Determination of Ionization Constant Value in Water-Acetonitrile Binary Mixtures of Favipiravir and Comparison of Two Different C18 Columns

Year 2023, , 129 - 139, 22.06.2023

Ümit Ayhan Arzuoğlu , İlkay Konçe , Ebru Çubuk Demiralay

https://doi.org/10.29233/sdufeffd.1192328

Abstract

Favipiravir (T-705) is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase of RNA viruses. The reverse phase liquid chromatography (RPLC) method is mostly preferred in the qualitative and quantitative analysis of this compound. This method is highly preferred for the determination of ionization/protonation (pKa) constants of compounds containing acidic and basic functional groups. The pKa value is important parameter to predict the physicochemical and biological properties of compounds. This parameter is an important data including the absorption, distribution, metabolism, excretion, and toxicity (ADMET) characterization of drugs. In this study, the RPLC method was developed using two different chromatographic columns for the determination of the pKa value of favipiravir in a water-acetonitrile binary mixture, and the chromatographic behavior of favipiravir was determined by changing the amount of acetonitrile in the mobile phase. The study was carried out at 37 ℃ column temperature and constant flow rates. The pKa value of the compound was determined by using sigmoidal and nonlinear models with the obtained retention data. The pKa value of hydrophilic favipiravir in water was calculated using the mobile phase pKa values and the macroscopic constants (mole fraction, dielectric constant, etc.) of acetonitrile. This important calculated physicochemical parameter is the first data obtained from the experimental study in the literature.

Keywords

Favipiravir, RPLC, Retention time, Ionization constant, Hydrophilic compound

Favipiravirin Su-Asetonitril İkili Karışımlarında İyonlaşma Sabiti Değerinin Belirlenmesi ve İki Farklı C18 Kolonun Karşılaştırılması

Abstract

Favipiravir (T-705), RNA virüslerinin RNA'ya bağımlı RNA polimerazını seçici ve güçlü bir şekilde inhibe eden bir anti-viral ajandır. Bu bileşiğin kalitatif ve kantitatif analizinde en çok ters faz sıvı kromatografi (RPLC) metodu tercih edilmektedir. Bu metot, asidik ve bazik fonksiyonel grup içeren bileşiklerin iyonlaşma/protonasyon (pKa) sabitlerinin tayini için çok tercih edilmektedir. pKa değeri, bileşiklerin fizikokimyasal ve biyolojik özelliklerini tahmin etmeye yarayan önemli bir parametredir. Bu parametre ilaçların absorpsiyon, dağılım, metabolizma, atılım, toksitite (ADMET) karakterizasyonunu da içeren önemli bir veridir. Sunulan bu çalışmada, favipiravirin su-asetonitril ikili karışımında pKa değerinin tayini için iki farklı özellikteki kromatografik kolonlar kullanılarak RPLC metot geliştirilmiş ve asetonitrilin mobil fazdaki miktarının değişimiyle favipiravirin kromatografik davranışı da belirlenmiştir. Çalışma 37℃ kolon sıcaklığında ve sabit akış hızlarında gerçekleştirilmiştir. Elde edilen alıkonma verileriyle sigmoidal ve doğrusal olmayan modeller kullanılarak bileşiğin pKa değeri belirlenmiştir. Hidrofilik özellikte olan favipiravirin su ortamındaki pKa değeri, mobil faz pKa değerleri ve asetonitrilin makroskopik sabitleri (mol kesri, dielektrik sabiti, vs.) kullanılarak hesaplanmıştır. Hesaplanan bu önemli fizikokimyasal parametre literatürdeki deneysel çalışma ile elde edilen ilk veridir.

