TENOKSİKAM, PİROKSİKAM VE MELOKSİKAM’IN pKa DEĞERLERİNİN RP-HPLC YÖNTEMİYLE 25℃ VE 37℃’DE THF-SU İKİLİ ORTAMINDA TAYİNİ

Abstract

Amaç: Bu çalışmada, oksikam grubu ilaç etken maddeleri olan tenoksikam, piroksikam ve meloksikamın hem ağrı ve iltihabı azaltmadaki etkinlikleri hem de farmasötik önemi nedeniyle iyonizasyon sabiti (pKa) değerleri araştırıldı.
Gereç ve Yöntem: pKa değerleri, 25 °C ve 37 °C'de tetrahidrofuran-su ikili karışımında (%30-40(h/h)) RP-HPLC yöntemiyle belirlendi. Bu bileşiklerin sudaki pKa değerleri, mol kesri ve Yasuda-Shedlovsky ekstrapolasyon yöntemleri ile değerlendirildi.
Sonuç ve Tartışma: Tenoksikam, piroksikam ve meloksikam için 25 °C'de mol kesri yöntemiyle hesaplanan pKa değerleri 5.067 ± 0.037; 5.237 ± 0.065; 4.027 ± 0.144; 37 °C'de pKa değerleri 5.166 ± 0.017; 5.197 ± 0.084; 4.161 ± 0.116. Yasuda-Shedlovsky ekstrapolasyonu ile 25 °C'de hesaplanan pKa değerleri 5.061 ± 0.035; 5.232 ± 0.063; 4.021 ± 0.141; 37 ℃'deki pKa değerleri 5.161 ± 0.013; 5.192 ± 0.053; 4.155 ± 0.094. Sonuçlar, 25 °C'de farklı yöntemler ve farklı çözücüler ile yapılan önceki çalışmalarla uyumludur. Bu çalışma, tetrahidrofuran-su ortamında ve ayrıca vücut fizyolojik sıcaklığı olan 37 °C'de tenoksikam, piroksikam ve meloksikam için yapılan ilk pKa belirleme çalışmasıdır.

Keywords

• Oksikam
• RP-HPLC
• THF-su ikili karışımı

DETERMINATION OF pKa VALUES OF TENOXICAM, PIROXICAM AND MELOXICAM BY RP-HPLC AT 25 ℃ AND 37 ℃ IN THF-WATER BINARY MIXTURES

Abstract

Objective: In this study, the ionization constant (pKa) values of oxicam group drug active ingredients, tenoxicam, piroxicam and meloxicam, were investigated both because of their effectiveness in reducing pain and inflammation and because of their pharmaceutical importance.
Material and Method: pKa values were determined by RP-HPLC method in tetrahydrofuran-water binary mixture (30%-40%(v/v)) at 25 °C and 37 °C. The pKa values of these compounds in water were evaluated by mole fraction and Yasuda-Shedlovsky extrapolation methods.
Result and Discussion: This study is the first pKa determination study for tenoxicam, piroxicam and meloxicam in tetrahydrofuran-water media and also at 37 ℃, which is body physiological temperature. For tenoxicam, piroxicam and meloxicam, the pKa values calculated by the mole fraction method at 25 °C were 5.067 ± 0.037; 5.237 ± 0.065; 4.027 ± 0.144; pKa values at 37 °C are 5.166 ± 0.017; 5.197 ± 0.084; 4.161 ± 0.116. By Yasuda-Shedlovsky extrapolation, pKa values calculated at 25 ℃ were 5.061 ± 0.035; 5.232 ± 0.063; 4.021 ± 0.141; pKa values at 37 ℃ are 5.161 ± 0.013; 5.192 ± 0.053; 4.155 ± 0.094. The results are in agreement with previous studies with different methods and different solvents at 25 °C. 

