TOF concentration in tablets. Finally, the method was verified using the International Conference on Harmonization procedure (ICH-Q2) and was successfully used to separate the TOF degradation products. A linearity range, the limits of detection and quantification were confirmed as 2.0-12.0, 0.416, and 1.260 μg/mL, respectively. Between-day and within-day accuracy (RSD%) were found to be as 0.290 and 0.462 for 4 μg/mL, respectively. The result indicates that the developed method is rather effective to isolate the parent drug from the degradation elements.

Keywords

Chromatography, Tofacitinib, RPLC, Method validation, Drug formulation, Forced degradation

Supporting Institution

Institutional Research Fund of the Suleyman Demirel University

Project Number

4580-D2-16

Thanks

The presented study is a part of the project number 4580-D2-16 supported by the Institutional Research Fund of the Suleyman Demirel University. I thank the Prof. Dr. Ebru Çubuk Demiralay for her expertise and assistance throughout all aspects of my study.

Janus Kinase İnhibitörünün Stabilitesini Değerlendirmeye Yönelik RPLC Metodu Kullanılarak Yapılan Zorunlu Bozunma Çalışmaları

Abstract

Optimizasyon çalışmalarında, iyonlaşabilen bir fonksiyonel grup içeren bileşiklerin belli kromatografik koşullar altında alıkonma davranışlarını incelemek önemlidir. Bu çalışma da, janus kinaz (JAK) inhibitörü olan tofasitinibin (TOF) kromatografik davranışlarında mobil faz asetonitril (ACN) bileşiminin ve pH’ın etkisi kapsamlıca araştırılmıştır. Öncelikle, pKa ve alıkonma faktörü değerleri kullanılarak kromatografik şartlar optimize edilmiştir. Ardından, geliştirilen metot çeşitli stres testleri altında stabilite çalışmaları ve tabletteki tofasitinibin konsantrasyon belirlenmesinde kullanılmıştır. Son olarak, metot Uluslararası Uyumlaştırma Konferansı (Q2) kılavuzuna göre valide edilmiş ve tofasitinibin bozunma ürünlerinin ayrılmasında başarılı olarak kullanılmıştır. Lineer aralık, tespit ve tayin limitleri sırasıyla 2.0-12.0, 0.416, and 1.260 μg/mL, olarak elde edilmiştir. Gün içi, günler arası doğruluk (RSD%), 4 μg/mL için sırasıyla 0.290 ve
0.462 μg/mL bulunmuştur. Bu sonuçlara göre, geliştirilen metot bozunma ürünlerinden ana ilacı ayırmak için oldukça etkilidir.

Keywords

Kromatografi, Tofasitinib, RPLC, Metot validasyonu, İlaç formülasyonu, Zorlanmış bozunma

