title: Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs.
abstract: The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603>Eudragit® L-100-55>AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, USA; Department of Chemical Engineering, College of Engineering, University of Rhode Island, Kingston, USA.
authors.forename: Ashish L
authors.initials: AL
authors.lastname: Sarode
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, USA; Department of Chemical Engineering, College of Engineering, University of Rhode Island, Kingston, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shin-Etsu Chemical Co., Ltd., Tokyo, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Obara
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, USA; Department of Chemical Engineering, College of Engineering, University of Rhode Island, Kingston, USA. Electronic address: DWorthen@ds.uri.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Worthen
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D003460:Crystallization; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D011108:Polymers; D014867:Water
keywords: Amorphous; Bioavailability; Biphasic dissolution; Drug polymer interaction; Hot melt extrusion; Nucleation and growth; Solid dispersion; Supersaturation