Department of Organic Chemistry and Technology, Budapest University of Technology and Economics (BME) , Műegyetem rkp. 3, H-1111 Budapest, Hungary.
Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics (BME) , Szent Gellért tér 4, H-1111, Budapest, Hungary.
Mol Pharm. 2017 Nov 6;14(11):3927-3934. doi: 10.1021/acs.molpharmaceut.7b00629. Epub 2017 Oct 16.
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.
本工作研究了在溶解过程中无定形伊曲康唑（ITR）的不利结晶现象。通过电喷法（使用乙烯基吡咯烷酮-醋酸乙烯酯共聚物）生成药物的完全无定形形式（固体分散体），并将所得纤维制成片剂。在标准溶解试验条件下，片剂的溶解不完全，之后可以过滤出沉淀物质。由于其中没有检测到镁含量，因此滤出液中包含 ITR 和硬脂酸。在溶解的同时，ITR 与硬脂酸形成不溶性缔合物，由氢键稳定，硬脂酸来自硬脂酸镁。这就是为什么溶解曲线在 100%处没有平台的原因。解决此问题有两种可行方法：改变润滑剂（使用顺丁烯二酸富马酸钠>95%的溶解可以完成）或改变固体分散体中的聚合物，使其能够与 ITR 形成氢键（例如羟丙基甲基纤维素）。这项工作引起了人们对可能导致原本良好的无定形固体分散体溶解恶化的一种现象的关注。
