Salt formation during freeze-drying - an approach to enhance indomethacin dissolution
Salt formation during freeze-drying - an approach to enhance indomethacin dissolution
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冷冻干燥过程中盐的形成 - 增强吲哚美辛溶出度的方法
DOI：
10.1007/s11095-015-1732-0
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发表时间：
2015
影响因子：
3.7
通讯作者：
R. Suryanarayanan
中科院分区：
文献类型：
--
作者：
S. Thakral;R. Suryanarayanan
目的（i）制备冻干的可注射吲哚美辛（IMC）剂型。(ii)在冷冻干燥过程中将IMC转化为其tris盐，以促进快速溶解（复溶）。(iii)调制盐结晶退火的冷冻solution.MethodsAqueous IMC解决方案与三聚氰胺缓冲冷冻干燥，有或没有退火的冷冻解决方案。的冻干粉，其特征在于通过X-射线衍射法，差示扫描量热法和红外光谱，并进行水的吸附和溶解studies.ResultsBased上的红外光谱，最终的冻干粉被证实含有IMC三盐。在不存在退火的情况下，冻干物是X射线无定形的，玻璃化转变温度为19°C。冷冻溶液退火导致亲液结晶度大幅增加。有趣的是，无定形和部分结晶的冻干物均“瞬时”且完全溶解在溶出介质中。相比之下，结晶IMC以及其与三的物理混合物表现出慢得多的溶解与~ 50%的药物溶解在30 min.ConclusionIn situIMC三盐的形成导致了一个优雅的冻干粉具有非常短的重建时间。三羟甲基氨基甲烷有两个作用-作为预冻干溶液中的缓冲液和作为最终冻干物中盐的平衡剂。这种溶解度增强的方法可以扩展到其他酸性药物，其中在冷冻干燥过程中观察到盐的形成。
Purpose(i) Prepare a freeze-dried injectable indomethacin (IMC) dosage form. (ii) Convert IMC to its tris salt during freeze-drying so as to facilitate rapid dissolution (reconstitution). (iii) Modulate salt crystallinity by annealing the frozen solution.MethodsAqueous IMC solutions buffered with tris were freeze dried, with or without annealing the frozen solutions. The lyophiles were characterized by X-ray diffractometry, differential scanning calorimetry and infra-red spectroscopy and also subjected to water sorption and dissolution studies.ResultsBased on IR spectroscopy, the final lyophile was confirmed to contain the IMC tris salt. In the absence of annealing, the lyophile was X-ray amorphous with a glass transition temperature of 19°C. Annealing the frozen solutions caused a substantial increase in lyophile crystallinity. Interestingly, both the amorphous and partially crystalline lyophiles dissolved “instantaneously” and completely in the dissolution medium. In contrast, the crystalline IMC as well as its physical mixture with tris exhibited much slower dissolution with ~ 50% drug dissolved in 30 min.ConclusionIn situIMC tris salt formation resulted in an elegant lyophile with a very short reconstitution time. Tris served two roles – as a buffer in the prelyophilization solution and as the counterion for the salt in the final lyophile. This approach for solubility enhancement could be extended to other acidic drugs wherein salt formation was observed during freeze-drying.