DETERMINATION OF CHROMATOGRAPHIC PROTONATION CONSTANTS OF SOME IMIDAZOLE ANTIMYCOTIC DRUGS IN ACETONITRILE-WATER BINARY MIXTURES

Yıl 2022, Cilt: 46 Sayı: 2, 405 - 417, 29.05.2022

Hayrettin Seçilmiş , Ebru Çubuk Demiralay , Kader Poturcu

https://doi.org/10.33483/jfpau.1081989

Cited By: 1

Öz

Objective: In this study, the thermodynamic protonation constant ((_s^s)〖pK〗_a ) of antifungal azole derivative miconazole and tioconazole were investigated by the reversed-phase liquid chromatography (RPLC) method. Although classical stationary phases are the most commonly used column-packed materials in the analyses of these compounds by the RPLC method, the determination of the pKa value of miconazole and tioconazole with a cyano-based column has not been reported so far.

Material and Method: Chromatographic behavior of the selected compounds was determined with Ultra Cyano column (Restek®, 150×3.0 mm I.D, 3µm) which is compatible with hydrophobic compounds. The dependence of the retention times on the acetonitrile content of the mobile phase and the effect of the mobile phase pH on the chromatographic retention was determined for each compound by changing the pH in the range of 3.0-7.50.

Result and Discussion: The (_s^s)〖pK〗_a values were determined by a nonlinear regression program. The thermodynamic aqueous pKa ((_w^w)〖pK〗_a ) value of the studied compounds was calculated from the (_s^s)〖pK〗_a value by using the macroscopic parameters (dielectric constant and mole fraction) that play an important role in the solvent properties. The calculated (_w^w)〖pK〗_a values were compared with literature values.

Anahtar Kelimeler

Combined effect, Imidazole, Nonlinear regression, RPLC

Teşekkür

We acknowledge Dr. Jose Luis Beltran (University of Barcelona) for kindly providing the NLREG 4.0 program.

ASETONİTRİL-SU İKİLİ KARIŞIMLARINDA BAZI İMİDAZOL ANTİMİKOTİK İLAÇLARIN KROMATOGRAFİK PROTONASYON SABİTLERİNİN BELİRLENMESİ

Öz

Amaç: Bu çalışmada, antifungal azol türevi mikonazol ve tiokonazolün termodinamik protonasyon sabiti ((_s^s)〖pK〗_a ) ters faz sıvı kromatografisi (RPLC) yöntemi ile araştırılmıştır. Bu bileşiklerin RPLC yöntemi ile analizlerinde klasik sabit fazlar en yaygın olarak kullanılan kolon dolgulu malzemeler olmasına rağmen, siyano bazlı bir kolonla şimdiye kadar mikonazol ve tiokonazolün pKa değerinin tayini rapor edilmemiştir.

Gereç ve Yöntem: Seçilen bileşiklerin kromatografik davranışları hidrofobik bileşiklerle uyumlu Ultra siyano kolon (Restek®, 150×3.0 mm I.D, 3µm) ile belirlenmiştir. Alıkonma sürelerinin mobil fazın asetonitril içeriğine bağımlılığı ve mobil faz pH'ının kromatografik alıkonma üzerindeki etkisi, pH 3.0-7.50 aralığında değiştirilerek her bir bileşik için belirlenmiştir.

Sonuç ve Tartışma: (_s^s)〖pK〗_a değerleri, doğrusal olmayan bir regresyon programı ile belirlenmiştir. Çalışılan bileşiklerin termodinamik suda pKa ((_w^w)〖pK〗_a ) değeri, çözücü özelliklerinde önemli bir rol oynayan makroskopik parametreler (dielektrik sabiti ve mol fraksiyonu) kullanılarak (_s^s)〖pK〗_a değerinden hesaplanmıştır. Hesaplanan (_w^w)〖pK〗_a değerleri literatür değerleri ile karşılaştırılmıştır.

