title: Heat induced evaporative antisolvent nanoprecipitation (HIEAN) of itraconazole.
abstract: Itraconazole (ITR) is an antifungal drug with a limited bioavailability due to its poor aqueous solubility. In this study, ITR was used to investigate the impact of nanonisation and solid state change on drug's apparent solubility and dissolution. A bottom up approach to the production of amorphous ITR nanoparticles (NPs), composed of 100% drug, with a particle diameter below 250 nm, using heat induced evaporative antisolvent nanoprecipitation (HIEAN) from acetone was developed. The NPs demonstrated improved solubility and dissolution in simulated gastro-intestinal conditions when compared to amorphous ITR microparticles. The incorporation of polyethylene glycol (PEG) or its methoxylated derivative (MPEG) as a stabiliser enabled the production of smaller NPs with narrower particle size distribution and enhanced apparent solubility. MPEG stabilised NPs gave the greatest ITR supersaturation levels (up to 11.6±0.5 μg/ml) in simulated gastric fluids. The stabilising polymer was in an amorphous state. Dynamic vapour sorption data indicated no solid state changes in NP samples with water vapour at 25 °C, while crystallisation was apparent at 50 °C. HIEAN proved to be an efficient method of production of amorphous ITR NPs, with or without addition of a polymeric stabiliser, with enhanced pharmaceutical properties.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Naila A
authors.initials: NA
authors.lastname: Mugheirbi
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Krzysztof J
authors.initials: KJ
authors.lastname: Paluch
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: lidia.tajber@tcd.ie.
authors.forename: Lidia
authors.initials: L
authors.lastname: Tajber
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D011232:Chemical Precipitation; D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D006358:Hot Temperature; D017964:Itraconazole / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013499:Surface Properties; D014835:Volatilization
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D012997:Solvents; D017964:Itraconazole
keywords: Amorphous; Itraconazole; Methoxylated poly(ethylene glycol); Nanoparticles; Poly(ethylene glycol)