A Review on Solubility Enhancement of Antifungal Drugs
DOI:
https://doi.org/10.32947/ajps.v25i5.1314Keywords:
antifungal drugs, solubility enhancement, low water solubility, formulation strategy, poorly water-soluble drugsAbstract
Fungal infections pose a significant threat to immunocompromised individuals, yet the efficacy of antifungal therapies is often hindered by the poor aqueous solubility of many antifungal agents, particularly azoles. Enhancing solubility is essential for improving bioavailability and achieving effective drug concentrations at the site of infection. This review comprehensively explores contemporary formulation strategies aimed at increasing the solubility of poorly water-soluble antifungal drugs.
Various techniques are discussed, including solid dispersions, cyclodextrin complexation, nanosuspensions, lipid-based systems (SLNs, liposomes, and niosomes), self-emulsifying drug delivery systems (SEDDS), microemulsions, salt formation, co-crystallization, and cosolvency. The article evaluates each method's mechanism, advantages, formulation considerations, and potential limitations. Emphasis is placed on the need for tailored approaches that integrate physicochemical drug properties with delivery goals to optimize antifungal efficacy and patient outcomes.
References
1- Kim J-K, Park J-S, Kim C-K. Development of a binary lipid nanoparticles formulation of itraconazole for parenteral administration and controlled release. International journal of pharmaceutics. 2010;383(1-2):209-15
2- Vallabhaneni S, Mody RK, Walker T, Chiller T. The global burden of fungal diseases. Infectious Disease Clinics. 2016;30(1):1-11
3- Gupta AK, Cooper EA. Update in antifungal therapy of dermatophytosis. Mycopathologia. 2008;166:353-67
4- Hussien AA. Preparation and evaluation of oral microsponge drug delivery system of ketoconazole. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2014;14(1):1-8
5- Chaudhary A, Nagaich U, Gulati N, Sharma V, Khosa R. Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review. Journal of Advanced Pharmacy Education and Research. 2012;2(1-2012):32-67
6- Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. The AAPS journal. 2009;11:740-6
7- Baldea I, Moldovan R, Nagy A-L, Bolfa P, Decea R, Miclaus MO, et al. Ketoconazole-Fumaric Acid Pharmaceutical Cocrystal: From Formulation Design for Bioavailability Improvement to Biocompatibility Testing and Antifungal Efficacy Evaluation. International Journal of Molecular Sciences. 2024;25(24):13346
8- Parashar B, Kabra A, Chandel A. Formulation and evaluation of gel containing miconazole nitrate an antifungal agent. Int J Pharm Res Rev. 2013;2(6):18-28
9- Štěpánek O, Parigger M, Procházková E, Čmoková A, Kolařík M, Dračínská H, et al. Prodrugging fungicidal amphotericin B significantly decreases its toxic effects. European Journal of Medicinal Chemistry. 2025;283:117157
10- VS Venugopal N, Bujji Reddy K. Assessment Swot on Performance of Micronized Itraconazole against Candida albicans and Aspergillus niger for Superior Health Security. 2021
11- Huang C, Klinzing G, Procopio A, Yang F, Ren J, Burlage R, et al. Understanding compression-induced amorphization of crystalline posaconazole. Molecular pharmaceutics. 2018;16(2):825-33
12- Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams III RO. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug development and industrial pharmacy. 2008;34(8):890-902
13- Li Y, Li C, Gao X, Lv H. Equilibrium solubility, preferential solvation and solvent effect study of clotrimazole in several aqueous co-solvent solutions. The Journal of Chemical Thermodynamics. 2020;151:106255
14- Durgun ME, Kahraman E, Hacıoğlu M, Güngör S, Özsoy Y. Posaconazole micelles for ocular delivery: in vitro permeation, ocular irritation and antifungal activity studies. Drug delivery and translational research. 2022:1-14
15- Gao S, Jiang J, Li X, Ye F, Fu Y, Zhao L. Electrospun polymer-free nanofibers incorporating hydroxypropyl-β-cyclodextrin/difenoconazole via supramolecular assembly for antifungal activity. Journal of Agricultural and Food Chemistry. 2021;69(21):5871-81
16- Leal AFG, Leite MC, Medeiros CSQ, Cavalcanti IMF, Wanderley AG, Santos Magalhães NS, et al. Antifungal activity of a liposomal itraconazole formulation in experimental Aspergillus flavus keratitis with endophthalmitis. Mycopathologia. 2015;179:225-9
17- Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nature reviews Drug discovery. 2007;6(3):231-48
18- Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharmaceutical research. 1992;9:87-93
19- Kassem AA, Mohsen AM, Ahmed RS, Essam TM. Self-nanoemulsifying drug delivery system (SNEDDS) with enhanced solubilization of nystatin for treatment of oral candidiasis: Design, optimization, in vitro and in vivo evaluation. Journal of molecular liquids. 2016;218:219-32
20- Kontogiannidou E, Meikopoulos T, Virgiliou C, Bouropoulos N, Gika H, Vizirianakis I, et al. Towards the development of Self-Nano-Emulsifying Drug Delivery Systems (SNEDDS) containing trimethyl chitosan for the oral delivery of amphotericin B: In vitro assessment and cytocompatibility studies, J Drug Deliv Sci Technol. 56 (2020) 101524. View PDF View article View in Scopus. 2020:101524
21- Yang T-L, Hsieh C-M, Meng L-J, Tsai T, Chen C-T. Oleic acid-based self micro-emulsifying delivery system for enhancing antifungal activities of clotrimazole. Pharmaceutics. 2022;14(3):478
22- Taupitz T, Dressman JB, Buchanan CM, Klein S. Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole. European Journal of Pharmaceutics and Biopharmaceutics. 2013;83(3):378-87
23- Kumar N, Shishu, Bansal G, Kumar S, Jana AK. Preparation and cyclodextrin assisted dissolution rate enhancement of itraconazolium dinitrate salt. Drug development and industrial pharmacy. 2013;39(2):342-51
24- Iftode A, Racoviceanu R, Susan R, Marti D, Pinzaru I, Lazau R, et al. Fluconazole-beta-cyclodextrin inclusion complexes. Preparation and characterization in solid state. Rev Chim. 2020;71:325-34
25- Şuta L-M, Ridichie A, Ledeţi A, Temereancă C, Ledeţi I, Muntean D, et al. Host–Guest Complexation of Itraconazole with Cyclodextrins for Bioavailability Enhancement. Pharmaceutics. 2024;16(4):560
26- 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
27- Moreira RSdS, Novais JS, SILVA RFd, Nunes RP, ABREU LCLd, Dias EP, et al. Preparation and evaluation of red propolis and nystatin cyclodextrin inclusion complexes against oral microbiome opportunistic microorganisms. Food Science and Technology. 2022;42:e118022
28- Childs SL, Stahly GP, Park A. The salt− cocrystal continuum: the influence of crystal structure on ionization state. Molecular pharmaceutics. 2007;4(3):323-38
29- Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Advanced drug delivery reviews. 2007;59(7):617-30
30- Patel JR, Carlton RA, Needham TE, Chichester CO, Vogt FG. Preparation, structural analysis, and properties of tenoxicam cocrystals. International journal of pharmaceutics. 2012;436(1-2):685-706
31- Ganie AA, Vishnoi P, Dar AA. Utility of bis-4-pyridines as supramolecular linkers for 5-sulfosalicylic acid centers: structural and optical investigations. Crystal Growth & Design. 2019;19(4):2289-97
32- Elder DP, Holm R, De Diego HL. Use of pharmaceutical salts and cocrystals to address the issue of poor solubility. International journal of pharmaceutics. 2013;453(1):88-100
33- Qadri H, Malik AA, Ahangar AA, Mir MA, Dar AA, Shah AH. Pharmaceutical salts of azole anti-fungal drugs: physicochemical behaviour and activity studies. RSC Pharmaceutics. 2024;1(4):705-15
34- Bagavatula H, Lankalapalli S, Tenneti V, Beeraka NMR, Bulusu BT. Comparative studies on solubility and dissolution enhancement of different itraconazole salts and their complexes. Adv Pharmacol Pharm. 2014;2:85-95
35- Hiendrawan S, Hartanti AW, Veriansyah B, Widjojokusumo E, Tjandrawinata RR. Solubility enhancement of ketoconazole via salt and cocrystal formation. Int J Pharm Pharm Sci. 2015;7(7):160-4
36- Pu X, Sun J, Li M, He Z. Formulation of nanosuspensions as a new approach for the delivery of poorly soluble drugs. Current nanoscience. 2009;5(4):417-27
37- Khare P, Chogale MM, Kakade P, Patravale VB. Gellan gum–based in situ gelling ophthalmic nanosuspension of Posaconazole. Drug Delivery and Translational Research. 2022;12(12):2920-35
38- Jansook P, Maw PD, Soe HMSH, Chuangchunsong R, Saiborisuth K, Payonitikarn N, et al. Development of amphotericin B nanosuspensions for fungal keratitis therapy: Effect of self-assembled γ-cyclodextrin. Journal of Pharmaceutical Investigation. 2020;50:513-25