Keywords

Favipiravir, RPLC, Alıkonma zamanı, İyonlaşma sabiti, Hidrofilik bileşik

References

• K. Shiraki, T. Daikoku, “Favipiravir, an anti-influenza drug against life-threatening RNA virus infections”, Pharmacology & Therapeutics, 209, 107512, 2020.
• O. S. Reddy, W.-F. Lai, “Tackling COVID-19 Using Remdesivir and Favipiravir as Therapeutic Options”. ChemBioChem, 22, 939−948, 2021.
• H. M. Marzouk, M. R. Rezk, A. S. Gouda, A. M. Abdel-Megied, “A novel stability-indicating HPLC-DAD method for determination of favipiravir, a potential antiviral drug for COVID-19 treatment; application to degradation kinetic studies and in-vitro dissolution profiling”, Microchemical Journal, 172, 106917, 2022.
• S. M. Megahed, A. A. Habib, S. F. Hammad, A. H. Kamal, “Chemometric approach based on factorial and Box-Behnken designs for determination of anti-coronavirus drug; favipiravir in bulk and spiked human plasma by green HPLC method”, Turkish Journal of Analytical Chemistry, 3(2), 70-78, 2021.
• S. M. Megahed, A. A. Habib, S. F. Hammad, A. H. Kamal, “Experimental design approach for development of spectrofluorimetric method for determination of favipiravir; a potential therapeutic agent against COVID-19 virus: Application to spiked human plasma”, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 249, 1192412, 2021.
• S. Allahverdiyeva, O. Yunusoglu, Y. Yardım, Z. Sentürk, “First electrochemical evaluation of favipiravir used as an antiviral option in the treatment of COVID-19: A study of its enhanced voltammetric determination in cationic surfactant media using a boron-doped diamond electrode”, Analytica Chimica Acta, 1159, 338418, 2021.
• P. Talay Pınar, T. Tuluk, Z. Şentürk,” Determination of Pravastatin Drug Formulation by Squarewave Voltammetry on Glassy Carbon Elektrode”, Dokuz Eylül Üniversitesi Mühendislik Fakültesi Fen ve Mühendislik Dergisi, 22(64), 29-35, 2020.
• M. Mehmandoust, Y. Khoshnavaz, M. Tuzen, N. Erk, “Voltammetric sensor based on bimetallic nanocomposite for determination of favipiravir as an antiviral drug”, Microchimica Acta, 188, 434, 2021.
• M. Hailat, I. Al-Ani, M. Hamad, Z. Zainab, W. A. Dayyih, “Development and Validation of a Method for Quantification of Favipiravir as COVID-19 Management in Spiked Human Plasma”, Molecules, 26, 3789, 2021.
• Y. Kazakevich, Y. Lobrutto, HPLC for Pharmaceutical Scientists, 1st ed. Wiley-Interscience, USA, 2007.
• V. R. Meyer, Practical High-Performance Liquid Chromatography, 5th ed., John Wiley and Sons, United Kingdom, 2010.
• R. Bergés, V. Sanz-Nebot, J. Barbosa, “Modelling Retention in Liquid Chromatography as a Function of Solvent Composition and pH of the Mobile Phase”, Journal of Chromatography A, 869, 27-39, 2000.
• M. Rosés, E. Bosch, “Influence of Mobile Phase Acid-Base Equilibria on The Chromatographic Behaviour of Protolytic Compounds”, Journal of Chromatography A, 982, 1-30, 2002.
• H. Seçilmiş, E. Çubuk Demiralay, K. Poturcu, “Determination of chromatographic protonation constants of some imidazole antimycotic drugs ın acetonitrile-water binary mixtures”, Journal of Faculty of Pharmacy of Ankara University, 46(2), 405-417, 2022.
• İ. Konçe, S. Akkoç, Z. Üstün, E. Çubuk Demiralay, “Liquid Chromatographic Determination of pKa Value of 1-(2-methylbenzonitrile)-3-benzylbenzimidazolium bromide as a Drug Candidate in Acetonitrile-Water Binary Mixtures”, Journal of Research in Pharmacy, 26(3), 655-662, 2022.
• N. Sun, A. Avdeef, “Biorelevant pKa (37℃) Predicted from the 2D Structure of the Molecule and its pKa at 25°C”, Journal of Pharmaceutical and Biomedical Analysis, 56, 173-182, 2011.
• R. J. Tallarida, R. B. Murray, Henderson-Hasselbalch Equation, Editors: R. J. Tallarida, R. B. Murray, Manual of Pharmacologic Calculations, Springer, New York, 1987, pp. 74-75.
• T. Mussini, A. K. Covington, P. Longhi, S. Rondinini, “Criteria for Standardization of pH Measurements in Organic Solvents and Water + Organic Solvent Mixtures of Moderate to High Permittivities”, Pure and Applied Chemistry, 57(6), 865-876, 1985.
• SwissADME program. http://www.swissadme.ch/index.php, Accessed: (ie. 25.09.2022).
• NLREG Version 4.0. P.H. Sherrod. http://www.sandh.com/Sherrod.1991, Accessed: (ie. 27.09.2022).
• E. M. Borges, D. A. Volmer, “Silica, Hybrid Silica, Hydride Silica and Non-Silica Stationary Phases for Liquid Chromatography. Part II: Chemical and Thermal Stability”, Journal of Chromatographic Science, 53, 1107-1122, 2015.
• A. Fanigliulo, D. Cabooter, G. Bellazzi, B. Allieri, A. Rottigni, G. Desmet, “Kinetic performance of reversed-phase C18 high-performance liquid chromatography columns compared by means of the Kinetic Plot Method in pharmaceutically relevant applications”, Journal of Chromatography A, 1218(21), 3351-335, 2011.
• G. da Silva, “Protonation, Tautomerism and Base Pairing of the Antiviral Favipiravir (T‐705)”, ChemRxiv, 1-7, 2020.
• L. Antonov, “Favipiravir tautomerism: A short theoretical report”, ChemRxiv, 1-13, 12115620, 2020.
• L. Antonov, “Favipiravir tautomerism: a theoretical insight”, Theoretical Chemistry Accounts, 139, 1-7 2020.
• Y. Umar, “Theoretical studies of the rotational and tautomeric states, electronic and spectroscopic properties of favipiravir and its structural analogues: a potential drug for the treatment of COVID-19”, Journal of Taibah University for Science, 14(1), 1613-1625, 2020.
• V. A. Babkin, D. S. Andreev, Y. A. Vashuta, A. V. Kozhukhova, V. S. Belousova, E. S. Titova, A. R. Titova, A. I. Rakhimov, A. K. Brel, R. O. Boldyrev, M. I. Artsis, G. E. Zaikov, “Theoretical Assessment of Acid Strength of Antiviral Favipiravir Medication”, Fluorine notes, 5(132), 1-5, 2020.
• A. Albert, J. N. Phillips, “Ionization constants of heterocyclic substances. Part II. Hydroxy-derivatives of nitrogenous six-membered ring-compounds”, Journal of the Chemical Society, 1254-1304, 1956.
• D. A. Keyworth, “Basicity and Ionization Constants of Some Pyrazine Derivatives”, The Journal of Organic Chemistry, 1355-1356, 1959.
• J. Barbosa, I. Toro, V. Sanz-Nebot, “Acid-Base Behaviour of Tripeptides in Solvents Used in Liquid Chromatography. Correlation Between pK Values and Solvatochromic Parameters of Acetonitrile-Water Mixtures”, Analytica Chimica Acta, 347(3), 295-304, 1997.
• Y. Motoo, “Dissociation Constants of Some Carboxylic Acids in Mixed Aqueous Solvents”, 32(5), 429-432, 1959.