AN ADDUCT: 5-FLUOROURACIL INCORPORATED β-CD INCLUSION COMPLEX FOR SOLUBILITY AND STABILITY ENHANCEMENT IN DOSAGE FORMS

RAHUL KUMAR SINGH; ANIRUDH SINGH DEORA

doi:10.22159/ijap.2022v14i2.43602

Authors

RAHUL KUMAR SINGH Department of Pharmaceutics, Rajiv Academy for Pharmacy, P. O. Chhatikara, Mathura 281001, Uttar Pradesh, India, Department of Pharmaceutics, Bhupal Nobel’s Institute of Pharmaceutical Sciences, Bhupal Nobel’s University, Central Area, Udaipur 313001, Rajasthan, India
ANIRUDH SINGH DEORA Department of Pharmaceutics, Bhupal Nobel’s Institute of Pharmaceutical Sciences, Bhupal Nobel’s University, Central Area, Udaipur 313001, Rajasthan, India

DOI:

https://doi.org/10.22159/ijap.2022v14i2.43602

Keywords:

5-fluorouracil, β-cyclodextrin, Inclusion complex, Kneading method, Stability study

Abstract

Objective: Current work aimed to enhance solubility and stability of 5-fluorouracil drugs by preparing inclusion complex with β-cyclodextrin.

Methods: In this study, inclusion complex preparation ratio selected on the basis of slope and Kc (binding constant) value in between 5-fluorouracil-β-cyclodextrin and best method out of the physical mixture, kneading method, and co-evaporation method for solubility and stability enhancement is selected on the basis of % yield, drug content, dissolution rate study and stability study.

Results: Based on the phase solubility graph, a 1:1 ratio was selected for complex formation by Kc value which decided a quite stable form of a complex. The characterization of all three types of inclusion complex was performed by DSC and SEM. It proved that different moiety of the complex was formed, but all are quite stable with negligible interaction. The kneading method as the best inclusion complex at ratio 1:1 was selected after evaluating by performing percent yield and drug content and dissolution rate study for solubility profile and physical appearance, drug content, and drug release study for stability profile.

Conclusion: We finally conclude that the Kc value proved that the inclusion complex is quite stable and ready to convert in any dosage form of choice. Inclusion complex formed by kneading method is one of the best options among all three techniques for solubility and stability enhancement of drug, which definitely help for a 5-fluorouracil drug to convert into a better dosage form to treat carcinoma.

Downloads

Download data is not yet available.

References

Dai X, Wu C, Li J, Liu L, He X, Lu T, Chen J. Modulating the solubility and pharmacokinetic properties of 5-fluorouracil via cocrystallization. Cryst Eng Comm. 2020;22(21):3670-82. doi: 10.1039/D0CE00409J.

Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther. 1990;48(3):381-95. doi: 10.1016/0163-7258(90)90056-8, PMID 1707544.

Wang X, Zhang R, Xie H. Combined effect of alpha-fetoprotein antisense oligodeoxynucleotides and 5-fluorouracil on human hepatoma cell growth. Chin Med J (Engl). 1999;112(8):743-6. PMID 11601286.

Ferguson PJ, Collins O, Dean NM, DeMoor J, Li CS, Vincent MD, Koropatnick J. Antisense down-regulation of thymidylate synthase to suppress growth and enhance the cytotoxicity of 5-FUdR, 5-FU and tomudex in HeLa cells. Br J Pharmacol. 1999;127(8):1777-86. doi: 10.1038/sj.bjp.0702728. PMID 10482907.

Wang N, Xie C, Lu H, Guo N, Lou Y, Su W, Hao H. Cocrystal and its application in the field of active pharmaceutical ingredients and food ingredients. Curr Pharm Des. 2018;24(21):2339-48. doi: 10.2174/1381612824666180522102732, PMID 29788878.

Chaudhari SP, Dugar RP. Application of surfactants in solid dispersion technology for improving the solubility of poorly water-soluble drugs. Journal of Drug Delivery Science and Technology. 2017;41:68-77. doi: 10.1016/j.jddst.2017.06.010.

Kavitha K, Srinivasa RA, Nalini CN. An investigation on the enhancement of solubility of 5fluorouracil by applying complexation technique-characterization, dissolution and molecular modelling studies. J Appl Pharm Sci. 2013;3(3):162-6. doi: 10.7324/JAPS.2013.30330.

Ren F, Jing Q, Tang Y, Shen Y, Chen J, Gao F, Cui J. Characteristics of bicalutamide solid dispersions and improvement of the dissolution. Drug Dev Ind Pharm. 2006;32(8):967-72. doi: 10.1080/03639040600637606, PMID 16954109.

Dizaj SM, Vazifehasl Zh, Salatin S, Adibkia Kh, Javadzadeh Y. Nanosizing of drugs: effect on dissolution rate. Res Pharm Sci. 2015;10(2):95-108. PMID 26487886.

