Formation Mechanism of Coamorphous Drug-Amino Acid Mixtures
Formation Mechanism of Coamorphous Drug-Amino Acid Mixtures
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DOI：
10.1021/acs.molpharmaceut.5b00295
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发表时间：
2015-07-01
影响因子：
4.9
通讯作者：
Rades, Thomas
中科院分区：
文献类型：
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作者：
Jensen, Katrine Tarp;Larsen, Flemming Hofmann;Rades, Thomas
分析了吲哚美辛色氨酸(IND-Trp)和呋塞米色氨酸(Fur-Trp)两种共无定形药物氨基加成体系在球磨过程中的非晶化程度和共非晶化机理。将这两种混合物与不含氨基酸的纯药物的相应非晶化进行了比较。对摩尔比为1：1的粉末混合物进行不同时间的球磨，并用XRPD、C-13固体核磁共振和DSC研究了它们的物理化学性质。将药物与氨基酸复合后，得到无定形粉末所需的研磨时间从纯药物的90min以上减少到共非晶粉末的30min。观察到非晶化为XRPD反射的减少，并基于单核磁共振谱的归一化主成分分析(PCA)分数进行了额外的量化。此外，共非晶体系的玻璃化温度(T-g)随时间的变化表明，球磨30分钟后完全实现了共非晶化。根据DSC数据，可以确定这两个共非晶系的形成机制。样品的T-g位置表明，共无定形Ind-Trp是由氨基酸溶解在无定形药物中形成的，而共无定形Fur-Trp是由药物溶解在无定形氨基酸中形成的。
Two coamorphous drug amino add systems, indomethacin tryptophan (Ind-Trp) and furosemide tryptophan (Fur-Trp), 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, C-13 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-Trp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur-Trp was formed by the drug being dissolved in the amorphous amino acid.