Krupa Anna, Majda Dorota, Mozgawa Włodzimierz, Szlęk Jakub, Jachowicz Renata
Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical College, Jagiellonian University, 9 Medyczna str, 30-688, Cracow, Poland.
Department of Chemistry, Jagiellonian University, Cracow, Poland.
AAPS PharmSciTech. 2017 May;18(4):1318-1331. doi: 10.1208/s12249-016-0599-7. Epub 2016 Aug 5.
The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70°C and was followed by the chemical degradation with the onset at 290°C. The highest thermal stability was stated for TA, which decomposed at ca. 320°C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190°C. The products of the drug decomposition were identified. FT-FIR was applied to study intra- and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies.
该研究提供了波生坦（BOS）与他达拉非（TA）和枸橼酸西地那非（SIL）相比的物理化学特性。尽管有一些关于SIL和TA热特性的报道，但迄今为止尚未对BOS的物理化学性质进行研究。最近的临床报告表明，波生坦与磷酸二酯酶-5抑制剂联合使用可提高肺动脉高压（PAH）药物治疗的有效性。然而，为了设计针对慢性罕见病治疗的个性化药物，每种药物的热行为和溶解度的详细信息是必不可少的。因此，应用X射线衍射（XRD）、差示扫描量热法（DSC）和热重-质谱联用分析法（TGA-QMS）来比较药物的性质、它们的热稳定性以及鉴定热降解产物。BOS的脱水在70°C开始，随后在290°C开始化学降解。TA的热稳定性最高，在约320°C分解，而SIL的热分解过程起始温度最低，即190°C。鉴定了药物分解产物。应用傅里叶变换红外光谱（FT-FIR）研究药物分子之间的分子内和分子间相互作用。使用傅里叶变换中红外光谱（FT-MIR）和拉曼光谱检查药物的化学结构。使用化学信息学工具预测药物的极性表面积、pKa或脂水分配系数（logP）。它们的结果与溶解度和溶出度研究一致。