Shanmuga Priya A, Sivakamavalli J, Vaseeharan B, Stalin T. Improvement on the dissolution rate of inclusion complex of Rifabutin drug with β-cyclodextrin. Int J Biol Macromol. 2013;62:472-80. doi: 10.1016/j.ijbiomac.2013.09.006.

Mendhe AA, Kharwade RS, Mahajan UN. Dissolution enhancement of poorly water-soluble drug by cyclodextrins inclusion complexation. Int J Appl Pharm. 2016;8(4):60-5. doi: 10.22159/ijap.2016v8i4.14156.

Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations I: Structure and physicochemical properties, formation of complexes, and types of complex. D Dis Today 2016; 21(2):356-62. doi: 10.1016/j. drudis.2015.11.017.

Van Eeckhaut A, Detaevernier MR, Michotte Y. Separation of neutral dihydropyridines and their enantiomers using electrokinetic chromatography. J Pharm Biomed Anal. 2004;36(4):799-805. doi: 10.1016/j.jpba.2004.08.024. PMID 15533673.

Kopecky F, Kopecka B, Kaclik P. Solubility study of nimodipine inclusion complexation with alpha- and beta-cyclodextrin and betasome substituted cyclodextrins. J Inclphenom Macro Chem. 2001;39(3-4):215-7. doi: 10.1023/A: 1011155208944.

Vandelli MA, Salvioli G, Mucci A, Panini R, Malmusi L, Forni F. 2-Hydroxypropyl-β-cyclodextrin complexation with ursodeoxycholic acid. International Journal of Pharmaceutics. 1995;118(1):77-83. doi: 10.1016/0378-5173(94)00342-3.

Takayama K, Nambu N, Nagai T. XIX Dissolution kinetics for coprecipitates of indomethacin with polyvinylpyrrolidone. Chem Pharm Bull. 1980;28(11):3304-9. doi: 10.1248/cpb.28.3304.

Archontaki HA, Vertzoni MV, Athanassiou-Malaki MH. Study on the inclusion complexes of Bromazepam with beta- and beta-hydroxypropyl-cyclodextrins. J Pharm Biomed Anal. 2002;28(3-4):761-9. doi: 10.1016/S0731-7085(01)00679-3.

Kontogiannidou E, Ferrari M, Deligianni AD, Bouropoulos N, Andreadis DA, Sorrenti M, Catenacci L, Nazari K, Arshad MS, Chang MW, Ahmad Z, Fatouros DG. In vitro and ex vivo evaluation of tablets containing piroxicam-cyclodextrin complexes for buccal delivery. Pharmaceutics. 2019;11(8):398. doi: 10.3390/pharmaceutics11080398, PMID 31398833.

Prandina A, Herfindal L, Radix S, Rongved P, Døskeland SO, Le Borgne M, Perret F. Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles. J Enzyme Inhib Med Chem. 2018;33(1):370-5. doi: 10.1080/14756366.2017.1421638. PMID 29336193.

Perret F, Marminon C, Zeinyeh W, Nebois P, Bollacke A, Jose J, Parrot Lopez H, Le Borgne M. Preparation and characterization of CK2 inhibitor-loaded cyclodextrin nanoparticles for drug delivery. Int J Pharm. 2013;441(1-2):491-8. doi: 10.1016/j.ijpharm.2012.11.004. PMID 23154152.

Nacereddine A, Bollacke A, Roka E, Marminon C, Bouaziz Z, Fenyvesi F, Bacskay IK, Jose J, Perret F, Le Borgne ML. Self-assembled supramolecular nanoparticles improve the cytotoxic efficacy of CK2 inhibitor THN7. Pharmaceuticals (Basel). 2018;11(1):10. doi: 10.3390/ph11010010, PMID 29373552.

Kurkov SV, Loftsson T. Cyclodextrins. Int J Pharm. 2013;453(1):167-80. doi: 10.1016/j.ijpharm.2012.06.055, PMID 22771733. ijpharm.2012.06.055.

Bera H, Chekuri S, Sarkar S, Kumar S, Muvva NB, Mothe S, Nadimpalli J. Novel pimozide-β-cyclodextrin-polyvinylpyrrolidone inclusion complexes for tourette syndrome treatment. J Mol Liq. 2016;215:135-43. doi: 10.1016/j.molliq.2015.12.054. molliq.2015.12.054.

Patil JS, Kadam DV, Marapur SC, Kamalapur MV. Inclusion complex system: A novel technique to improve the solubility and bioavailability of poorly soluble drugs: a review. Int J Pharm Sci Rev Res. 2010;2(2):29-34. ISSN 0976-044X.

Deshmukh SS, Potnis VV, Shelar DB, Mahaparale PR. Studies on inclusion complexes of ziprasone hydrochloride with β cyclodextrin and hydroxypropyl β-cyclodextrin. Ind Drugs. 2007;44(9):677-82. ISBN: 0019-462X.

