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

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

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

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