Anahtar Kelimeler

Birleşik etki, İmidazol, Nonlineer regresyon, RPLC

Kaynakça

• 1. Bongomin, F., Gago, S., Oladele R.O, Denning D.W. (2017). Global and multi-national prevalence of fungal diseases-estimate precision. Journal of Fungi, 3, 1-29. [CrossRef]
• 2. Moraes, F., Bittencourt, S.F., Perissutti, E., Frencentese, F., Arruda, A.M.M., Shi Chen, L., Babadópulos, T., Nucci, G. (2014). Quantification of dapaconazole in human plasma using high-performance liquid chromatography coupled to tandem mass spectrometry: Application to a phase I study. Journal of Chromatography B, 958, 102-107. [CrossRef]
• 3. Shalini, K., Kumar, N., Drabu, S., Sharma, P.K. (2011). Advances in synthetic approach to and antifungal activity of triazoles. Beilstein journal of organic chemistry, 7, 668-677. [CrossRef]
• 4. Carrillo-Muñoz, A.J., Tur-Tur, C., Hernández-Molina, J.M., Santos, P., Cárdenes, D. et.al. (2010). Antifungal agents for onychomycoses. Revista Iberoamericana de Micologia, 27, 49-56. [CrossRef]
• 5. Piel, G., Evrard, B., Fillet, M., Llabres, G., Delattre, L. (1998). Development of a non-surfactant parenteral formulation of miconazole by the use of cyclodextrins. International journal of pharmaceutic, 169, 15-22. [CrossRef]
• 6. Zan, M.M., Cámara, M.S., Robles, J.C., Kergaravat, S.V., Goicoechea, H.C.(2009). Development and validation of a simple stability-indicating high performance liquid chromatographic method for the determination of miconazole nitrate in bulk and cream formulations. Talanta, 79, 762-767. [CrossRef]
• 7. Manallack, D. (2007). The pKa Distribution of Drugs: Application to Drug Discovery. Perspectives in Medicinal Chemistry, 1, 25-38. [CrossRef]
• 8. Avdeef, A. (2012). Absorption and Drug Development, Solubility, Permeability, and Charge State. John Wiley & Sons, Inc.
• 9. Box, K., Bevan, C., Comer, J., Hill, A., Allen, R., Reynolds, D. (2003). High-throughput measurement of pKa values in a mixed-buffer linear pH gradient system. Analytical Chemistry, 75, 883-892. [CrossRef]
• 10. Box, K., Comer, J. (2008). Using Measured pKa, LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Current drug metabolism, 9, 869-878. [CrossRef]
• 11. Jelfs, S., Ertl, P., Selzer, P. (2007). Estimation of pKa for druglike compounds using semiempirical and information-based descriptors. Journal of Chemical Information and Modeling, 47, 450-459. [CrossRef]
• 12. Babić, S., Horvat, A.J.M, Mutavdžić, P., Kaštelan-Macan, M. (2007). Determination of pKa values of active pharmaceutical ingredients. TrAC - Trends in Analytical Chemistry, 26, 1043-1061. [CrossRef]
• 13. Canals, I., Valkó, K., Bosch, E., Hill, A.P., Rosés, M. (2001). Retention of ionizable compounds on HPLC. 8. Influence of mobile-phase pH change on the chromatographic retention of acids and bases during gradient elution. Analytical Chemistry,73, 4937-4945. [CrossRef]
• 14. Yılmaz, H., Üstün, Z., Çubuk Demiralay, E. (2016). RPLC determination of acid dissociation constants and quantitative estimation for sulfasalazine. Journal of the Iranian Chemical Society, 13, 103-110. [CrossRef]
• 15. Manderscheid, M., Eichinger, T. (2003). Determination of pKa values by liquid chromatography. Journal of Chromatographic Science, 41, 323-326. [CrossRef]
• 16. Bocian, S., Krzemińska, K. (2019). The Separations Using Pure Water as A Mobile Phase in Liquid Chromatography Using Polarembedded Stationary Phases, Green chemistry letters and reviews, 12(1), 69-78. [CrossRef]