Attama AA, Ndibe ON, Nnamani PO. Studies on diclofenac -β- cyclodextrin inclusion complexes. Journal of Pharmaceutical Research 2004;3(3). doi: 10.18579/jpcrkc/2004/3/3/79682.

Chopade TA, Joshi HA. Phase solubility study of glimepiride with β-cyclodextrin and hydroxyl propyl-β-cyclodextrin in different pH. Indo Am J Pharm Res. 2017;7(8):604-12. doi: 10.5281/zenodo.1036514.

Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329(1-2):1-11. doi: 10.1016/j.ijpharm.2006.10.044, PMID 17137734. ijpharm.2006.10.044.

Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II: Solubilization, binding constant, and complexation efficiency. Drug Discov Today. 2016;21(2):363-8. doi: . PMID 26687191. drudis.2015.11.016.

Connors KA, Mollica JA. Theoretical analysis of comparative studies of complex formation. J Pharm Sci. 1966;55(8):772-80. doi: 10.1002/jps.2600550805, PMID 5975288.

Yadav N, Chhabra G, Pathak K. Enhancement of solubility and dissolution rate of a poorly water-soluble drug using single and double hydrophilization approach. Int J Pharm Pharm Sci. 2012;4(1):395-405. Corpus ID: 45157751.

Alghaith AF, Mahrous GM, Zidan DE, Alhakamy NA, Alamoudi AJ, Radwan AA. Preparation, characterization, dissolution, and permeation of flibanserin - 2-HP-β-cyclodextrin inclusion complexes. Saudi Pharm J. 2021;29(9):963-75. doi: 10.1016/j.jsps.2021.07.019. PMID 34588842.

Dhurve P, Tripathi A, Gidwani B, Vyas A. Investigating the phase-solubility and compatibility study of anticancer drug complexed with β-cyclodextrin and HP–β-cyclodextrin. IJAPS. 2017;9(3):69-74. doi: 10.5138/09761055.1929.

Rubim AM, Rubenick JB, Maurer M, Laporta LV, Rolim CMB. Inclusion complex of amiodarone hydrochloride with cyclodextrins: preparation, characterization and dissolution rate evaluation. Braz J Pharm Sci. 2017;53(2). doi: 10.1590/s2175-97902017000216083.

Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and Enhancement Techniques. ISRN Pharm. 2012;2012:195727. doi: 10.5402/2012/195727, PMID 22830056.

Al-Zein H, Sakeer K, Alanazi FK. Designing an extended-release waxy matrix tablet containing nicardipine-hydroxy propyl β cyclodextrin complex. Saudi Pharm J. 2011;19(4):245-53. doi: 10.1016/j.jsps.2011.05.004. PMID 23960765.

Patel RC, Keraliya RA, Patel NM, Patel MM. Commonsensical predetermine dissolution time of furosemide achieved by preparing inclusion complex. Int J Pharm Pharm Sci. 2010;2(3):142-6. ISSN 0975-1491.

Sulaiman HT, Kassab HJ. Preparation and characterization of econazole nitrate inclusion complex for ocular delivery system. Int J Appl Pharm. 2018;10(3):175-81. doi: 10.22159/ijap.2018v10i3.24254.

Sid D, Baitiche M, Elbahri Z, Djerboua F, Boutahala M, Bouaziz Z, Le Borgne M. Solubility enhancement of mefenamic acid by inclusion complex with β-cyclodextrin: in silico modelling, formulation, characterisation, and in vitro studies. J Enzyme Inhib Med Chem. 2021;36(1):605-17. doi: 10.1080/14756366.2020.1869225, PMID 33557644.

Bhopate SB, Dhole SN. Preparation and characterization of β-cyclodextrin nebivolol inclusion complex. Int J Pharm Sci Res. 2015;6(5):2205-13. doi: 10.13040/IJPSR.0975-8232.6(5).2205-13.

Jagdale SC, Mohanty P, Chabukswar AR, Kuchekar BS. Dissolution rate enhancement, design and development of buccal drug delivery of darifenacin hydroxypropyl β-cyclodextrin inclusion complexes. J Pharm (Cairo). 2013;2013:983702. doi: 10.1155/2013/983702, PMID 26556003.

Birdar VS, Patil AR, Sudarshan VG, Pokharkar BV. A comparative study of approaches used to improve the solubility of roxythromycin. Intl J Pharm 2006;169(1):22-32. doi: 10.1016/j. powtec.2006.07.016.

Saokham P, Muankaew C, Jansook P, Loftsson T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molecules. 2018;23(5):1-15. doi: 10.3390/molecules23051161, PMID 29751694.

Giordano F, Novak C, Moyano JR. Thermal analysis of cyclodextrins and their inclusion compounds. Thermochim Acta. 2001;380(2):123-51. doi: 10.1016/S0040-6031(01)00665-7.

Ghosh A, Biswas S, Ghosh T. Preparation and evaluation of silymarin β-cyclodextrin molecular inclusion complexes. J Young Pharm. 2011;3(3):205-10. doi: 10.4103/0975-1483.83759, PMID 21897659.