2-hidroksipropil-β-siklodekstrin ile Metronidazolün İnklüzyon Kompleksi Oluşumunun HPLC Yöntemi ile Belirlenmesi

Year 2021, Volume: 16 Issue: 2, 523 - 532, 25.11.2021

İlkay Konçe Ebru Çubuk Demiralay Zehra Üstün

https://doi.org/10.29233/sdufeffd.985584

Abstract

Metronidazol, bakteri, protozoa ve parazitlerin neden olduğu enfeksiyonları tedavi etmek için kullanılan nitroimidazol sınıfı bir antibiyotiktir. Aktif farmasötik bileşenin düşük çözünürlüğü, ilaç absorpsiyonu ve biyoyararlanımı üzerindeki olumsuz etkisinden dolayı oral katı dozaj formlarının geliştirilmesi ve büyük ölçekli üretiminin önündeki en büyük engeldir. Bu çalışmada lipofilik yapıya sahip ve suda çözünürlüğü düşük olan metronidazolün çözünürlüğünü ve stabilitesini arttırmak için 2-hidroksipropil-β-siklodekstrin ile inklüzyon kompleksi oluşumu gerçekleştirilmiştir. 2-hidroksipropil-β-siklodekstrinin metronidazolün çözünürlüğü üzerindeki etkisi, faz çözünürlük metoduna göre değerlendirilmiştir. Metronidazolün 2-hidroksipropil-β-siklodekstrin ile kompleksleşmesi yüksek performans sıvı kromatografisi yöntemi ile belirlenmiştir. Sıvı kromatografik tayin, 25oC'de Kinetex Core-Shell C8 (Phenomenex, 150 x 4,6 mm I.D., 2,6 µm) kolonu ile gerçekleştirilmiştir. Mobil faz olarak %30 (h/h) asetonitril içeren asetonitril-su ikili karışımı kullanılmıştır. Sonuç olarak kompleksin stokiyometrisi 1:1’dir ve kompleksin kararlılık sabiti yüksek performans sıvı kromatografisi yöntemi ile belirlenmiştir.

Keywords

Metronidazol, İnklüzyon kompleksi, Faz çözünürlük metodu, HPLC

Supporting Institution

Süleyman Demirel Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi

Project Number

FDK-2020-8125

Determination of Inclusion Complex Formation of Metronidazole with 2-Hydroxypropyl-β-Cyclodextrin by HPLC Method

Abstract

Metronidazole is a nitroimidazole class antibiotic used to treat infections caused by bacteria, protozoa, and parasites. The low solubility of the active pharmaceutical ingredient is the major obstacle to the development and large-scale production of oral solid dosage forms due to its adverse effect on drug absorption and bioavailability. In this study, inclusion complex formation was carried out with 2-hydroxypropyl-β-cyclodextrin to increase the solubility and stability of metronidazole, which has a lipophilic structure and low water solubility. The influence of 2-hydroxypropyl-β-cyclodextrin on the metronidazole solubility was evaluated in respect of the phase solubility method. The complexation of metronidazole with 2-hydroxypropyl-β-cyclodextrin was proven by high performance liquid chromatography method. Liquid chromatographic determination was carried out on a Kinetex Core-Shell C8 (Phenomenex, 150 x 4.6 mm I.D., 2.6 μm) column at 25oC. The acetonitrile-water binary mixture containing 30% (v/v) acetonitrile was used as a mobile phase. As a result, the stoichiometry of the complex was 1:1 and the stability constant of the complex was determined by the high performance liquid chromatography method.

