College of Pharmacy, CHA University, Sungnam 13844, Korea.
Department of Chemistry, Ajou University, Suwon 16499, Korea.
Molecules. 2017 Jul 14;22(7):1182. doi: 10.3390/molecules22071182.
Tenofovir disoproxil (TD), an anti-virus drug, is currently marketed under its most stable form, Form-I of Tenofovir disoproxil fumarate (TDF). However, studies regarding the properties of TD free base crystal as a promising drug as well as its crystal structure have not yet been reported. This assumption was made because TD free base is not directly produced in a solid form during the manufacturing process. TD free base is first obtained in an oil form, and is then synthesized into TDF crystal. In this regard, the present study was conducted to investigate both the potentiality of TD free base to be an active pharmaceutical ingredient (API) and its crystal structure. Here, TD free base solid was produced by means of drowning-out crystallization. Next, single crystal X-ray diffraction (SXD) was employed to determine the crystal structure. Powder X-ray diffraction (PXRD) and a differential scanning calorimetry (DSC) analysis were performed to evaluate the crystal's properties. Furthermore, experiments were carried out at 15%, 35%, 55%, 75%, and 95% relative humidity (RH) for 12 h using a hygroscopic tester to determine and to compare the hygroscopicity and stability of TD free base with TDF crystal. Additionally, experiments were conducted under accelerated (40 °C, RH 75%) and stress storage (60 °C, RH 75%) conditions for 30 days to investigate the changes in purity and the formation of dimer. In this work, we report that TD free base possesses lower hygroscopicity, and thus does not generate dimer impurity from hydrolysis. Primarily, this is attributed to the fact that TD free base is not an easily ionized salt but comprises neutral hydrophobic molecules. According to the structural properties, the improved hygroscopic property of the TD free base crystal was due to the decrease of crystal polarity owing to the intermolecular H-bonds present in TD free base rings. In addition, the solubility investigation study carried out in aqueous solution and at gastrointestinal pH revealed a similarity in TDF and TD free base solubility under the mentioned conditions. Accordingly, we could confirm the potentiality of TD free base as an active pharmaceutical ingredient.
替诺福韦二吡呋酯（TD）是一种抗病毒药物，目前以其最稳定的形式，富马酸替诺福韦二吡呋酯（TDF）的 Form-I 形式销售。然而，关于 TD 游离碱晶体作为一种有前途的药物以及其晶体结构的研究尚未报道。之所以做出这样的假设，是因为在制造过程中，TD 游离碱并没有直接以固体形式直接产生。TD 游离碱最初以油的形式获得，然后合成 TDF 晶体。在这方面，本研究旨在研究 TD 游离碱作为活性药物成分（API）的潜力及其晶体结构。在这里，通过淹没结晶法生产 TD 游离碱固体。接下来，采用单晶 X 射线衍射（SXD）来确定晶体结构。进行粉末 X 射线衍射（PXRD）和差示扫描量热法（DSC）分析以评估晶体的性质。此外，在吸湿测试仪上进行了在 15%、35%、55%、75%和 95%相对湿度（RH）下进行 12 小时的实验，以确定和比较 TD 游离碱和 TDF 晶体的吸湿性和稳定性。此外，在加速（40°C，RH 75%）和应激储存（60°C，RH 75%）条件下进行了 30 天的实验，以研究纯度变化和二聚体的形成。在这项工作中，我们报告说 TD 游离碱具有较低的吸湿性，因此不会因水解而产生二聚体杂质。主要原因是 TD 游离碱不是易电离的盐，而是包含中性疏水分子。根据结构性质，TD 游离碱晶体吸湿性的提高是由于 TD 游离碱环中存在的分子间氢键导致晶体极性降低所致。此外，在水相和胃肠道 pH 下进行的溶解度研究表明，在所述条件下 TDF 和 TD 游离碱的溶解度相似。因此，我们可以确认 TD 游离碱作为活性药物成分的潜力。
