Determination of Ionization Constants of Loratadine and Desloratadine by HPLC Method

Abstract

One of the increasingly common diseases of the age is allergic rhinitis. In the treatment of allergic rhinitis, primarily allergens and drug treatment are used. Antihistamines are used to reduce the effect of allergens. Therefore, physicochemical parameters, side effects and drug interactions such as solubility, biological activity, absorption, lipophilic effects and ionization constants of these drugs have been investigated in recent years. The ionization constant (pK_a) is the pH at which the ionized and non-ionized forms of a molecule are equal to each other. pK_a value affects the drug absorption. Because most of the drugs are low water-soluble molecules, water-organic solvent binary mixtures are used in the determination of ionization constants. In this study, ionisation constant values ​​of loratadine and desloratadine in water-acetonitrile solvent were determined by HPLC method. The pK_a values ​​obtained by using non linear regression program (NLREG) were changed to aqueous pK_a values by means of Mole fraction-pK_a method and Yasuda-Shedlovsky extrapolation method. It was observed that the data obtained were in harmony with the data calculated by the computer program.

Keywords

• Ionization constant,HPLC,Allergic rhinitis

Loratadin ve Desloratadin’in İyonlaşma Sabitlerinin HPLC Yöntemi ile Tayini

Abstract

Çağın giderek yaygınlaşan hastalıklarından biri alerjik rinittir. Alerjik rinitin tedavisinde öncelikle alerjenlerden kaçınma ve ilaç tedavisi kullanılır. İlaç olarak daha çok alerjenin etkisini azaltan antihistaminikler kullanılır. Bu sebeple son yıllarda bu ilaçların çözünürlük, biyolojik aktivite, absorpsiyon, lipofilik etkileri ve iyonlaşma sabitleri gibi fizikokimyasal parametreleri, yan etkileri ve ilaç etkileşimleri daha kapsamlı araştırılmaktadır. İyonlaşma sabiti (pK_a) bir molekülün iyonlaşmış ve iyonlaşmamış formlarının birbirine eşit olduğu pH değeridir. pK_a değeri ilaç absorbsiyonunu etkiler. İlaçların çoğu suda çözünürlüğü az olan moleküller olduğu için iyonlaşma sabitlerinin tayinlerinde su-organik çözücü ikili karışımları kullanılır. Bu çalışmada loratadin ve desloratadin’in su-asetonitril çözücü karışımında iyonlaşma sabiti değerleri HPLC yöntemiyle tayin edilmiştir. Non lineer regresyon programı (NLREG) kullanılarak elde edilen pK_a değerlerinden Mol kesri-pK_a yöntemi ve Yasuda-Shedlovsky ekstrapolasyon yöntemiyle sudaki pK_a değerlerine geçilmiştir. Elde edilen verilerin bilgisayar programı ile hesaplanan verilerle uyum içerisinde olduğu gözlenmiştir.

Keywords

• İyonlaşma sabiti,HPLC,Alerjik rinit

References

1. [1] Anonim, 2015. Türkiye Ulusal Allerji ve Klinik İmmünoloji Derneği. http://www.aid.org.tr/tr/allerjik-hastaliklar-menusu/allerjik-rinit-allerjik-nezle.html (ErişimTarihi: 25.08.2016).
2. [2] Bousquet, J., Van Cauwenberge, P., Khaltaev, N. 2001. Allergic rhinitis and its impact on asthma. Journal of allergy and clinical immunology, 108(5), 147-334.
3. [3] Kaleli, E. 2010. Loratadin’den desloratadin sentezi ve polimorfik yapılarının incelenmesi. Gazi Üniversitesi, Fen Bilimleri Enstitüsü, Yüksek Lisans Tezi, Ankara.
4. [4] Özluoğlu, L.N., Saydan, L., Kızılay, A., 1994. Antihistaminikler. KBB ve Baş Boyun Cerrahi Dergisi, 2(1), 71-74.
5. [5] Anonim, 2003. tipedu.cumhuriyet.edu.tr/Donem3/.../Farmakoloji/.../HistaminveAntihistaminikler.doc (Erişim Tarihi: 25.08.2016).
6. [6] Li, J.J., Johnson, D.S., Sliskovic, D.R., Roth, B.D. 2004. Contemporary drug synthesis. John Wiley & Sons. New Jersey, 221s.
7. [7] Rossotti, J. C., Rossotti, H. 1961. The Determination of Stability Constants. McGraw-Hill. New York, 425s.
8. [8] Paul, W.W., Lois, E.W. 1966. Spectrophotometric determination of the acid dissociation constants of 3-hydroxypyridine. Analytical Biochemistry, 15(3), 421-425.

