Vogt Frederick G, Dell'Orco Philip C, Diederich Ann M, Su Qiaogong, Wood Jeffery L, Zuber Gary E, Katrincic Lee M, Mueller Ronald L, Busby David J, Debrosse Charles W
Chemical and Pharmaceutical Development, GlaxoSmithKline plc., P.O. Box 1539, King of Prussia, PA 19406, USA.
J Pharm Biomed Anal. 2006 Mar 18;40(5):1080-8. doi: 10.1016/j.jpba.2005.08.032. Epub 2005 Oct 20.
Topotecan hydrochloride, a pharmaceutical compound developed as a treatment for cancer, exhibits variable hydration states in a crystalline solid form chosen for manufacturing. This variability requires additional controls for successful development, and presents a characterization and detection challenge for analytical methods. In this study, overall water content was determined by Karl Fischer titration and thermogravimetric analysis (TGA) on topotecan HCl equilibrated at different relative humidity levels. These results, when combined with information obtained from dynamic water vapor sorption and differential scanning calorimetry (DSC), indicate that this form of topotecan HCl contains 3 mol of water integral to the crystalline structure and up to two additional moles of water depending on the relative humidity. Powder X-ray diffraction experiments did not detect significant differences in topotecan HCl samples equilibrated at trihydrate and pentahydrate states, and showed that the crystal lattice dimensions are not affected unless the form is dried below the trihydrate state. This behavior is typical of crystal structures with channels that can accommodate additional loosely bound water. To study the role of the loosely bound water in the crystal structure in more detail, solid-state (13)C and (15)N nuclear magnetic resonance (NMR) were used to examine the differences between the hydration states. Both the trihydrate and pentahydrate states yielded similar solid-state NMR spectra, consistent with the lack of change in the crystal lattice. However, minor but readily detectable differences in the (13)C spectra are observed with changes in water content. Interpretation of this data suggests that the loosely bound channel water is hydrogen-bonding to specific portions of the topotecan parent molecule. Topotecan HCl trihydrate was hydrated with D(2)O vapor to confirm the nature and location of the channel water using (13)C and (2)H solid-state NMR. Despite the detectable association of the channel water with hydrogen bonding sites on the topotecan molecule, (2)H quadrupolar echo experiments indicate that the channel water is highly mobile at room temperature and at -60 degrees C.
盐酸拓扑替康是一种开发用于治疗癌症的药物化合物，在用于制造的结晶固体形式中呈现出可变的水合状态。这种变异性需要额外的控制措施才能成功开发，并且对分析方法提出了表征和检测挑战。在本研究中，通过卡尔费休滴定法和热重分析（TGA）测定了在不同相对湿度水平下平衡的盐酸拓扑替康的总含水量。这些结果与从动态水蒸气吸附和差示扫描量热法（DSC）获得的信息相结合，表明这种形式的盐酸拓扑替康含有3摩尔与晶体结构结合的水，并且根据相对湿度还含有多达两摩尔额外的水。粉末X射线衍射实验未检测到在三水合物和五水合物状态下平衡的盐酸拓扑替康样品中的显著差异，并且表明除非该形式在低于三水合物状态下干燥，否则晶格尺寸不会受到影响。这种行为是具有可容纳额外松散结合水的通道的晶体结构的典型特征。为了更详细地研究松散结合水在晶体结构中的作用，使用固态（13）C和（15）N核磁共振（NMR）来检查水合状态之间的差异。三水合物和五水合物状态都产生了相似的固态NMR光谱，这与晶格没有变化一致。然而，随着含水量的变化，在（13）C光谱中观察到微小但易于检测到的差异。对该数据的解释表明，松散结合的通道水与拓扑替康母体分子的特定部分形成氢键。用D（2）O蒸气使盐酸拓扑替康三水合物水合，以使用（13）C和（2）H固态NMR确认通道水的性质和位置。尽管通道水与拓扑替康分子上的氢键位点有可检测到的关联，但（2）H四极回波实验表明通道水在室温下和-60℃时具有高度的流动性。
