RP-LC Determination of Dissociation Constants and Quantitative Estimation of Antiulcer drugs, Famotidine, Nizatidine and Ranitidine in their Dosage Forms

Year 2015, Volume: 43 Issue: 3, 159 - 166, 01.09.2015

Bediha Akmeşe Yüksel Altun Senem Şanlı Nurullah Şanlı

Abstract

Dissociation constant value pKa is key parameter for predicting the extent of the ionization of a drug molecule at different pH. In this study, pKa values of famotidine, ranitidine and nizatidine in different percentages of acetonitrile-water binary mixtures 10%, 15%, and 20%, v/v were determined from the mobile phase pH dependence of retention factor with reverse phase liquid chromatographic method RPLC . From calculated pKa values, the aqueous pKa values of studied compounds were estimated by mole fraction of acetonitrile. Moreover, the correlation established between retention factor and the pH of the water-acetonitrile mobile phase was used to determination of optimum separation condition. In order to validate the optimized condition, famotidine, ranitidine and nizatidine were studied in their dosage forms. A X-Terra C-18 reverse-phase column 250x4.6mm I.D., 5 μm particles was preferred to carry out the developed method. Mobile phase of acetonit- rile-methanol-water 10:6:84, phosphate buffer pH: 6.5 and diode array detection system at wavelengths 210 and 320 nm were used as separation conditions. Under studied conditions detection limits of 0.5678 μg/mL for famotidine, 0.3100 μg/mL for ranitidine and 1.3144 μg/mL for nizatidine were found. The parameters, linearity, precision, accuracy, limit of detection, and limit of quantitation were studied according to U.S. Pharmacopoeia.

Keywords

Antiulcer Drugs, Famotidine, Ranitidine, Nizatidine, pKa, HPLC, Method validation

Antiülser İlaçlardan Famotidin, Nizatidin ve Ranitidin’nin Ayrışma Sabitlerinin RP-LC Tayini ve Dozaj Formlarından Kantitatif olarak Belirlenmesi

Abstract

Ayrışma sabiti değeri pKa , farklı pH değerinde, bir ilaç molekülünün iyonlaşma derecesini tahmin etmek için önemli bir parametredir. Bu çalışmada, Famotidin, Ranitidin ve Nizatidin’in farklı yüzdelerdeki asetonitril-su ikili karışımlarındaki %10, %15, %20, v/v pKa değerleri, sıvı kromatografisi yöntemi RPLC alıkonma faktörü ve hareketli faz pH değişimi ile belirlenmiştir. Hesaplanan pK değerlerinden incelenen bileşiklerin su ortamı pKa değerleri, asetonitrilin mol kesri kullanılarak tahmin edilmiştir. Ayrıca, alıkonma faktörü ve su-asetonitril hareketli fazının pH’sı arasında kurulan ilişki optimum ayırma koşulunun belirlenmesi için kullanılmıştır. Optimize edilmiş koşulu valide etmek için, Famotidin, Ranitidin ve Nizatidin kendi dozaj formlarından incelenmiştir. X-Terra C-18 ters-faz kolonu 250 x 4.6 mm ID, 5 um partikül , geliştirilen yöntem için tercih edilmiştir. Hareketli faz olarak asetonitril-metanol-su 10:6:84, fosfat tamponu pH: 6.5 , 210 ve 320 nm dalga boylarında diyot dizi algılama sistemi ayrım koşulları olarak kullanılmıştır. Çalışılan koşullarda Famotidin’in tayin sınırı 0.5678 ug/mL, Ranitidin ve Nizatidin için sırasıyla 0.3100 ug/mL ve 1.3144 ug/mL bulunmuştur. Doğrusallık, kesinlik, doğruluk, duyarlılık sınırı ve kantitatif tayin sınırı parametreleri, ABD Farmakopesine göre incelenmiştir

Keywords

Antiülser ilaçlar, Famotidin, Ranitidin, Nizatidin, pKa, HPLC, Methot validasyonu.