Keywords

• Oxicam
• RP-HPLC
• THF-water binary mixtures

References

1. 1. Bindu, S., Mazumder, S., Bandyopadhyay, U. (2020). Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochemical Pharmacology, 180, 114147. [CrossRef]
2. 2. Starek, M., Krzek, J. (2009). A review of analytical techniques for determination of oxicams, nimesulide and nabumetone. Talanta, 77(3), 925-942. [CrossRef]
3. 3. Szabó-Révész, P. (2018). Modifying the physicochemical properties of NSAIDs for nasal and pulmonary administration. Drug Discovery Today Technologies, 27, 87-93. [CrossRef]
4. 4. Alves, L. P., Da Silva Oliveira, K., Da Paixão Santos, J. A., Da Silva Leite, J. M., Rocha, B. P., Lucena Nogueira, P. de, Araújo Rêgo, R. I. de, Oshiro-Junior, J. A., Damasceno, B.P.G.d.L. (2020). A review on developments and prospects of anti-inflammatory in microemulsions. Journal of Drug Delivery Science and Technology, 60, 102008. [CrossRef]
5. 5. Christian, A., Iorgulescu, E. E., Mihailciuc, C. (2010). Electrochemıcal Studıes Usıng Actıvated Glassy Carbon. I. Meloxıcam. Academia Romana, 55(5), 329-334.
6. 6. Cruciani, G., Milletti, F., Loriano, S., Sforna, G., Goracci, L. (2009). In silico pKa Prediction and ADME Profiling. Chemistry & Biodiversity, 6, 1812-1821. [CrossRef]
7. 7. Manallack, D. T. (2007). The pKa Distribution of Drugs: Application to Drug Discovery. Perspectives in Medicinal Chemistry, 1, 25-38. [CrossRef]
8. 8. Babić, S., Horvat, A. J., Mutavdžić Pavlović, D., Kaštelan-Macan, M. (2007). Determination of pKa values of active pharmaceutical ingredients. TrAC Trends in Analytical Chemistry, 26(11), 1043-1061. [CrossRef]

