Lengauer Hannes, Makuc Damjan, Šterk Damjan, Perdih Franc, Pichler Arthur, Trdan Lušin Tina, Plavec Janez, Časar Zdenko
Sandoz GmbH, Early Stage Development, API Characterization, Biochemiestraße 10, AT-6250 Kundl, Austria.
National Institute of Chemistry, Slovenian NMR Centre, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Pharmaceutics. 2020 Apr 10;12(4):342. doi: 10.3390/pharmaceutics12040342.
Tenofovir alafenamide fumarate (TAF) is the newest prodrug of tenofovir that constitutes several drug products used for the treatment of HIV/AIDS. Although the solid-state properties of its predecessor tenofovir disoproxil fumarate have been investigated and described in the literature, there are no data in the scientific literature on the solid state properties of TAF. In our report, we describe the preparation of two novel polymorphs II and III of tenofovir alafenamide monofumarate (TA MF2 and TA MF3). The solid-state structure of these compounds was investigated in parallel to the previously known tenofovir alafenamide monofumarate form I (TA MF1) and tenofovir alafenamide hemifumarate (TA HF). Interestingly, the single-crystal X-ray diffraction of TA HF revealed that this derivative exists as a co-crystal form. In addition, we prepared a crystalline tenofovir alafenamide free base (TA) and its hydrochloride salt (TA HCl), which enabled us to determine the structure of TA MF derivatives using N-ssNMR (N-solid state nuclear magnetic resonance). Surprisingly, we observed that TA MF1 exists as a mixed ionization state complex or pure salt, while TA MF2 and TA MF3 can be obtained as pure co-crystal forms.
富马酸替诺福韦艾拉酚胺（TAF）是替诺福韦的最新前体药物，构成了几种用于治疗HIV/AIDS的药品。尽管其前体富马酸替诺福韦酯的固态性质已在文献中得到研究和描述，但科学文献中尚无关于TAF固态性质的数据。在我们的报告中，我们描述了两种新型的富马酸替诺福韦艾拉酚胺多晶型物II和III（TA MF2和TA MF3）的制备。这些化合物的固态结构与先前已知的富马酸替诺福韦艾拉酚胺晶型I（TA MF1）和富马酸替诺福韦艾拉酚胺半富马酸盐（TA HF）同时进行了研究。有趣的是，TA HF的单晶X射线衍射表明该衍生物以共晶形式存在。此外，我们制备了结晶态的替诺福韦艾拉酚胺游离碱（TA）及其盐酸盐（TA HCl），这使我们能够使用N-ssNMR（N-固态核磁共振）确定TA MF衍生物的结构。令人惊讶的是，我们观察到TA MF1以混合电离态络合物或纯盐的形式存在，而TA MF2和TA MF3可以以纯共晶形式获得。
