Formation Mechanism of Coamorphous Drug鈥揂mino Acid Mixtures

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• 作者：Katrine Tarp Jensen ; Flemming Hofmann Larsen ; Claus Cornett ; Korbinian L枚bmann ; Holger Grohganz ; Thomas Rades
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：July 6, 2015
• 年：2015
• 卷：12
• 期：7
• 页码：2484-2492
• 全文大小：468K
• ISSN：1543-8392

文摘

Two coamorphous drug鈥揳mino acid systems, indomethacin鈥搕ryptophan (Ind鈥揟rp) and furosemide鈥搕ryptophan (Fur鈥揟rp), were analyzed toward their ease of amorphization and mechanism of coamorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar ratio were milled for varying times, and their physicochemical properties were investigated using XRPD, ¹³C solid state NMR (ssNMR), and DSC. Comilling the drug with the amino acid reduced the milling time required to obtain an amorphous powder from more than 90 min in the case of the pure drugs to 30 min for the coamorphous powders. Amorphization was observed as reductions in XRPD reflections and was additionally quantified based on normalized principal component analysis (PCA) scores of the ssNMR spectra. Furthermore, the evolution in the glass temperature (T_g) of the coamorphous systems over time indicated complete coamorphization after 30 min of milling. Based on the DSC data it was possible to identify the formation mechanism of the two coamorphous systems. The T_g position of the samples suggested that coamorphous Ind鈥揟rp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur鈥揟rp was formed by the drug being dissolved in the amorphous amino acid.