Use of Two Different Approaches to Determine The Ionization and Protonation Constants of Aciclovir by Spectrophotometric Method

Yıl 2024, Cilt: 14 Sayı: 1, 101 - 113, 15.03.2024

Yaşar Doğan Daldal

https://doi.org/10.31466/kfbd.1359190

Öz

In this study, the determination of the ionization and protonation constant (pKa) of aciclovir, a guanine derivative with potent antiviral activity against herpes simplex and varicella zoster viruses, was performed using the UV-Vis spectrophotometric method. In the study, due to the poor water solubility of aciclovir, it was studied in binary acetonitrile-water mixtures at different concentrations. The program STAR and the log [AHA -Ai)/(Ai- AA)]-pH relationship were used to evaluate the data obtained by the spectrophotometric method for the ionization and protonation constants, and it was found that the pKa values determined by these calculation methods were very close for different acetonitrile-water concentrations. To determine the pKa values of the compound in water, the relationship between the pKa values determined in binary acetonitrile-water mixtures and the macroscopic properties of the binary acetonitrile-water mixtures studied was used. As a result of the calculation, it was found that the pKa values of acyclovir in water determined in this study are compatible with the values in the literature.

Anahtar Kelimeler

Aciclovir, Ionization and protonation constant, pKa, Herpes Simplex, UV-Vis Spectrophotometry

Asiklovirin Spektrofotometrik Yöntemle İyonlaşma ve Protonasyon Sabiti Tayininde İki Farklı Yaklaşımın Kullanılması

Öz

Bu çalışmada herpes simpleks ve varicella zoster virüslerine karşı güçlü antiviral etkiye sahip bir guanin türevi olan asiklovirin iyonlaşma ve protonasyon sabiti tayini (pKa), UV-Vis spektrofotometrik yöntem kullanarak gerçekleştirilmiştir. Çalışmada asiklovirin suda zayıf çözünürlüğünden dolayı, farklı derişimlerdeki asetonitril-su ikili karışımlarında çalışılmıştır. İyonlaşma ve protonasyon sabiti için spektrofotometrik yöntemden belirlenen verilerin değerlendirilmesinde STAR programı ve log [AHA-Ai)/(Ai-AA)]-pH ilişkisi kullanılmış ve bu hesaplama yöntemleriyle farklı asetonitril-su derişimleri için hesaplanan pKa değerlerinin birbirine çok yakın olduğu belirlenmiştir. Bileşiğin sudaki pKa değerlerinin tayini için asetonitril-su ikili karışımlarında belirlenmiş pKa değerleri ve çalışılan asetonitril-su ikili karışımlarının makroskopik özellikleri arasındaki ilişkiden yararlanılmıştır. Hesaplama sonucunda, asiklovirin bu çalışmada belirlenen sudaki pKa değerleri ile literatürdeki değerlerin uyumlu olduğu belirlenmiştir.

Anahtar Kelimeler

Asiklovir, İyonlaşma ve protonasyon sabiti, pKa, Herpes Simpleks, UV-Vis Spektrofotometri

Teşekkür

Yazar, bu çalışmada kullanılan STAR programının tedariği için Barselona Üniversitesinden Dr. Jose L. Beltrán’a teşekkür eder.

