title: Understanding improved dissolution of indomethacin through the use of cohesive poorly water-soluble aluminium hydroxide: effects of concentration and particle size distribution.
abstract: The objective of this study was to explore the effects of concentration and particle size distribution of an added poorly water-soluble inorganic salt, aluminium hydroxide, on the dissolution of a poorly water-soluble drug, indomethacin (IMC), from lactose interactive mixtures. Dissolution was studied using the United States Pharmacopeia paddle method in buffer pH 5.0 and the data most aptly fitted a bi-exponential dissolution model which represented dissolution occurring from dispersed and agglomerated particles. The dispersion of IMC mixtures was measured in dissolution media under non-sink conditions by laser diffraction. The dissolution of IMC increased as a function of the concentration of aluminium hydroxide (5-20%) added to the mixtures. Increasing the proportion of larger particles of the cohesive aluminium hydroxide increased the dissolution rate of IMC. The enhanced dissolution was attributed to increases in both the dissolution rate constant and initial concentration of dispersed particles. Mechanistically, the aluminium hydroxide was found to facilitate the detachment of IMC particles from the carrier surface, forming a complex interactive mixture that more readily deagglomerated than the cohesive drug agglomerates. The outcomes of this work would therefore allow more careful control and selection of the excipient specifications in producing solid dosage formulations with improved dissolution of poorly water-soluble drugs.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Tracy
authors.initials: T
authors.lastname: Tay
authors.forename: Ayman
authors.initials: A
authors.lastname: Allahham
authors.forename: David A V
authors.initials: DA
authors.lastname: Morton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stewart
mesh_terms: D000536:Aluminum Hydroxide / Q000737:chemistry*; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000737:chemistry*; D007700:Kinetics; D007785:Lactose / Q000737:chemistry; D008956:Models, Chemical; D010316:Particle Size; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D002021:Buffers; D005079:Excipients; D000536:Aluminum Hydroxide; D007785:Lactose; D007213:Indomethacin