title: Amorphization alone does not account for the enhancement of solubility of drug co-ground with silicate: the case of indomethacin.
abstract: The solubility advantage of indomethacin amorphized by co-grinding with Neusilin US2 in various media was investigated. Physical mixtures of gamma-indomethacin and Neusilin US2 (in the ratios 1:1, 1:4 and 1:5) were amorphized at room temperature employing 75% RH in a porcelain jar mill using zirconia balls. The crystallinity of the samples was determined using ATR-FTIR and PXRD. The solubility and dissolution profiles of co-ground powders and crystalline counterparts were evaluated in 0.1 N HCl, water and phosphate buffer (pH 6.8) in a USP type II dissolution apparatus at 250 rpm and 37 degrees C. Very high concentrations of dissolved indomethacin as compared to the solubility of gamma-indomethacin (approximately 500 times in water and approximately 3.7 times in phosphate buffer) were attained. However, the presence of other polymorphs detected by PXRD and a change in the pH of the medium made interpretation of the results difficult. In 0.1 N HCl the solubility (i.e., the peak in a concentration versus time plot) of the amorphized drug in a 1:5 ratio with Neusilin increased to 109 times the solubility of crystalline gamma-indomethacin alone. An increase in amount of drug and Neusilin in the same ratio added to the dissolution medium also increased peak and plateau dissolution concentrations. The presence of silicic acid and ions (Mg(2+) and Al(3+)) in the dissolution media were found to cause the increase in the plateau concentration of indomethacin. Amorphization alone does not account for all of the dissolution enhancement; acidity, ions, and silicic acid are major contributors to dissolution enhancement.
authors.affiliation: School of Pharmacy, University of Connecticut, Storrs, Connecticut, 06269, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bahl
authors.forename: Robin H
authors.initials: RH
authors.lastname: Bogner
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D004058:Diffusion; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D005079:Excipients / Q000737:chemistry*; D007213:Indomethacin / Q000737:chemistry*; D008422:Materials Testing; D017640:Silicates / Q000737:chemistry*; D012995:Solubility
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D005079:Excipients; D017640:Silicates; D007213:Indomethacin