References

• 1. A.H. Mohamed, R.H. Hunt, The rationale of acid suppression in the treatment of acid-related disease, Aliment. Pharmacol. Ther., 8 (1994), 3-10.
• 2. A. Avdeef, K.J. Box, J.E.A. Comer, M. Gilges, M. Hadley, C. Hibbert, W. Patterson, K.Y. Tom, pH-metric logP 11. pKa determination of water-insoluble drugs in organic solvent–water mixtures, J. Pharm. Biomed. Anal., 20 (1999) 631-641.
• 3. M. Meloun, S. Bordovská, T. Syrový, A novel computational strategy for the pKa estimation of drugs by non-linear regression of multiwavelength spectrophotometric pH-titration data exhibiting small spectral changes, J. Phys. Org. Chem., 20 (2007) 690-701.
• 4. P. Wiczling, M.J. Markuszewski, R. Kaliszan, Determination of pKa by pH gradient reversed-phase HPLC, Anal. Chem., 76 (2004) 3069-3077.
• 5. E. Koçak, M. Çelebier, S. Altınöz, Application of RPHPLC for Determination of the Dissociation Constants of Rosuvastatin Calcium, Hacettepe Univ. J. Faculty Pharm., 32 (2012) 133-144.
• 6. F.Z. Erdemgil, S. Sanli, N. Sanli, G. Ozkan, J. Barbosa, J. Guiteras, J.L. Beltran, Determination of pKa values of some hydroxylated benzoic acids in methanol– water binary mixtures by LC methodology and potentiometry, Talanta, 72 (2007) 489–496.
• 7. M. Zrncic, S. Babic, D. Mutavzdic, Determination of thermodynamic pKa values of pharmaceuticals from five different groups using capillary electrophoresis, J. Sep. Sci., 38 (2015) 1232-1239.
• 8. A. Zarghi, A. Shafaati, S.M. Foroutan, A. Khoddam, Development of a rapid HPLC method for determination of famotidine in human plasma using a monolithic column, J. Pharm. Biomed. Anal., 39 (2005) 677–680.
• 9. D.A.I. Ashiru, R. Patel, A.W. Basit, Simple and universal HPLC-UV method to determine cimetidine, ranitidine, famotidine and nizatidine in urine: Application to the analysis of ranitidine and its metabolites in human volunteers, J. Chromatogr. B, 860 (2007) 235–240.
• 10. D. Zendelovska, T. Stafilov, Development of an HPLC method for the determination ofranitidine and cimetidine in human plasma following SPE, J. Pharm. Biomed. Anal., 33 (2003) 165-173.
• 11. L.G. Hare, D.S. Mitchel, J.S. Millership, P.S. Collier, J.C. McElnay, M.D. Shields, D.J. Carson, R. Fair, Liquid chromatographic determination including simultaneous “on-cartridge” separation of ranitidine drug combinations from paediatric plasma samples using an automated solid-phase extraction procedure, J. Chromatogr. B, 806 (2004) 263–269.
• 12. M.A. Campanero, A. Lopez-Ocariz, E. García-Quetglàs, B. Sàdaba, A. de la Maza, Rapid Determination of Ranitidine in Human Plasma by High-Performance Liquid Chromatography, Chromatographia, 47 (1998) 391-395.
• 13. A. Khedr, Sensitive determination of ranitidine in rabbit plasma by HPLC with fluorescence detection, J. Chromatogr. B, 862 (2008) 175–180.
• 14. Y. Gao, Y. Tian, X. Sun, X.B. Yin, Q. Xiang, G. Ma, E. Wang, Determination of ranitidine in urine by capillary electrophoresis-electrochemiluminescent detection, J. Chromatogr. B Analyt. Technol. Biomed Life Sci., 832 (2006) 236-240.
• 15. T. Perez-Ruiz, C. Martínez-Lozano, V. Tomás, E. Bravo, R. Galera, Direct determination of ranitidine and famotidine by CE in serum, urine and pharmaceutical formulations, J. Pharm. Biomed. Anal., 30 (2002) 1055-1061.
• 16. M.S. Lant, L.E. Martin, J. Oxford., Qualitative and quantitative analysis of ranitidine and its metabolites by high-performance liquid chromatography-mass spectrometry, J. Chromatogr., 323 (1985) 143-152.
• 17. L.E. Martin, J. Oxford, R.J.N. Tanner, The use of online high-performance liquid chromatography-mass spectrometry for the identification of ranitidine and its metabolites in urine, Xenobiotica, 11 (1981) 831-840.
• 18. L.E. Martin, J. Oxford, R.J.N. Tanner, Use of high-performance liquid chromatography-mass spectrometry for the study of the metabolism of ranitidine in man, J. Chromatogr., 251 (1982) 215-224.
• 19. Y. Imai, S. Kobayashi, A simple method for the quantification of famotidine in human plasma and urine by paired-ion high performance liquid chromatography, Biomed. Chromatogr., 6 (1992) 222- 223.
• 20. P.F. Carey, L.E. Martin, P.E. Owen, Determination of ranitidine and its metabolites in human urine by reversed-phase ion-pair high-performance liquid chromatography, J. Chromatogr. B Biomed. Sci. Appl., 225 (1981) 161-168.
• 21. P. Vinas, N. Campillo, C. Lopez-Erroz, M. HernandezCordoba, Use of post-column fluorescence derivatization to develop a liquid chromatographic assay for ranitidine and its metabolites in biological fluids, J. Chromatogr. B Biomed. Sci. Appl., 693 (1997) 443-449.
• 22. S.A. Shah, I.S. Rathod, S.S. Savale, B.D. Patel, Development of a sensitive high-performance thin-layer chromatography method for estimation of ranitidine in urine and its application for bioequivalence decision for ranitidine tablet formulations, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 767 (2002) 83-91.
• 23. M.S. Smith, J. Oxford, M.B. Evans, Improved method for the separation of ranitidine and its metabolites based on supercritical fluid chromatography, J. Chromatogr. A, 683 (1994) 402-406.
• 24. T. Degim, V. Zaimoglu, C. Akay, Z. Degim, pH-Metric logK calculations of famotidine, naproxen, nizatidine, ranitidine and salicylic acid, Il Farmaco, 56 (2001) 659–663.
• 25. P.H. Sherrod, NLREG Version 4.0. www.sandh.com/ Sherrod.
• 26. C.M. Riley, T.W. Rosanske, Development and Validation of Analytical Methods, Elsevier, New York, 3–14, 1996.
• 27. M.E. Swartz, I.S. Krull, Analytical Development and Validation, Marcel Dekker Inc., New York, 25–38, 1997.