Insights to the phase solubility diagrams of flurbiprofen with inclusion complex

Year 2021, Volume: 25 Issue: 2, 196 - 208, 27.06.2025

Ayşe Nur Oktay

https://doi.org/10.29228/jrp.10

Cited By: 2

Abstract

Flurbiprofen (FB) is one of the nonsteroidal anti-inflammatory drugs with poor water solubility. Cyclodextrins have a special structure (hydrophobic inner phase and hydrophilic outer phase), which have been widely used to enhance the solubility and stability of drug substances in pharmaceutical applications. The present study is intended to improve the solubility of FB with the inclusion complexes assembled by using beta-cyclodextrin (β-CD) and hydroxypropyl beta-cyclodextrin (HPβ-CD) and to perform the phase solubility studies to estimate the stability constant and complexation efficiency. The results of phase solubility studies showed that the FB/β-CD complexes have Bs type and FB/HPβ-CD complexes have AL type profiles in both PBS and water media. The interaction forces between FB and HPβ-CD were stronger than FB and β-CD for the formation of inclusion complex in water. Moreover, the complexation efficiency value of FB/HPβ-CD complex in water media was found higher than the FB/HPβ-CD complex in PBS media. These results of phase solubility studies absolutely demonstrated the advantage of HPβ-CD instead of β-CD to obtain the inclusion complex with 1:1 Molar ratio in water and to improve the apparent water solubility of FB. According to these results, the FB/HPβ-CD inclusion complex was prepared with the Freeze-drying method and it was achieved to enhance the water solubility of FB 52.6-fold with using HPβ-CD. In conclusion, the presence of the inclusion complex was successfully confirmed by differential scattering calorimetry, X-ray diffraction, scanning electron microscopy and fourier transform infrared analysis.

Keywords

Flurbiprofen , phase solubility , cyclodextrins , inclusion complex , freeze-drying.

