期刊
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
卷 112, 期 -, 页码 85-95出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejpb.2016.11.023
关键词
Co-amorphous; Amino acid; Supersaturation; Precipitation; Biorelevant
资金
- Doctoral Programme in Drug Research in the Doctoral School of University of Eastern Finland
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 super saturation 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 arginineindomethacin salt with possibly some residual crystalline starting materials. (C) 2016 Elsevier B.V. All rights reserved.
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