title: Mathematical Model-Based Accelerated Development of Extended-release Metformin Hydrochloride Tablet Formulation.
abstract: A computational fluid dynamic (CFD) model was developed to predict metformin release from a hydroxypropylmethylcellulose (HPMC) matrix-based extended-release formulation that took into consideration the physical and chemical properties of the drug substance, composition, as well as size and shape of the tablet. New high dose strength (1000 mg) tablet geometry was selected based on the surface area/volume (SA/V) approach advocated by Lapidus/Lordi/Reynold to obtain the desired equivalent metformin release kinetics. Maintaining a similar SA/V ratio across all extended-release metformin hydrochloride (Met XR) tablet strengths that had different geometries provided similar simulations of dissolution behavior. Experimental dissolution profiles of three lots of high-strength tablets agreed with the simulated release kinetics. Additionally, a pharmacokinetic absorption model was developed using GastroPlus™ software and known physicochemical, pharmacokinetic, and in vitro dissolution properties of metformin to predict the clinical exposure of the new high strength (1000 mg) tablet prior to conducting a human clinical bioequivalence study. In vitro metformin release kinetics were utilized in the absorption model to predict exposures in humans for new 1000-mg Met XR tablets, and the absorption model correctly projected equivalent in vivo exposure across all dose strengths. A clinical bioequivalence study was pursued based on the combined modeling results and demonstrated equivalent exposure as predicted by the simulations.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Co., P.O. Box 191, New Brunswick, New Jersey, 08903-0191, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Co., P.O. Box 191, New Brunswick, New Jersey, 08903-0191, USA. divyakant.desai@bms.com.
authors.forename: D
authors.initials: D
authors.lastname: Desai
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Co., P.O. Box 191, New Brunswick, New Jersey, 08903-0191, USA.
authors.forename: D
authors.initials: D
authors.lastname: Good
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Co., P.O. Box 191, New Brunswick, New Jersey, 08903-0191, USA.
authors.forename: J
authors.initials: J
authors.lastname: Crison
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb, Moreton, Merseyside, CH46 1QW, UK.
authors.forename: P
authors.initials: P
authors.lastname: Timmins
authors.affiliation: Appco Pharmaceuticals, Somerset, New Jersey, USA.
authors.forename: S
authors.initials: S
authors.lastname: Paruchuri
authors.affiliation: Teva Pharmaceuticals, North Wales, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Co., P.O. Box 191, New Brunswick, New Jersey, 08903-0191, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ha
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000737:chemistry; D065347:Hypromellose Derivatives / Q000737:chemistry; D007700:Kinetics; D008687:Metformin / Q000737:chemistry*; D008962:Models, Theoretical; D013607:Tablets / Q000737:chemistry*; D013810:Therapeutic Equivalency
chemical_list: D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D013607:Tablets; D065347:Hypromellose Derivatives; D008687:Metformin
keywords: CFD; GastroPlus; HPMC; diffusion; mathematical model; scale-up; surface area; volume