• 17. Kazakevich, Y., Lobrutto, Y. (2007). HPLC for Pharmaceutical Scientists, first ed. USA: Wiley-Interscience.
• 18. Espinosa, S., Bosch, E., Rosés, M. (2002). Retention of ionizable compounds in high-performance liquid chromatography. IX. Modelling retention in reversed-phase liquid chromatography as a function of pH and solvent composition with acetonitrile-water mobile phases. Journal of Chromatography A, 947(1), 47-58. [CrossRef]
• 19. Daldal, Y.D., Çubuk Demiralay, E. (2020). Chromatographic and UV-Visible Spectrophotometric pKa Determination of Some Purine Antimetabolites. Journal of Molecular Liquids, 317, 1-8. [CrossRef]
• 20. Bosch, E., Espinosa, S., Rosés, M. (1998). Retention of Ionizable Compounds on High-Performance Liquid Chromatography III. Variation of pKa Values of Acids And pH Values of Buffers in Acetonitrile-Water Mobile Phases. Journal of Chromatography A, 824, 137-146. [CrossRef]
• 21. Poole, C.F., Poole, S.K. (1991). Chromatography Today. Elsevier, Amsterdam.
• 22. Pallicer, J.M., Calvet, C., Port, A., Rosés, M., Ràfols, C. et.al. (2012). Extension of the liquid chromatography/quantitative structure-property relationship method to assess the lipophilicity of neutral, acidic, basic and amphotheric drugs. Journal of Chromatography A, 1240, 113-122. [CrossRef]
• 23. Peeters, J. (1978). Determination of ionization constants in mixed aqueous solvents of varying composition by a single titration. Journal of Pharmaceutical Sciences, 67, 127-129. [CrossRef]
• 24. Miller, J.M., Blackburn, A.C., Shi, Y., Melzak, A.J., Ando, H.Y. (2002). Semi-empirical relationships between effective mobility, charge, and molecular weight of pharmaceuticals by pressure-assisted capillary electrophoresis: Applications in drug discovery. Electrophoresis, 23, 2833-2841. [CrossRef]
• 25. Şanli, S., Başaran, F., Şanli, N., Akmeşe, B., Bulduk, I. (2013). Determination of dissociation constants of some antifungal drugs by two different methods at 298 K. Journal of Solution Chemistry, 42, 1976-1987. [CrossRef]
• 26. Mussini, T., Covington, A.K., Longhi, P., Rondinini, S. (1985). 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. [CrossRef]
• 27. 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 Permittivities. Pure and Applied Chemistry, 59, 1549-1560. [CrossRef]
• 28. Dolan, J.A. (2009). A Guide to HPLC and LC-MS Buffer Selection. New York. [CrossRef]
• 29. Barbosa, J., Bergés, R., Sanz-Nebot, V. (1998). Retention behaviour of quinolone derivatives in high-performance liquid chromatography: Effect of pH and evaluation of ionization constants, Journal of Chromatography A, 823(1-2), 411-422. [CrossRef]
• 30. Sherrod, P. H. Nonlinear Regression Analysis Program (NLREG) Version 4.0. Nashville, TN, USA. 1998. Accessed May 20, 2021.
• 31. SwissADME program. http://www.swissadme.ch/. Accessed June 08, 2020.
• 32. Barbosa, J., Sanz-Nebot, V. (1991). Autoprotolysis Constants and Standardization of the Glass Electrode in Acetonitrile-Water Mixtures. Effect of Solvent Composition. Anaytica Chimica Acta, 244, 183-191. [CrossRef]
• 33. Tallarida, R.J., Murray, R.B. (1987). Henderson-Hasselbalch Equation, in: R.J. Tallarida, R.B. Murray (Eds.), Manual of Pharmacologic Calculations. New York: Springer.
• 34. http://www.chemicalize.org. accessed 20 July 2018.