Kaynakça

• Albert, A., and Serjeant, E. P. (1984). The determination of ionization constants a laboratory manual (1st ed.). USA: Chapman and Hall.
• Alqahtani, S. M., Altharawi, A., Altamimi, M. A., Alossaimi, M. A., Mahdi, W. A., Ramzan, M., and Hussain, A. (2022). Method development, stability, and pharmacokinetic studies of acyclovir-loaded topical formulation in spiked rat plasma. Processes, 10(10), 1-17.
• Arnal, J., Gonzalez-Alvarez, I., Bermejo, M., Amidon, G. L., Junginger, H. E., Kopp, S., Midha, K. K., Shah, V. P., Stavchansky, S., Dressman, J. B., and Barends, D.M. (2008). Biowaiver monographs for immediate release solid oral dosage forms: Aciclovir. Journal of Pharmaceutıcal Sciences, 97(12), 5061-5072.
• Avdeef, A. (2003). Absorption and drug development solubility. permeability, and charge state (1st ed.). Canada: John Wiley & Sons Inc.
• Beltrán, J. L., Codony, R., and Prat, M. D. (1993). Evaluation of stability constants from multiwavelength absorbance data: program STAR. Analytica Chimica Acta, 276, 441–454.
• Canbay, H. S., Demiralay, E. C., Alsancak, G., and Ozkan, S. A. (2011). Chromatographic determination of pKa values of some water-ınsoluble arylpropionic acids and arylacetic acids in acetonitrile + water media. Journal of Chemical & Engineering Data, 56(5), 2071-2076.
• Daldal, Y. D., and Demiralay, E. Ç. (2020). Chromatographic and UV–visible spectrophotometric pKa determination of some purine antimetabolites. Journal of Molecular Liquids, 317, 1-8.
• Daldal, Y. D., Çakır, C., Yılmaz, H., Demiralay, E. Ç. Özkan, S. A., and Alsancak G. (2014). Liquid chromatographic, spectrophotometric and potentiometric pka determination of ranitidine and famotidine. Current Drug Therapy, 9, 277-284 .
• Daldal, Y. D., Demiralay, E. Ç., and Alsancak, G. (2017). Determination of spectrophotometric protonation constant of cholinesterase inhibitors. International Journal of Chemistry and Technology, 1, 7-13.
• Dar, B. P. W., Öksüz, Z., ve Algül, Ö. (2019). Antiviral ilaçlardaki gelişmeler ve değerlendirilmesi. Lokman Hekim Dergisi, 9(2),160-170.
• González-Olvera, J. C., Martínez-Reyes, J., González-Jasso, E., and Pless, R. C. (2015). Determination of pKa values for deprotonable nucleobases in short model oligonucleotides. Biophysical Chemistry, 206, 58-65.
• Herrero-Martínez, J., Repollés, C., Bosch, E., Rosés, M., and Ràfols, C. (2008). Potentiometric determination of aqueous dissociation constants of flavonols sparingly soluble in water. Talanta, 74, 1008–1013.
• Jang, Y. H., Goddard, W. A., Noyes, K. T., Sowers, L. C., Hwang, S., and Chung, D. S. (2003). pKa values of guanine in water:  density functional theory calculations combined with poisson−boltzmann continuum−solvation model, Journal of Physical Chemistry B, 107(1), 344–357.
• Katzung, B. G. (2011). Basic & clinical pharmacology (12th ed.). San Francisco: The McGraw-Hill Companies.
• Kayaalp, O. (2000). Rasyonel tedavi yönünden tıbbi farmakoloji (9th ed.). Ankara: Hacettepe-Taş Kitapçılık Ltd. Şti.
• Kazakevich, Y., and Lobrutto, R. (2007). HPLC for pharmaceutical scientists (1st ed.). New Jersey: John Wiley & Sons.
• Laurence, L. B. (2011). Goodman & gilman’s the pharmacological basis of therapeutics (12th ed.). New York: McGraw Companies.
• Malik N. S., Ahmad, M., Minhas, M. U., and Khalid, Q. (2019). Determination of acyclovir in rabbit plasma by high performance liquid chromatographıc (HPLC) technique. Acta Poloniae Pharmaceutica-Drug Research, 76(3), 421-429.
• Manallack, D. T. (2007). The pKa distribution of drugs: application to drug discovery. Perspectives in Medicinal Chemistry, 1, 25–38.
• Mulabagal, V., Annaji, M., Kurapati, S., Dash, R. P., Srinivas, N. R., Tiwari, A. K., and Babu, R. J. (2020). Stability-indicating HPLC method for acyclovir and lidocaine in topical formulations. Biomedical Chromatography, 34(e4751), 1-9.
• Narasimham, L., and Dnyandeo Barhate, V. (2011). Physico-chemical characterization of some beta blockers and anti-diabetic drugs - potentiometric and spectrophotometric pKa determination in different co-solvents. European Journal of Chemistry, 2(1), 36‐46.
• Reijenga, J., van Hoof, A., van Loon, A., and Teunissen, B. (2013). Development of methods for the determination of pKa Values. Analytical Chemistry Insights, 8, 53–71.
• Salgado, L. E., and Vargas-Hernández, V. C. (2014). Spectrophotometric determination of the pKa, isosbestic point and equation of absorbance vs. pH for a universal pH indicator. American Journal of Analytical Chemistry, 5, 1290-1301.
• Sanli, N., Sanli, S., Sizir, U., Gümüştaş, M., and Özkan, S. A. (2011). Determination of pK(a) values of cefdinir and cefixime by lc and spectrophotometric methods and their analysis in pharmaceutical dosage forms. Chromatographia, 73(11-12), 1171-1176.
• Sayed, R., El-Masry, M., Hassan, W., El-Mammli, M., Shalaby, A., and Aboul-Enein, H. Y. (2018). Validated HPLC Method for the simultaneous determination of acyclovir and co-administered vitamin B3 and gabapentin in spiked human plasma. Separation Science Plus, 1, 475–482.
• Shedlovsky, T. (1962). The behavior of carboxylic acids in mixed solvents (1st ed.). London: Pergamon Press. Singh, P., Gupta, E., Mishra, N., and Mishra, P. (2020). Phytochemicals as lead compounds for new drug discovery (1st ed.). USA: Elsevier.
• Soleimani, F., Karimi, R., and Gharib, F. (2016). Thermodynamic studies on protonation constant of acyclovir at different ıonic strengths. Journal of Solution Chemistry, 45, 920–931.
• Takács-Novák, K., Box, K. S., and Avdeef, A. (1997). Potentiometric pKa determination of water-insoluable compounds. Validation study in methanol/water mixtures. International Journal of Pharmaceutics, 151, 235-248.
• Urinovska, R., Kacirova, I., and Sagan, J. (2021). Determination of acyclovir and its metabolite 9-carboxymethoxymethylguanide in human serum by ultra-high-performance liquid chromatography-tandem mass spectrometry. Journal of Separation Science, 44, 3080–3088.
• Yasuda, M. (1959). Dissociation constants of some carboxylic acids in mixed aqueous solvents. Bulletin of The Chemical Society of Japan, 32(5), 429-432.