title: Population data analysis of dissolution time profiles: Assessment of physicochemical properties of the drug, drug particles and the pharmaceutical formulation.
abstract: Disintegration of finished dosage forms (FDF) and drug dissolution are fundamentally important processes that affect bioavailability. Established theories do not account for disintegration and usually assume sink conditions for drug dissolution that often do not apply. We present the theory to describe the disintegration of FDF with subsequent dissolution of liberated particles containing the active pharmaceutical ingredient (API) and its application using population data analysis. Population modeling, using dissolution profiles of 400mg cefditoren pivoxil tablets manufactured under various tableting pressures, characterized the intrinsic lifetime distribution of the particles and identified the presence of crystalline API in the formulation that was proven by X-ray diffraction. Modeling further estimated the disintegration time of FDF, the solubility of the amorphous API and its chemical instability in the medium that were in agreement with the experimentally determined values. This novel approach provides a quantitative understanding of the manufacturing process of FDF and can substantially contribute to the targeted development of finished dosage forms.
authors.affiliation: Sandoz GmbH, Biochemiestr. 10, A-6250 Kundl, Austria. Electronic address: stefan.horkovics-kovats@sandoz.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Horkovics-Kovats
authors.affiliation: Comenius University, Bratislava, Slovakia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Brunovský
authors.affiliation: Sandoz GmbH, Biochemiestr. 10, A-6250 Kundl, Austria.
authors.forename: Arthur
authors.initials: A
authors.lastname: Pichler
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
mesh_terms: D002511:Cephalosporins / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D008956:Models, Chemical; D033362:Powder Diffraction; D011208:Powders; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D002511:Cephalosporins; D004304:Dosage Forms; D011208:Powders; C057710:cefditoren pivoxil
keywords: Disintegration; Dissolution; Physicochemical property; Polymorphic form; Population data analysis; S-ADAPT