• Halah Talal Sulaiman Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq
  • Hanan Jalal Kassab Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq



Econazole nitrate, Nil, Kneading method, Ophthalmic gel


Objective: Econazole nitrate (ECZ) is one of the triazole antifungal drugs with poor aqueous solubility and dissolution rate; there is a need for enhancement of solubility. Therefore; inclusion complexation with β cyclodextrin (βCD) was performed.

Methods: In this study kneading method and co-evaporation method of preparation of inclusion complex between βCD and ECZ using two molar ratios of βCD. The solubility of these complexes in isotonic saline solution and distilled water was studied. Complexes prepared by kneading method were used for the preparation of different ophthalmic gel formulas using carbomer (CB) and sodium carboxymethylcellulose (sod CMC) as a gelling agent. The release profile and the rheological behaviour of the gel were studied.

Results: The solubility of ECZ was enhanced by complexation with β CD, and both complexation methods showed Ap type solubility curve, but the solubility of ECZ was significantly enhanced by complexation using kneading method over co-evaporation. EZC-βCD complex prepared by kneading method with 0.88 *10-3 MβCD molar ratio and formulated in a gel using CB 0.75% w/w and sod CMC 0.25% w/w may be considered as a good candidate for ECZ ophthalmic gel dosage form, which showed Super case II transport release profile, and pseudo-plastic shear thinning behavior.

Conclusion: Kneading method was found to be the best method for inclusion of ECZ into βCD, which significantly enhanced ECZ solubility; enabling to be formulated into an ophthalmic gel using CB as a polymer, for further development.


Thomas PA. Current perspectives on ophthalmic mycoses. Clin Microbiol Rev 2003;16:730-97.

Vylkova S. Environmental pH modulation by pathogenic fungi as a strategy to conquer the host. PLOS Pathogens 2017;13:1-6.

Gulheme GG, Newton K Joes, Rosane SD, Müller GG, Kara-José N, Castro RS. Antifungals in eye infections: drugs and routes of administration. Rev Bras Oftalmol 2013;72:132-41.

Mahashabde S, Nahata MC, Shrivastava U. A comparative study of anti-fungal drugs in the mycotic corneal ulcer. Indian J Ophthalmol 1987;35:149-52.

Fatohy HA. Formulation of econazole nitrate as an ophthalmic ointment. Zanco J Med Sci 2009;13:1-6.

FDA official website AHFS monographs. Available from: [Last accessed on 10 Nov 2017].

Yang W, Wiederhold NP, Williams RO 3rd. Drug delivery strategies for improved azole antifungal action. Expert Opin Drug Delivery 2008;5:1199-216.

Samin LH. Formulation of econazole nitrate as topical solution. Iraqi J Parma Sci 2005;14:20-9.

Elkasabgy NA. Ocular supersaturated self-nano emulsifying drug delivery systems (S-SNEDDS) to enhance econazole nitrate bioavailability. Int J Pharm 2014;460:33-44.

Akhtar N, Verma A, Pathak K. Topical delivery of drugs for the effective treatment of fungal infections of the skin. Curr Pharm Des 2015;21:2892-913.

Mahmoud AA, El-Feky GS, Kamel R, Awad GE. Chitosan/sulfobuty lether-β-cyclodextrin nanoparticles as a potential approach for ocular drug delivery. Int J Pharm 2011;413:229-36.

Ambrogi V, Perioli L, Pagano C, Marmottini F, Moretti M, Mizzi F, et al. Econazole nitrate-loaded MCM-41 for an antifungal topical powder formulation. J Pharma Sci 2010;99:4738–45.

Loftsson Th, Duchene D. Cyclodextrins and their pharmaceutical applications. Int J Pharma 2007;329:1-11.

Tiwari G, Tiwari R, Rai AK. Cyclodextrins in delivery systems: applications. J Pharm Bioallied Sci 2010;2:72–9.

Srivalli KMR, Mishra B. Improved aqueous solubility and anti-hypercholesterolemic activity of ezetimibe on formulating with hydroxypropyl-β-cyclodextrin and hydrophilic auxiliary substances. AAPS PharmSciTech 2016;17:272-82.