References

• [1] Rudrangi SRS, Kaialy W, Ghori MU, Trivedi V, Snowden MJ, Alexander BD. Solid-state flurbiprofen and methyl-β-cyclodextrin inclusion complexes prepared using a single-step, organic solvent-free supercritical fluid process. Eur JPharm Biopharm. 2016; 104: 164-170.[CrossRef]
• [2] Moya-Ortega MD, Alvarez-Lorenzo C, Concheiro A, Loftsson T. Cyclodextrin-based nanogels for pharmaceutical andbiomedical applications. Int J Pharm. 2012; 428(1-2): 152-163. [CrossRef]
• [3] Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. A provisional biopharmaceuticalclassification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol Pharm. 2006;3(6): 631-643. [CrossRef]
• [4] Charman W, Stella V. Transport of lipophilic molecules by the intestinal lymphatic system. Adv Drug Deliv Rev.1991; 7(1): 1-14. [CrossRef]
• [5] Heimbach T, Fleisher D, Kaddoumi A. Overcoming poor aqueous solubility of drugs for oral delivery. In: Stella VJ,Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW (eds) Prodrugs. Biotechnology: Pharmaceutical Aspects,vol V. Springer, New York, 2007, pp.157-215. [CrossRef]
• [6] Oh DH, Park YJ, Kang JH, Yong CS, Choi HG. Physicochemical characterization and in vivo evaluation offlurbiprofen-loaded solid dispersion without crystalline change. Drug Deliv. 2011; 18(1): 46-53. [CrossRef]
• [7] Habib MJ, Phan MT, Owusu-Ababio G. Dissolution profiles of flurbiprofen in phospholipid solid dispersions.Drug Dev IndPharm. 1998; 24(11): 1077-1082. [CrossRef]
• [8] Patel J, Patel A, Raval M, Sheth N. Formulation and development of a self-nanoemulsifying drug delivery system ofirbesartan. J Adv Pharm Technol Res. 2011; 2(1): 9. [CrossRef]
• [9] Zhang ZL, Le Y, Wang JX., Chen JF. Preparation of stable micron-sized crystalline irbesartan particles for theenhancement of dissolution rate. Drug Dev Ind Pharm. 2011; 37(11): 1357-1364. [CrossRef]
• [10] Oktay AN, Karakucuk A, Ilbasmis-Tamer S, Celebi N. Dermal flurbiprofen nanosuspensions: Optimization withdesign of experiment approach and in vitro evaluation. Eur J Pharm Sci. 2018; 122: 254-263. [CrossRef]
• [11] Willems L, Van der Geest R, De Beule K. Itraconazole oral solution and intravenous formulations: a review ofpharmacokinetics and pharmacodynamics. J Clin Pharm Ther. 2001; 26(3): 159-169. [CrossRef]
• [12] Schönbeck C, Madsen TL, Peters GH, Holm R, Loftsson T. Soluble 1: 1 complexes and insoluble 3:2 complexes–Understanding the phase-solubility diagram of hydrocortisone and γ-cyclodextrin. Int J Pharm. 2017; 531(2): 504-511.[CrossRef]
• [13] Nicolescu C, AramăC, Nedelcu A, Monciu CM. Phase solubility studies of the inclusion complexes of repaglinidewith β-cyclodextrin and β-cyclodextrin derivatives. Farmacia 2010; 58(5): 620-628. [CrossRef]
• [14] Mura P. Analytical techniques for characterization of cyclodextrin complexes in aqueous solution: a review. J PharmBiomed Anal. 2014; 101: 238-250. [CrossRef]
• [15] Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, andcomplexation efficiency. Drug Discov Today. 2016; 21(2): 363-368. [CrossRef]
• [16] Tonkova A. Bacterial cyclodextrin glucanotransferase. Enzyme Microb Technol. 1998; 22(8): 678-686. [CrossRef] [17] Muankaew C, Jansook P, Stefánsson E, Loftsson T. Effect of γ-cyclodextrin on solubilization and complexation ofirbesartan: influence of pH and excipients. Int J Pharm. 2014; 474(1-2): 80-90. [CrossRef]
• [18] Jansook P, Ogawa N, Loftsson T. Cyclodextrins: structure, physicochemical properties and pharmaceuticalapplications. Int J Pharm. 2018; 535(1-2): 272-284. [CrossRef]
• [19] Rudrangi SRS, Bhomia R, Trivedi V, Vine GJ, Mitchell JC., Alexander BD, Wicks SR. Influence of the preparationmethod on the physicochemical properties of indomethacin and methyl-β-cyclodextrin complexes. Int J Pharm. 2015;479(2): 381-390 284. [CrossRef]
• [20] Erden N, Çelebi N. A study of the inclusion complex of naproxen with β-cyclodextrin. Int J Pharm. 1988; 48(1-3): 83-89. [CrossRef]
• [21] Carrier RL, Miller LA, Ahmed I. The utility of cyclodextrins for enhancing oral bioavailability. J Control Release.2007; 123(2): 78-99. [CrossRef]
• [22] Loftsson T, Duchene D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007; 329(1-2): 1-11.[CrossRef]
• [23] Loftsson T, Brewster ME. Cyclodextrins as functional excipients: methods to enhance complexation efficiency.JPharmSci. 2012; 101(9): 3019-3032. [CrossRef]
• [24] Higuchi T, Connors K. Phase solubility diagram. Adv Anal Chem Instrum. 1965; 4: 117-212. [CrossRef] [25] Loftsson T, Magnúsdóttir A, Másson M, Sigurjónsdóttir JF. Self‐association and cyclodextrin solubilization of drugs.J Pharm Sci. 2002; 91(11): 2307-2316. [CrossRef]
• [26] Brewster ME, Loftsson, T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007; 59(7): 645-666.[CrossRef]
• [27] Hirayama F, Uekama K.Cyclodextrins and their industrial uses. Editions de Santé, Paris, 1987, 133
• [28] Bilensoy E. Cyclodextrins in pharmaceutics, cosmetics, and biomedicine: current and future industrial applications.John Wiley & Sons, 2011. [CrossRef]
• [29] Cirri M, Rangoni C, Maestrelli F, Corti G, Mura P. Development of fast-dissolving tablets of flurbiprofen-cyclodextrincomplexes. Drug Dev Ind Pharm. 2005; 31(7): 697-707.[CrossRef]
• [30] Connors KA. Binding constants: the measurement of molecular complex stability. Wiley-Interscience, 1987.[CrossRef]
• [31] Cetin E, Ilem D, Gundogdu E, Asikoglu M, Kirilmaz L. Correlation and in vitro studies on radioactive andnonradioactive albendazole-ß-cyclodextrin complex tablets. Die Pharmazie-An International Journal ofPharmaceutical Sciences. 2011; 66(9): 672-676. [CrossRef]
• [32] Govindarajan R, Nagarsenker MS. Formulation studies and in vivo evaluation of a flurbiprofen-hydroxypropylβ-cyclodextrin system. Pharmaceutical development and technology 2005; 10(1): 105-114. [CrossRef]
• [33] BayrakcıMT, Ertul SE, Yilmaz M. Phase solubility studies of poorly soluble drug molecules by using O- phosphorylated calixarenes as drug-solubilizing agents. J Chem Eng Data. 2011; 57(1): 233-239. [CrossRef]
• [34] Williams III RO, Mahaguna V, Sriwongjanya M. Characterization of an inclusion complex of cholesterol andhydroxypropyl-β-cyclodextrin. Eur J Pharm Biopharm. 1998; 46(3): 355-360. [CrossRef]
• [35] Preiss A, Mehnert W, Frömming KH. Complexation of Hydrocortison with β‐Cyclodextrin and Hydroxypropyl‐β‐Cyclodextrin. Archiv der Pharmazie. 1994; 327(11): 729-734. [CrossRef]
• [36] Choudhury S, Nelson KF. Improvement of oral bioavailability of carbamazepine by inclusion in 2-hydroxypropyl-β-cyclodextrin. Int J Pharm. 1992; 85(1-3): 175-180. [CrossRef]
• [37] Akyüz L, Duman F, Kaya M. Encapsulation of Flurbiprofen by Chitosan Using a Spray-Drying Method with In VitroDrug Releasing and Molecular Docking. Turk J Pharm Sci. 2017; 14(1). [CrossRef]
• [38] Hadziabdi'c J, Elezovi'c A, Rahi'c O, Mujezin I. Effect of cyclodextrin complexation on the aqueous solubility ofdiazepam and nitrazepam: phase-solubility analysis, thermodynami cproperties. Am J Analyt Chem. 2012; 3(12).[CrossRef]
• [39] Russo E, Villa C. Poloxamer Hydrogels for Biomedical Applications. Pharmaceutics. 2019; 11(12): 671. [CrossRef]