39- Aldosari BN, Ibrahim MA, Alqahtani Y, Amal El Sayeh F. Formulation and evaluation of Fluconazole Nanosuspensions: In vitro characterization and transcorneal permeability studies. Saudi Pharmaceutical Journal. 2024;32(7):102104
40- Pornpitchanarong C, Rojanarata T, Opanasopit P, Ngawhirunpat T, Patrojanasophon P. Clotrimazole nanosuspensions-loaded hyaluronic acid-catechol/polyvinyl alcohol mucoadhesive films for oral candidiasis treatment. Journal of Drug Delivery Science and Technology. 2020;60:101927
41- Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodríguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. International journal of pharmaceutics. 2013;453(1):101-25
42- Bavishi DD, Borkhataria CH. Spring and parachute: How cocrystals enhance solubility. Progress in Crystal Growth and Characterization of Materials. 2016;62(3):1-8
43- Vemuri VD, Lankalapalli S, Guntaka PCR. Posaconazole-amino acid cocrystals for improving solubility and oral bioavailability while maintaining antifungal activity and low In vivo toxicity. Journal of Drug Delivery Science and Technology. 2022;74:103491
44- Ahangar AA, Qadri H, Malik AA, Mir MA, Shah AH, Dar AA. Physicochemical and Anti-fungal Studies of the Pharmaceutical Co-crystal/Salt of Fluconazole. Molecular Pharmaceutics. 2023;20(7):3471-83
45- Loxley A. Solid lipid nanoparticles for the delivery of pharmaceutical actives. Drug Delivery Technology. 2009;9(8):32
46- Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art. European journal of pharmaceutics and biopharmaceutics. 2000;50(1):161-77
47- Mirza MA, Panda AK, Asif S, Verma D, Talegaonkar S, Manzoor N, et al. A vaginal drug delivery model. Drug delivery. 2016;23(8):3123-34
48- Aljaeid BM, Hosny KM. Miconazole-loaded solid lipid nanoparticles: formulation and evaluation of a novel formula with high bioavailability and antifungal activity. International journal of nanomedicine. 2016:441-7
49- Samee A, Usman F, Wani TA, Farooq M, Shah HS, Javed I, et al. Sulconazole-Loaded Solid Lipid Nanoparticles for Enhanced Antifungal Activity: In Vitro and In Vivo Approach. Molecules. 2023;28(22):7508
50- Tian Q, Ren F, Xu Z, Xie Y, Zhang S. Preparation of high solubilizable microemulsion of naproxen and its solubilization mechanism. International journal of pharmaceutics. 2012;426(1-2):202-10
51- Bachhav YG, Patravale VB. Microemulsion based vaginal gel of fluconazole: formulation, in vitro and in vivo evaluation. International Journal of Pharmaceutics. 2009;365(1-2):175-9
52- Tiwari N, Sivakumar A, Mukherjee A, Chandrasekaran N. Enhanced antifungal activity of Ketoconazole using rose oil based novel microemulsion formulation. Journal of Drug Delivery Science and Technology. 2018;47:434-44
53- Sadique A, Khalid SH, Asghar S, Irfan M, Qadir M. Miconazole nitrate microemulsion: Preparation, characterization and evaluation for enhancement of antifungal activity. Lat Am J Pharm. 2018;37(8):1578-86
54- Ag Seleci D, Seleci M, Walter J-G, Stahl F, Scheper T. Niosomes as nanoparticular drug carriers: fundamentals and recent applications. Journal of nanomaterials. 2016;2016(1):7372306
55- Marianecci C, Rinaldi F, Mastriota M, Pieretti S, Trapasso E, Paolino D, et al. Anti-inflammatory activity of novel ammonium glycyrrhizinate/niosomes delivery system: human and murine models. Journal of controlled release. 2012;164(1):17-25
56- Mehta S, Jindal N. Tyloxapol niosomes as prospective drug delivery module for antiretroviral drug nevirapine. AAPS PharmSciTech. 2015;16:67-75
57- Garg AK, Maddiboyina B, Alqarni MHS, Alam A, Aldawsari HM, Rawat P, et al. Solubility enhancement, formulation development and antifungal activity of luliconazole niosomal gel-based system. Journal of Biomaterials Science, Polymer Edition. 2021;32(8):1009-23
58- Wagh VD, Deshmukh OJ. Itraconazole niosomes drug delivery system and its antimycotic activity against Candida albicans. International Scholarly Research Notices. 2012;2012(1):653465
59- Yassin GE, Amer MA, Mannaa IM, Khalifa MKA. Fluconazole-Niosome-Laden Contact Lens: A Promising Therapeutic Approach for Prolonged Ocular Delivery and Enhanced Antifungal Activity. Journal of Pharmaceutical Innovation. 2024;19(4):45