George SJ, Vanderson DT. Studies on the preparation, characterization, and solubility of 2-HP-β-cyclodextrin-meclizine HCl inclusion complexes. J Young Pharma 2012;4:220-7.

Gera S, Cheruvu S, Zakkula A, Sampathi S. Synthesis and evaluation of olmesartan medoxomil complex with SBE7 β-CD for enhanced dissolution and bioavailability. Int J Pharm Pharm Sci 2016;8:333-43.

Cappello B, Maio CD, Iervolino M, Miro A. Improvement of solubility and stability of valsartan by hydroxypropyl-β-cyclodextrin. J Inclusion Phenom Macrocyclic Chem 2006; 54:289-94.

Loftsson Th, Stefansson E. Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye. Acta Ophthalmol Scand 2002;80:144–50.

Calles JA, Bermudez J, Valles E, Allemandi D, Palma S. Polymers in Ophthalmology. In: Advanced polymers in medicine © Springer International Publishing: Switzerland; 2015. p. 147-76.

Tinu TS, Thomas L, Kumar AB. Polymers used in ophthalmic in situ gelling system. Int J Pharm Sci Rev Res 2013;20:176-83.

Ludwig A. The use of mucoadhesive polymers in ocular drug delivery. Adv Drug Delivery Rev 2005;57:1595-639.

Doile MM, Fortunato KA, Schmücker IC, Schucko SK, Silva MAS, Rodrigues PO. Physicochemical properties and dissolution studies of dexamethasone acetate-β-cyclodextrin inclusion complexes produced by different methods. AAPS PharmSciTech 2008;9:314-21.

Treasa MS, Kumari JP. Characterization and solubility studies of mefloquine hydrochloride inclusion complex with α-Cyclodextrin/Hydroxypropyl α-cyclodextrin. Int J Sci Res Publications 2015;5:1-5.

Phase solubility analysis The International Pharmacopoeia 6th ed. WHO; 2016. [Last accessed on 10 Nov 2017]

Clarke's Analysis of Drugs and Poisons. Moffat AC, Osselton MD, Widdop B (Consulting editors), Galichet LY (Managing Editor) 3rd Ed. © Pharmaceutical Press; 2005.

Ribeiro A, Figueiras A, Santos D, Veiga F. Preparation and solid-state characterization of inclusion complexes formed between miconazole and methyl-β-cyclodextrin. AAPS PharmSciTech 2008;9:1102-9.

Pandya P, Pandey NK, Singh SK, Kumar M. Formulation and characterization of a ternary complex of poorly soluble duloxetine hydrochloride. J Appl Pharm Sci 2015;5;88-96.

Abd El-Gawad AH, Soliman OA, Shams ME, Maria DN. Formulation and in vitro evaluation of loratadine gels for ophthalmic use RGUHS. J Pharm Sci 2014;4:62-9.

Pooja, Kumar GA. Formulation and evaluation of aceclofenac ophthalmic gel. Afr J Pharm Pharmacol 2013;7:2382-91.

Cavrini V, Di Pietra AM, Gatti R. Analysis of miconazole and econazole in pharmaceutical formulations by derivative UV spectroscopy and liquid chromatography (HPLC). J Pharm Biomed Anal 1989;7:1535-43.

Abd El-Gawad AH, Soliman OA, El-Dahan MS, Al-Zuhairy SA. Formulation and evaluation of ophthalmic preparations containing econazole nitrate-cyclodextrin complexes. Am J Pharm Health Res 2016;4:74-96.

Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DD solver: an add-in program for modelling and comparison of drug dissolution profiles. AAPS J 2010;12:263-71.

Zuo J, Gao Y, Bou Chacra N, Lobenberg R. Evaluation of the DD solver software applications. BioMed Res Int 2014:1-9.

El Sayeh AF, El Khatib MM. Formulation and evaluation of new long-acting metoprolol tartrate ophthalmic gels. Saudi Pharm J 2014;22:555-63.

Al-Malah K. Rheological properties of carbomer dispersions. Annu Trans Nord Rheol Soc 2006;14:1-9.

