title: Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold.
abstract: Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.
authors.affiliation: a Formulation Research and Development , F. Hoffmann-La Roche Ltd , Basel , Switzerland.
authors.forename: Tim
authors.initials: T
authors.lastname: Wenzel
authors.affiliation: a Formulation Research and Development , F. Hoffmann-La Roche Ltd , Basel , Switzerland.
authors.forename: Cordula
authors.initials: C
authors.lastname: Stillhart
authors.affiliation: b Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University , Düsseldorf , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kleinebudde
authors.affiliation: a Formulation Research and Development , F. Hoffmann-La Roche Ltd , Basel , Switzerland.
authors.forename: Anikó
authors.initials: A
authors.lastname: Szepes
mesh_terms: D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding / Q000379:methods*; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry*; D007700:Kinetics; D008528:Mefenamic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D010316:Particle Size; D012995:Solubility; D013607:Tablets; D014867:Water / Q000737:chemistry*
chemical_list: D005079:Excipients; D013607:Tablets; D014867:Water; D008528:Mefenamic Acid
keywords: Roll compaction; dissolution; particle size; percolation threshold; poorly soluble drug