Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

中文翻译：

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非晶态伊曲康唑溶解性恶化的研究：与硬脂酸镁不相容的描述和可能的解决方案

在这项工作中研究了无定形伊曲康唑（ITR）在溶解过程中发生的不利结晶现象。通过电吹法（用乙烯基吡咯烷酮-乙酸乙烯酯共聚物）产生药物的完全无定形形式（固体分散体），并将获得的纤维配制成片剂。在标准溶出度试验的情况下，发现片剂的溶出度不完全，此后可以过滤沉淀的物质。滤液由ITR和硬脂酸组成，因为其中没有检测到镁含量。与溶解同时，ITR形成不溶性缔合物，通过氢键稳定，其中硬脂酸衍生自硬脂酸镁。这就是为什么溶出曲线没有100％的平稳期的原因。解决该问题的两种方法是可行的：更换润滑剂（富马酸钠硬脂酸钠的溶解度可达到95％以上）或将固体分散体中的聚合物更改为能够与ITR形成氢键的类型（例如，羟丙基甲基纤维素） 。这项工作引起人们对一种可能导致无定形固体分散体原本良好溶解的恶化的现象的关注。