Project Number

4580-D2-16

References

• [1] Ghoreschi, K., Laurence, A., O’shea, J. J. 2009. Janus kinases in immune cell signaling. Immunological Reviews, 228, 273-287.
• [2] Sandborn, W. J., Ghosh, S., Panes, J., Vranic, I., Su C, Rousell, S., Niezychowski W. 2012. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. New England Journal of Medicine, 367, 616-624.
• [3] Papp, K. A., Menter, A., Strober, B., Langley, R. G., Buonanno, M., Wolk, R., Gupta, P., Krishnaswami, S., Tan, H., Harness, J. A. 2012. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. British Journal of Dermatology, 67, 668- 677.
• [4] Craiglow, B. G., King, B. A. 2014. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. Journal of Investigative Dermatology. 134, 2988- 2990.
• [5] Hodge, J. A., Kawabata, T. T., Krishnaswami, S., Clark, J. D., Telliez, J. B., Dowty, M. E., Menon, S., Lamba, M., Zwillich, S. 2016. The mechanism of action of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clinical and Experimental Rheumatology. 34, 318-328.
• [6] Lloyd, R., Snyder, J., Kirkland, J., Joseph, L. G., 2002. Practical HPLC method development. Pinehurst, North Carolina, USA.
• [7] Demiralay, E. C, Alsancak, G., Ozkan, S.A. 2009. Determination of pKa values of nonsteroidal antiinflammatory drug-oxicams by RP–HPLC and their analysis in pharmaceutical dosage forms. Journal of Separation Science. 32, 2928- 2936.
• [8] Canbay, H. S., Demiralay, E. C., Alsancak, G., Ozkan, S. A. 2012. The combined effect of the organic modifier content and pH of the mobile phase on the chromatographic behavior of some arylpropionic and arylacetic acids to optimize their liquid chromatographic determinations. Chromatographia, 75, 711-720.
• [9] García-Álvarez-Coque, M. C., Torres-Lapasió, J. R., Baeza-Baeza, J. J. 2006. Models and objective functions for the optimization of selectivity in reversed-phase liquid chromatography. Analytica Chimica Acta, 579, 125-145.
• [10] Snyder, L. R., Kirkland, J. J., Dolan, J. W. 2010. Introduction to modern liquid chromatography. Third edition, A John Wiley&Sons.
• [11] Ortak, H. Y. Demiralay, E. C. 2019. Effect of temperature on the retention of Janus Kinase 3 inhibitor in different mobile phase compositions using reversed-phase liquid chromatography. Journal of Pharmaceutical and Biomedical Analysis 5, 706-712.
• [12] Sankar, A. S. K., Datchayani, B., Balakumaran, N., Mohammed, R., Subaranjani, R. 2017. Development of a validated reverse phase liquid chromatographic assay-method for determination of tofacitinib in pure form and in physical admixtures. Research Journal of Pharmacy and Technology, 10, 223-226.
• [13] Prathyusha Naik C. N. Chandra Sekhar K. B. 2018. Novel stability indicating chromatographic method development and validation for the quantification of tofacitinib in pure and its dosage form. IOSR Journal of Applied Chemistry, 11, 33-37.
• [14] Kiran, B. S. S., Raja, S. 2018. RP-HPLC method development and validation for the quantification of tofacitinib. Research Journal of Life Sciences, Bioinformatics, Pharmaceutical and Chemical Sciences. 4, 646-653.
• [15] Dowty, M. E., Lin, J., Ryder, T. F., Wang, W., Walker, G. S., Vaz, A., Chan, G. L., Krishnaswami, S., Prakash, C. 2014. The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans. Journal of Pharmacology and Experimental Therapeutics, 348, 165-173.
• [16] Kumar, V., Dhiman, V., Kumar, K., Sharma, G.K., Zainuddin, M., Mullangi, R. 2015. Development and validation of a RP‐HPLC method for the quantitation of tofacitinib in rat plasma and its application to a pharmacokinetic study. Biomedical Chromatography, 29, 1325-1329.
• [17] Sharma, K., Giri, K., Dhiman, V., Dixit, A., Zainuddin, M., Mullangi, R. 2015. A validated LC‐ MS/MS assay for simultaneous quantification of methotrexate and tofacitinib in rat plasma: application to a pharmacokinetic study. Biomedical Chromatography, 29, 722-732.
• [18] Kadi, A. A., Abdelhameed, A. S., Darwish, H. W., Attwa, M. W. Bakheit, A. H. 2016. Liquid chromatographic-tandem mass spectrometric assay for simultaneous quantitation of tofacitinib, cabozantinib and afatinib in human plasma and urine. Tropical Journal of Pharmaceutical Research, 15, 2683-2692.
• [19] Wu, X., Zeng, X., Wang, L., Hang, T. and Song, M., 2017. Identification of related substances in tofacitinib citrate by LC-MS techniques for synthetic process optimization. Journal of Pharmaceutical and Biomedical Analysis, 143, 17-25.
• [20] Barbosa, J. Sanz-Nebot, V. 1992. pH measurements in acetonitrile-water mixtures by use of a glass electrode. Journal of Pharmaceutical and Biomedical Analysis, 10, 1047-1051.
• [21] Rondinini, S., Mussini, P. R., Mussini T. 1987. Reference value standards and primary standards for pH measurements in Organic Solvents and Water + Organic Solvent Mixtures of Moderate to High Permittivity’s. Pure and Applied Chemistry, 59(11), 1549-1560.
• [22] Yilmaz H., Demiralay, E. Ç. 2015. Investigation of chromatographic behavior of leflunomide and its identification in pharmaceutical dosage form by reversed phase liquid chromatography. Journal of Liquid Chromatography & Related Technologies, 38, 1.
• [23] Stout, R. W., De Stefano, J. J., Snyder, L. R. 1983. High-performance liquid chromatographic column efficiency as a function of particle composition and geometry and capacity factor. Journal of Chromatography A, 282, 263-286.
• [24] International Conference on Harmonisation, 2003. International conference on harmonization of technical requirements for registration of pharmaceuticals for human use, topic Q1A (R2): stability testing of new drug substances and products.
• [25] Dogan Daldal, Y., Çakır, C., Yılmaz, H., Cubuk Demiralay, E., A Ozkan, S., Alsancak, G., 2014. Liquid Chromatographic, Spectrophotometric and Potentiometric pKa Determination of Ranitidine and Famotidine. Current Drug Therapy, 9(4), 277-284.
• [26] Yilmaz, H., Cobandede, Z., Yilmaz, D., Cinkilic, A., Culha, M., Demiralay, E. C. 2020. Monitoring forced degradation of drugs using silica coated AgNPs with surface-enhanced Raman scattering. Talanta, 214(1), 120828.