Keywords

Metronidazole, Inclusion complex, Phase solubility method, HPLC

Project Number

FDK-2020-8125

References

• [1] D. Leitsch, “A review on metronidazole: an old warhorse in antimicrobial chemotherapy”, Parasitology, 146(9), 1167-1178, 2019.
• [2] L. L. Brunton, J. S. Lazo, K. L. Parker (editors): Goodman & Gilman’s the pharmacological basis of therapeutics: Tedavinin farmakolojik temeli. Çeviri editörü: Ö. Süzer, İstanbul: Nobel Yayınevi, 2009.
• [3] D. O. Thompson, “Cyclodextrins-enabling excipients: their present and future use in pharmaceuticals”, Crit Rev Ther Drug Carrier Syst, 1997(14), 1-104, 1997.
• [4] T. Loftsson, M. E. Brewster, “Pharmaceutical applications of cyclodextrins, I: drug solubilization and stabilization”, J Pharm Sci., 1996(85), 1017-1025, 1996.
• [5] R. Challa, A. Alka, A. Javed, R. K. Khar, “Cyclodextrins in drug delivery: an updated review”, AAPS PharmSciTech. , 2005(6), 329-357, 2005.
• [6] A. M. Denadai, K. I. Teixeira, M. M. Santoro, A. M. Pimenta, M. E. Cortes, R. D. Sinisterra, “Supramolecular self-assembly of beta-cyclodextrin: an effective carrier of the antimicrobial agent chlorhexidine”, Carbohydr. Res. 342, 2286–2296, 2007.
• [7] T. Irie, K. Uekama, “Pharmaceutical applications of cyclodextrins 3. Toxicological issues and safety evaluation”, J. Pharm. Sci. 86, 147–162, 1997.
• [8] E. M. M. Del Valle, “Cyclodextrins and their uses: a review”, Process Biochemistry, 39(9), 1033-1046, 2004.
• [9] The Merck Index. 14th Ed. New Jersey: Merck Research Laboratories, p, 2006, 1061.
• [10] N. M. Mahfouz, M. A. Hassan, “Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility”, J Pharm Pharmacol, 53, 841–8, 2001.
• [11] A. Celebioglu, T. Uyar, “Metronidazole/Hydroxypropyl-β-Cyclodextrin inclusion complex nanofibrous webs as fast-dissolving oral drug delivery system”, Int Journal of Pharmaceutics, 572, 11882, 2009.
• [12] C. T. Abhiman, J. H. Anantrao, “Phase solubility studies of glimepiride wıth β-cyclodextrin and hydroxy propyl-β-cyclodextrin in different pH”, Indo Am. j. pharm., 7(08), 2017.
• [13] S. J. George, D. T. Vasudevan, “Studies on the Preparation, Characterization, and Solubility of 2-HP-β-Cyclodextrin-Meclizine HCl Inclusion Complexes”, J Young Pharmacists, 4, 220-7, 2012.
• [14] J. Zeng, Y. Ren, C. Zhou, S. Yu, W.Chen, “Preparation and physicochemical characteristics of the complex of edaravone with hydroxypropyl-β-cyclodextrin”, Carbohydr. Polym 83, 1101–1105, 2011.
• [15] E. Pinho, M. Grootveld, G. Soares, M. Henriques, “Cyclodextrins as encapsulation agents for plant bioactive compounds”, Carbohydr. Polym, 101, 121-135, 2014.
• [16] T. Higuchi, K. A. Connors, “Phase Solubility Techniques”, Advances in Analytical Chemistry and Instrumentation, 4, 117-150, 1965.
• [17] T. Higuchi, H. Kristiansen, “Binding specificity between small organic solutes in aqueous solution: Classification of some solutes into two groups according to binding tendencies”, Journal of Pharmaceutical Science, 59, 1601–1608, 1970.
• [18] L. Hu, H. Zhang, W. Song, D. Gu, Q. Hu, “Investigation of inclusion complex of cilnidipine with hydroxypropyl-b-cyclodextrin”, Carbohydr. Polym., 90, 1719–1724, 2012.
• [19] B. Cheirsilp, J. Rakmai, “Inclusion complex formation of cyclodextrin with its guest and their applications”, Biol Eng Med, 2(1), 1-6, 2016.
• [20] R. Chadha, D. V. S. Jain, A. Aggarwal, S. S. D. Thakur, “Binding constants of inclusion complexes of nitroimidazoles with β-cyclodextrins in the absence and presence of PVP”, Thermochimica Acta 459, 111–115, 2007.
• [21] S. Bensouiki, F. Belaib, M. Sindt, S. Rup-Jacques, P. Magri, A. Ikhlef, A. Meniai, “Synthesis of Cyclodextrins-Metronidazole Inclusion Complexes and Incorporation of Metronidazole - 2-Hydroxypropyl-β-Cyclodextrin Inclusion Complex in Chitosan Nanoparticles”. Journal of Molecular Structure, 2021, InPress.
• [22] S. Malli, C. Bories, G. Ponchel, P. M. Loiseau, K. Bouchemal, “Phase solubility studies and anti-Trichomonas vaginalis activity evaluations of metronidazole and methylated β-cyclodextrin complexes: Comparison of CRYSMEB and RAMEB”, Exp. Parasitol. 189, 72–75, 2018.