60- El-Ridy MS, Abdelbary A, Essam T, Abd EL-Salam RM, Aly Kassem AA. Niosomes as a potential drug delivery system for increasing the efficacy and safety of nystatin. Drug development and industrial pharmacy. 2011;37(12):1491-508
61- Fo’ad T, Hameed GS, Raauf AM. Thermal Analysis in the Pre-formulation of Amorphous Solid Dispersion for Poorly Water-soluble Drugs. International Journal of Drug Delivery Technology. 2022;12:1595-9
62- Hashim GM, Hameed GS, Hanna DB. The possible techniques that used to improve the bioavailablity, pharmacological activity, solubility and permeability of anti-viral drugs: Insight for COVID-19 antiviral drugs. AJPS. 2023:231
63- Naama NA, Hameed GS, Hanna DB, Mahdi ZH. Formulation of Cefdinir Ternary Solid Dispersion and Stability Study under Harsh Conditions. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2025;25(1):27-48
64- Ghaderi R, Artursson P, Carlfors J. Preparation of biodegradable microparticles using solution-enhanced dispersion by supercritical fluids (SEDS). Pharmaceutical research. 1999;16:676-81
65- Nagy ZK, Balogh A, Démuth B, Pataki H, Vigh T, Szabó B, et al. High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole. International journal of pharmaceutics. 2015;480(1-2):137-42
66- Kanase SJ, Burade KB, Khandekar AM, Sawant GR, Repal AR. Solubility and dissolution rate enhancement of antifungal voriconazole by hot melt extrusion and development of sustained release tablets. World J Pharm Res. 2014;3(4):1827-53
67- Mahfud MASb, Syahirah NA, Akram M, Mahfufah U, Saputra MD, Elim D, et al. Solid Dispersion Incorporated into Dissolving Microneedles for Improved Antifungal Activity of Amphotericin B: In Vivo Study in a Fungal Keratitis Model. Molecular Pharmaceutics. 2023;20(12):6246-61
68- Al-Obaidi H, Kowalczyk RM, Kalgudi R, Zariwala MG. Griseofulvin solvate solid dispersions with synergistic effect against fungal biofilms. Colloids and Surfaces B: Biointerfaces. 2019;184:110540
69- Bhandari L, Patil AS, Bolmal U, Masareddy R, Dandagi P. Formulation and evaluation of natamycin solid dispersion incorporated ophthalmic films. Indian J Pharm Educ Res. 2022;56
70- Vemula V, Lagishetty V, Lingala S. Solubility enhancement approaches. Int J Pharm Sci Rev Res Dev. 2010;5(1):41-51
71- Sodeifian G, Sajadian SA, Razmimanesh F, Hazaveie SM. Solubility of the Ketoconazole (an Antifungal Drug) in Supercritical Carbon Dioxide and Menthol as a Cosolvent (Ternary System): Experimental Data and Empirical Correlations. 2021
72- Li H, Ding X, Zhao H, Jouyban A. Investigation on itraconazole solubility in aqueous solutions based on models, solvent effect, thermodynamic analysis and quantum chemical calculations. The Journal of Chemical Thermodynamics. 2024;197:107349
73- Akay S, Kayan B, Martínez F. Solubility of fluconazole in (ethanol+ water) mixtures: Determination, correlation, dissolution thermodynamics and preferential solvation. Journal of Molecular Liquids. 2021;333:115987
74- Nemati A, Rezaei H, Poturcu K, Hanaee J, Jouyban A, Zhao H, et al., editors. Effect of temperature and propylene glycol as a cosolvent on dissolution of clotrimazole. Annales Pharmaceutiques Françaises; 2023: Elsevier.
75- Shehata T, Ogawara K-i, Higaki K, Kimura T. Prolongation of residence time of liposome by surface-modification with mixture of hydrophilic polymers. International journal of pharmaceutics. 2008;359(1-2):272-9
76- Anwekar H, Patel S, Singhai A. Liposome-as drug carriers. International journal of pharmacy & life sciences. 2011;2(7)
77- Veloso DF, Benedetti NI, Ávila RI, Bastos TS, Silva TC, Silva MR, et al. Intravenous delivery of a liposomal formulation of voriconazole improves drug pharmacokinetics, tissue distribution, and enhances antifungal activity. Drug delivery. 2018;25(1):1585-94
78- Kumar N, Goindi S. Development, characterization and preclinical evaluation of nanosized liposomes of itraconazole for topical application: 32 full factorial design to estimate the relationship between formulation components. Journal of Drug Delivery Science and Technology. 2021;66:102785
79- Perez AP, Altube MJ, Schilrreff P, Apezteguia G, Celes FS, Zacchino S, et al. Topical amphotericin B in ultradeformable liposomes: Formulation, skin penetration study, antifungal and antileishmanial activity in vitro. Colloids and Surfaces B: Biointerfaces. 2016;139:190-8
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