title: In Vitro and In Vivo Performance of Different Sized Spray-Dried Crystalline Itraconazole.
abstract: The objectives of the present study were to formulate and optimize different sized liquid and solid nanocrystalline formulations and evaluate their in vitro and in vivo performance to determine the effect of particle size on the oral bioavailability of solid nanocrystalline formulations. Nanotechnology is a promising approach to solve the problem of poor oral bioavailability of Biopharmaceutical Classification System class II/IV compounds. However, the highly exposed surface area of nanocrystals and hence their high Gibb's free energy poses a great challenge to nanocrystalline suspension stabilization. In this study, stabilization was achieved by preparing spray-dried nanocrystalline powders. A design of experiment approach was utilized to optimize the nanocrystalline suspensions/powders. On the basis of drug solubility studies, polyvinylpyrrolidone 40 KDa and sodium lauryl sulfate were selected for wet milling processing. Mannitol was chosen as the auxiliary excipient for spray-drying processing. In vitro dissolution utilizing a United States Pharmacopeia (USP) apparatus II showed superior release profiles for both liquid and nanocrystalline powder formulations compared with coarse-sized and unmilled formulations. Significantly, the oral bioavailability of nanocrystalline formulations with particle size of 280 nm was more than 20 times that of the unmilled formulation, whereas the nanocrystalline formulation with particle size of 750 nm showed only a 2.8 times increase in bioavailability compared with the unmilled formulation.
authors.affiliation: University of Connecticut, School of Pharmacy, Department of Pharmaceutics, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut, 06269.
authors.forename: Sumit
authors.initials: S
authors.lastname: Kumar
authors.affiliation: University of Connecticut, School of Pharmacy, Department of Pharmaceutics, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut, 06269.
authors.forename: Rajan
authors.initials: R
authors.lastname: Jog
authors.affiliation: University of Connecticut, School of Pharmacy, Department of Pharmaceutics, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut, 06269.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: FDA/CDER/OPS, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993-0002.
authors.forename: Banu
authors.initials: B
authors.lastname: Zolnik
authors.affiliation: FDA/CDER/OPS, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993-0002.
authors.forename: Nakissa
authors.initials: N
authors.lastname: Sadrieh
authors.affiliation: University of Connecticut, School of Pharmacy, Department of Pharmaceutics, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut, 06269.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Burgess
mesh_terms: D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005079:Excipients / Q000737:chemistry; D017964:Itraconazole / Q000737:chemistry* / Q000493:pharmacokinetics*; D008353:Mannitol / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods; D010316:Particle Size; D011205:Povidone / Q000737:chemistry; D011208:Powders / Q000737:chemistry; D051381:Rats; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D013535:Suspensions / Q000737:chemistry
chemical_list: D005079:Excipients; D011208:Powders; D013535:Suspensions; D017964:Itraconazole; D012967:Sodium Dodecyl Sulfate; D008353:Mannitol; D011205:Povidone
keywords: DoE; absorption; bioavailability; itraconazole nano-crystals; milling; nano-crystalline powders; nanoparticles; nanotechnology; spray drying