Martin’s Physical Pharmacy and Pharmaceutical Sciences. 6th ed. Patrick J. Sinko (Editor), Yashveer Singh. (Assistant editor). Philadelphia: Lippincott Williams and Wilkins; 2011.

Reddi BA. Why is saline so acidic (and Does It Really Matter?). Int J Med Sci 2013;10:747-50.

Chen Z, Lu D, Weber SG. High-throughput-distribution method to determine drug-cyclodextrin binding constants. J Pharm Sci 2009;98:229-38.

Pedersen M, Edelsten M, Nielsen VF, Scarpellini A, Skytte S, Slot C. Formation and antimycotic effect of cyclodextrin inclusion complexes of econazole and miconazole. Int J Pharm 1993;90:247-54.

Del Valle EMM. Cyclodextrins and their uses: a review. Process Biochem 2003;14:449-59.

Kaur D, Raina A, Singh N. Formulation and evaluation of carbopol 940 based glibenclamide transdermal gel. Int J Pharm Pharm Sci 2014;6:434-40.

Al-Marzouq AH, Solieman A, Shehadi I, Adem A. Influence of the preparation method on the physicochemical properties of econazole-β-cyclodextrin complexes. J Inclusion Phenom Macrocyclic Chem 2008;60:85–93.

Cheirsilp B, Rakmai J. Inclusion complex formation of cyclodextrin with its guest and their application. Biol Eng Med 2016;2:1-6.

Al-Marzouqi AH, Elwy HM, Shehadi I, Abdu Adem A. Physicochemical properties of antifungal drug-cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques. J Pharm Biomed Anal 2008;49:227-33.

Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci 1996;85:1017-25.

Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech 2005;6:329–57.

Pedersen M, Bjerregaard S, Jacobsen J, Larsen AR, Sørensen AM. An econazole β-cyclodextrin inclusion complex: An unusual dissolution rate, supersaturation, and biological efficacy example. Int J Pharm 1998;165:57-68.

Lobering HS, Polzer H. Gel, especially for ophthalmology. US 5397567 A patent; 1995.

Sherafudeen SP, Vasantha PV. Development and evaluation of in situ nasal gel formulations of loratadine. Res Pharm Sci 2015;10:466–76.

Rodriguez Tenreiro C, Alvarez Lorenzo C, Rodriguez Perez A, Concheiro A, Torres Labandeira JJ. Estradiol sustained release from high-affinity cyclodextrin hydrogels. Eur J Pharm Biopharm 2007;66:55–62.

Costa P, Lobo JMS. Modeling and comparison of dissolution profiles. Eur J Pharm Sci 2001;13:123–33.

Jacques CHM, Hopfenberg HB, Stannett V. Super case II transport of organic vapors in glassy polymers (Chapter 10). In: Permeability of Plastic Films and Coating (Vol. 6) Hopfenberg (ed.) part of: Polymer Science and Technology series; Springer. Plenum Press, New York; 1974. p. 73-86.

Mady O. Mechanisms and percent of drug release of each new mathematic approach. Int Res J Pharm Appl Sci 2013;3:56-69.

Miao J, Tsige M, Taylor PL. A generalized model for the diffusion of solvents in glassy polymers: From Fickian to super Case II. J Chem Phys 2017;147:1-15.

Sah SK, Badola A, Mukhopadhyay S. Development and evaluation of tioconazole loaded emulgel. Int J Appl Pharm 2017;9:83-90.

Tan YTF, Peh KK, Al-Hanbali O. Effect of carbopol and polyvinylpyrrolidone on the mechanical, rheological, and release properties of bioadhesive polyethene glycol gels. AAPS Pharm SciTech 2000;1:69–78.

Roberts GP, Barens HA. New measurements of the flow curves for carbopol dispersions without slip artifacts. Rheologica Acta 2001;40:499-503.

Coffey MJ, DeCory HH, Lane SS. Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop. Clin Ophthalmol 2013;7:299–312.



How to Cite

Sulaiman, H. T., & Kassab, H. J. (2018). PREPARATION AND CHARACTERIZATION OF ECONAZOLE NITRATE INCLUSION COMPLEX FOR OCULAR DELIVERY SYSTEM. International Journal of Applied Pharmaceutics, 10(3), 175-181.



Original Article(s)