title: Application of a continuous intrinsic dissolution-permeation system for relative bioavailability estimation of polymorphic drugs.
abstract: A new continuous dissolution-permeation system, consisting of an intrinsic dissolution apparatus and an Ussing chamber, was developed for screening and identification of high-bioavailability polymorphisms at pre-formulation stages. Three different solid forms of two model drugs (agomelatine and carbamazepine) were used to confirm the system's predictive ability. Ranks for cumulative permeation of the three solids were: Form III>Form I>Form II for agomelatine, and Form III>Form I>the dihydrate form for carbamazepine. Regression analysis of these parameters and published pharmacokinetics confirmed linear IVIVCs (most correlation coefficients >0.9). To confirm dissolution-absorption relationships, permeability coefficients were calculated. Relatively constant values among various polymorphisms for each drug supported a linear dependency between polymorphism-increased dissolution and polymorphism-enhanced permeation. A combined analysis of intrinsic dissolution rates and permeability coefficients revealed that both drugs are of the BCS II class and have dissolution-limited absorption. In conclusion, our new system was valuable not only for high-bioavailability polymorphism screening, but also for drug classification within the BCS system.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Weijing
authors.initials: W
authors.lastname: Chu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China. Electronic address: zhaocs@mail.sysu.edu.cn.
authors.forename: Chunshun
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001702:Biopharmaceutics; D002220:Carbamazepine / Q000493:pharmacokinetics*; D004386:Duodenum / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D010539:Permeability; D017207:Rats, Sprague-Dawley; D012995:Solubility; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D002220:Carbamazepine; C084711:agomelatine; D009281:Naphthalenes
keywords: Agomelatine (PubChem CID: 82148); Bioavailability; Biopharmaceutical classification system; Carbamazepine (PubChem CID: 2554); Dissolution; In vitro–in vivo correlations; Polymorphism; Prediction