title: Influence of pH Modulation on Dynamic Behavior of Gel Layer and Release of Weakly Basic Drug from HPMC/Wax Matrices, Controlled by Acidic Modifiers Evaluated by Multivariate Data Analysis.
abstract: The solubility of weakly basic drugs in passage through gastrointestinal tract leads to their pH-dependent release from extended release formulations and to lower drug absorption and bioavailability. The aim of this study was to modulate the micro-environmental pH of hypromellose/montanglycol wax matrices and to observe its influence on the release of weakly basic drug verapamil hydrochloride (VH) with a pH-dependent solubility with respect to gel layer formation and its dynamics. For this study, malic and succinic acids differing in their solubility and pKa were selected as pH modifiers. The dissolution studies were performed by the method of changing pH. Within the same conditions, pH, thickness, and penetration force of the gel layer were measured as well. From the PCA sub-model, it is evident that a higher acid concentration ensured lower gel pH and conditions for higher drug solubility, thus creating larger gel layer with smaller rigidity, resulting in higher VH release during the dissolution test. Incorporation of stronger and more soluble malic acid (100 mg/tablet) created the most acidic and the thickest gel layer through which a total of 74% of VH was released. Despite having lower strength and solubility, matrices containing succinic acid (100 mg/tablet) released a comparable 71% of VH in a manner close to zero-order kinetics. The thinner and less rigid gel layers of the succinic acid matrices allowed an even slightly faster VH release at pH 6.8 than from matrices containing malic acid. Thus acid solubility is more parametrically significant than acid pKa for drug release at pH 6.8.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42, Brno, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Mašková
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42, Brno, Czech Republic. kubovak@vfu.cz.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kubová
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42, Brno, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Vysloužil
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42, Brno, Czech Republic.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pavloková
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42, Brno, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Vetchý
mesh_terms: D003692:Delayed-Action Preparations / Q000737:chemistry*; D065546:Drug Liberation; D005782:Gels; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D007700:Kinetics; D008293:Malates / Q000737:chemistry; D015999:Multivariate Analysis; D012995:Solubility; D013386:Succinates / Q000737:chemistry; D013607:Tablets; D014700:Verapamil / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D014885:Waxes
chemical_list: D003692:Delayed-Action Preparations; D005782:Gels; D008293:Malates; D013386:Succinates; D013607:Tablets; D014885:Waxes; D065347:Hypromellose Derivatives; C030298:malic acid; D014700:Verapamil
keywords: gel layer thickness; matrix tablets; multivariate data analysis; pH modifiers; pH-independent drug release