9. 9. Dardonville, C. (2018). Automated techniques in pKa determination: Low, medium and high-throughput screening methods. Drug Discovery Today Technologies, 27, 49-58. [CrossRef]
10. 10. Reijenga, J., van Hoof, A., van Loon, A., Teunissen, B. (2013). Development of Methods for the Determination of pKa Values. Analytical Chemistry Insights, 8, 53-71. [CrossRef]
11. 11. Subirats, X., Fuguet, E., Rosés, M., Bosch, E., Ràfols, C. (2015). Methods for pKa Determination (I): Potentiometry, Spectrophotometry, and Capillary Electrophoresis. In Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. Elsevier. [CrossRef]
12. 12. Fuguet, E., Subirats, X., Ràfols, C., Bosch, E., Rosés, M. (2015). Methods for pKa Determination (II): Sparingly Soluble Compounds and High-Throughput Approaches. In Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. Elsevier. [CrossRef]
13. 13. Trapl, D., Del Río, C.C., Kříž, P., Spiwok, V. (2020). Prediction of pKa in a system with high orthogonal barriers: Alchemical flying Gaussian method. Chemical Physics Letters, 760, 138012. [CrossRef]
14. 14. Settimo, L., Bellman, K., Knegtel, R.M.A. (2014). Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharmaceutical Research, 31(4), 1082-1095. [CrossRef]
15. 15. Balogh, G.T., Tarcsay, A., Keserű, G.M. (2012). Comparative evaluation of pKa prediction tools on a drug discovery dataset. Journal of Pharmaceutical and Biomedical Analysis, 67(68), 63-70. [CrossRef]
16. 16. Mioduszewska, K., Dołżonek, J., Wyrzykowski, D., Kubik, Ł., Wiczling, P., Sikorska, C., Toński, M., Kaczyński, Z., Stepnowski, P., Białk-Bielińska, A. (2017). Overview of experimental and computational methods for the determination of the pKa values of 5-fluorouracil, cyclophosphamide, ifosfamide, imatinib and methotrexate. TrAC Trends in Analytical Chemistry, 97, 283-296. [CrossRef]
17. 17. Manderscheid, M., Eichinger, T. (2003). Determination of pKa Values by Liquid Chromatography. Journal of Chromatographic Science, 41, 323-326. [CrossRef]
18. 18. Kütt, A., Selberg, S., Kaljurand, I., Tshepelevitsh, S., Heering, A., Darnell, A., Kaupmees, K., Piirsalu, M., Leito, I. (2018). pKa values in organic chemistry – Making maximum use of the available data. Tetrahedron Letters, 59(42), 3738-3748. [CrossRef]
19. 19. Völgyi, G., Ruiz, R., Box, K., Comer, J., Bosch, E., Takács-Novák, K. (2007). Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: Validation study in a new cosolvent system. Analytica Chimica Acta, 583(2), 418-428. [CrossRef]
20. 20. Demiralay, E. Ç., Yılmaz, H. (2012). Potentiometric pKa Determination of Piroxicam and Tenoxicam in Acetonitrile-Water Binary Mixtures. SDU Journal of Science, 7(1), 34-44.
21. 21. Yasuda, M. (1959). Dissociation Constants of Some Carboxylic Acids in Mixed Aqueous Solvents. Bulletin of the Chemical Society of Japan, 32(5), 429-432.
22. 22. Shedlovsky, T. (1962). Electrolytes: The behaviour of carboxylic acids in mixed solvents. Pergamon Press.
23. 23. Barbosa, J., Barrón, D., Butı́, S. (1999). Chromatographic behaviour of ionizable compounds in liquid chromatography. Part 1. pH scale, pKa and pHS values for standard buffers in tetrahydrofuran–water. Analytica Chimica Acta, 389(1-3), 31-42. [CrossRef]
24. 24. Sun, N., Avdeef, A. (2011). Biorelevant pKa (37 °C) predicted from the 2D structure of the molecule and its pKa at 25 °C. Journal of Pharmaceutical and Biomedical Analysis, 56(2), 173-182. [CrossRef]
25. 25. NLREG Nonlinear Regression Analysis and Curve Fitting Program, Version 4.0 http//www.nlreg.com Accessed: 18 December 2018.
26. 26. Muinasmaa, U., Ràfols, C., Bosch, E., Rosés, M. (1997). Ionic equilibria in aqueous organic solvent mixtures the dissociation constants of acids and salts in tetrahydrofuran/water mixtures. Analytica Chimica Acta, 340(1-3), 133-141. [CrossRef]
27. 27. David, V., Albu, F., Medvedovici, A. (2004). Structure–Retention Correlation of Some Oxicam Drugs in Reversed‐Phase Liquid Chromatography. Journal of Liquid Chromatography & Related Technologies, 27(6), 965-984. [CrossRef]
28. 28. Demiralay, E. C., Alsancak, G., Ozkan, S. A. (2009). Determination of pKa values of nonsteroidal antiinflammatory drug-oxicams by RP-HPLC and their analysis in pharmaceutical dosage forms. Journal of Separation Science, 32(17), 2928-2936. [CrossRef]
29. 29. Shayesteh, O. H., Musavi, S. M., Mahjoub, P., Ataie, Z. (2017). Application of Chemometrics in determination of the effects of ionic and non-ionic surfactants on acid dissociation constant (pKa) of Meloxicam using spectrophotometric method. Iranıan Journal of Pharmacology & Therapeutıcs, 15(1), 1-7.
30. 30. Garrido, G., Rosés, M., Ràfols, C., Bosch, E. (2008). Acidity of Several Anilinium Derivatives in Pure Tetrahydrofuran. Journal of Solution Chemistry, 37(5), 689-700. [CrossRef]
31. 31. Hartono, A., Saeed, M., Kim, I., Svendsen, H.F. (2014). Protonation Constant (pKa) of MDEA in Water as Function of Temperature and Ionic Strength. Energy Procedia, 63, 1122-1128. [CrossRef]
32. 32. Pobudkowska, A., Ràfols, C., Subirats, X., Bosch, E., Avdeef, A. (2016). Phenothiazines solution complexity- Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37°C. European Journal of Pharmaceutical Sciences, 93, 163-176. [CrossRef]
33. 33. Chakraborty, H., Banerjee, R., Sarkar, M. (2003). Incorporation of NSAIDs in micelles: implication of structural switchover in drug–membrane interaction. Biophysical Chemistry, 104(1), 315-325. [CrossRef]
34. 34. Rodríguez-Barrientos, D., Rojas-Hernández, A., Gutiérrez, A., Moya-Hernández, R., Gómez-Balderas, R., Ramírez-Silva, M.T. (2009). Determination of pKa values of tenoxicam from 1H NMR chemical shifts and of oxicams from electrophoretic mobilities (CZE) with the aid of programs SQUAD and HYPNMR. Talanta, 80(2), 754-762. [CrossRef]
35. 35. Ramírez-Silva, M. T., Guzmán-Hernández, D.S., Galano, A., Rojas-Hernández, A., Corona-Avendaño, S., Romero-Romo, M., Palomar-Pardavé, M. (2013). Spectro-electrochemical and DFT study of tenoxicam metabolites formed by electrochemical oxidation. Electrochimica Acta, 111, 314-323. [CrossRef]
36. 36. Dal, A.G., Oktayer, Z., Doğrukol-Ak, D. (2014). Validated method for the determination of piroxicam by capillary zone electrophoresis and its application to tablets. Journal of Analytical Methods in Chemistry, 2014, 352698. [CrossRef]
37. 37. Damiani, P., Bearzotti, M., Cabezón, M., Olivieri, A. (1998). Spectrofluorometric determination of piroxicam. Journal of Pharmaceutical and Biomedical Analysis, 17(2), 233-236. [CrossRef]
38. 38. Goosen, C., Du Plessis, J., Müller, D., van Janse Rensburg, L. (1998). Correlation between physicochemical characteristics, pharmacokinetic properties and transdermal absorption of NSAID's. International Journal of Pharmaceutics, 163(1-2), 203-209. [CrossRef]