9. [9] Albert, A., Serjeant, E. P. 1971. The Determination Of Ionization Constants and Laboratory Manual. Chapman and Hall, 115s.
10. [10] Benet, L.Z., Goyan, J.E. 1967. Potentiometric determination of dissociation constants. J Pharm Sci 56(6), 665-680.
11. [11] Sixma, F. L. J., Wynberg, H. 1964. A Manual of Physical Methods in Organic Chemistry. John Wiley & Sons, Inc. New York, 342s.
12. [12] Kroflic, A., Apelbla,t A., Bešter-Rogac, M. 2012. Dissociation constants of parabens and limiting conductance’s of their ions in water. J Phys Chem B. 116(4), 1385-1392.
13. [13] Rabenstein, D.L., Sayer, T.L. 1976. Carbon-13 chemical shift parameters for amines, carboxylic acids, and amino acids. Journal of Magnetic Resonance, 24,27.
14. [14] Zimmerman, I. 1982. Determination of pKa values from solubility data. International Journal of Pharmaceutics, 13(1), 57-65.
15. [15] Horvath, C., Melander, W., Molnár, I. 1977. Liquid chromatography of ionogenic substances with nonpolar stationary phases (Solvophobic Theory of Reversed Phase Chromatography, Part II). Anal Chem 49(1), 142-154.
16. [16] Chung, T.D., Kim, H. 2001. Voltammetric determination of the pKa of various acids in polar aprotic solvents using 1,4-benzoquinone. J Electroanalytical Chemistry 498(1-2), 209-215.
17. [17] Tajc, S.G., Tolbert, B.S., Basavappa, R., Miller, B.L. 2004. Direct determination of thiol pKa by isothermal titration microcalorimetry. J Am Chem Soc 126(34), 10508-10509.
18. [18] Fuguet, E., Ràfols, C., Bosch, E., Roses, M. 2009. Fast highthroughput method for the determination of acidity constants by capillary electrophoresis. J Chromatogr A, 1216(17), 3646-3651.
19. [19] Rosenberg, L.S., Simons, J., Schulman, S.G. 1979. Determination of pKa values of N-heterocyclic bases by fluorescence spectrophotometry. Talanta 26(9), 867-871.
20. [20] Katzin, L.I., Gulyas, E. 1960. Dissociation constants of tartaric acid with the aid of polarimetry. J Phys Chem. 64(11), 1739-1741.
21. [21] Bunnett, J.F., Nudelman, N.S. 1969. Ndependent, Kinetic Method for Determining Acid Dissociation Constants in Methanol. Journal of Organic Chemistry 34(7), 2043-2046.
22. [22] Tehan, B.G., Lloyd, E.J., Wong, M.G., Pitt. W.R., Montana, J.G. 2002. Estimation of pKa using semi empirical molecular orbital methods. Part 1: Application to phenols and carboxylic acids. QSAR 21(5), 457-472.
23. [23] ter Laak, A.M., Tsai, R.S., Donne-Op den Kelder, G.M., Carrupt, P.A., Testa, B., Timmerman, H. 1994. Lipophilicity and hydrogen-bonding capacity of H1-antihistaminic agents in relation to their central sedative side-effects. Eur. J. Pharm. Sci, 2, 373–384.
24. [24] Popovic´, G., Cakar, M., Agbaba, D. 2009. Acid–base equilibria and solubility of loratadine and desloratadine in water and micellar media. Journal of Pharmaceutical and Biomedical Analysis 49, 42–47.