title: Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin.
abstract: Arginine, phenylalanine, and tryptophan have been previously shown to improve the solid-state stability of amorphous indomethacin. The present study investigates the ability of these amino acids to prolong the supersaturation of indomethacin in both aqueous and biorelevant conditions either when freely in solution or when formulated as co-amorphous mixtures. The co-amorphous amino acid-indomethacin mixtures (molar ratio 1:1) and amorphous indomethacin were prepared by cryomilling. Dissolution and precipitation tests were performed in buffer solutions (pH 5 and 6.5) and in Fed and Fasted State Simulated Intestinal Fluids (FeSSIF and FaSSIF, respectively). Precipitation tests were conducted with the solvent shift method. The supersaturation stability of indomethacin and the precipitation inhibitory effect of amino acids were evaluated by calculating the supersaturation factor and the excipient gain factor, respectively. Biorelevant media exerted a significant effect on indomethacin solubility but had little effect on the supersaturation stability. Arginine had the most significant impact on the dissolution properties of indomethacin, but also phenylalanine and tryptophan stabilized supersaturation in some media when formulated as co-amorphous mixtures with indomethacin. Only arginine stabilized supersaturation without co-amorphization, an effect only observed in media of pH 6.5. The unique behavior of the arginine-indomethacin mixture was further demonstrated by the abrupt formation of a precipitate, when an excess physical mixture of arginine and indomethacin was added to FeSSIF (pH 6.5). The solid-state investigation of this precipitate indicated that it probably consisted of crystalline arginine-indomethacin salt with possibly some residual crystalline starting materials.
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: rami.ojarinta@uef.fi.
authors.forename: Rami
authors.initials: R
authors.lastname: Ojarinta
authors.affiliation: Admescope Ltd, Typpitie 1, 90620 Oulu, Finland; School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Aki T
authors.initials: AT
authors.lastname: Heikkinen
authors.affiliation: Department of Chemistry, University of Jyväskylä, P.O. Box 35, 40014 University of Jyväskylä, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Sievänen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Laitinen
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D007213:Indomethacin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D033362:Powder Diffraction; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000596:Amino Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin
keywords: Amino acid; Biorelevant; Co-amorphous; Precipitation; Supersaturation