Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Mol Pharm. 2012 Dec 3;9(12):3515-25. doi: 10.1021/mp3003573. Epub 2012 Oct 30.
Paroxetine hydrochloride (HCl) is an antidepressant drug, reported to exist in the anhydrous form (form II) and as a stable hemihydrate (form I). In this study, we investigate the hydration behavior of paroxetine HCl form II with a view to understanding both the nature of the interaction with water and the interchange between forms II and I as a function of both temperature and water content. In particular, we present new evidence for both the structure and the interconversion process to be more complex than previously recognized. A combination of characterization techniques was used, including thermal (differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)), spectroscopic (attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR)), dynamic vapor sorption (DVS) and X-ray powder diffraction (XRPD) with variable humidity, along with computational molecular modeling of the crystal structures. The total amount of water present in form II was surprisingly high (3.8% w/w, 0.8 mol of water/mol of drug), with conversion to the hemihydrate noted on heating in hermetically sealed DSC pans. XRPD, supported by ATR-FTIR and DVS, indicated changes in the unit cell dimensions as a function of water content, with clear evidence for reversible expansion and contraction as a function of relative humidity (RH). Based on these data, we suggest that paroxetine HCl form II is not an anhydrate but rather a nonstoichiometric hydrate. However, no continuous channels are present and, according to molecular modeling simulation, the water is moderately strongly bonded to the crystal, which is in itself an uncommon feature when referring to nonstoichiometric hydrates. Overall, therefore, we suggest that the anhydrous form of paroxetine HCl is not only a nonstoichiometric hydrate but also one that shows highly unusual characteristics in terms of gradual unit cell expansion and contraction despite the absence of continuous channels. These structural features in turn influence the tendency of this drug to convert to the more stable hemihydrate. The study has implications for the recognition and understanding of the behavior of pharmaceutical nonstoichiometric hydrates.
盐酸帕罗西汀是一种抗抑郁药，据报道它以无水形式（形式 II）和稳定的半水合物（形式 I）存在。在这项研究中，我们研究了盐酸帕罗西汀形式 II 的水合行为，旨在了解与水的相互作用的性质以及形式 II 和 I 之间的相互转换，这是温度和含水量的函数。特别是，我们提出了新的证据，证明其结构和互变异构过程比以前认识的更为复杂。我们使用了多种表征技术，包括热（差示扫描量热法（DSC）和热重分析（TGA））、光谱（衰减全反射傅里叶变换红外光谱（ATR-FTIR））、动态蒸汽吸附（DVS）和 X 射线粉末衍射（XRPD）与可变湿度，以及晶体结构的计算分子建模。令人惊讶的是，形式 II 中存在的总水量非常高（3.8%w/w，即 0.8 摩尔水/摩尔药物），在密封的 DSC 锅中加热时会转化为半水合物。XRPD 结合 ATR-FTIR 和 DVS 表明，随着含水量的变化，晶胞尺寸发生变化，有明确的证据表明相对湿度（RH）的可逆膨胀和收缩。根据这些数据，我们认为盐酸帕罗西汀形式 II 不是无水物，而是一种非化学计量的水合物。然而，没有连续的通道，并且根据分子建模模拟，水与晶体中度强结合，这在非化学计量水合物中是不常见的特征。因此，总体而言，我们认为盐酸帕罗西汀的无水形式不仅是非化学计量的水合物，而且在没有连续通道的情况下，其晶胞逐渐膨胀和收缩的特性也非常不寻常。这些结构特征反过来又影响了该药物转化为更稳定的半水合物的趋势。该研究对识别和理解药物非化学计量水合物的行为具有重要意义。
