Braun Doris E, Griesser Ulrich J
Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
Front Chem. 2018 Feb 22;6:31. doi: 10.3389/fchem.2018.00031. eCollection 2018.
The observed moisture- and temperature dependent transformations of the dapsone (4,4'-diaminodiphenyl sulfone, DDS) 0. 33-hydrate were correlated to its structure and the number and strength of the water-DDS intermolecular interactions. A combination of characterization techniques was used, including thermal analysis (hot-stage microscopy, differential scanning calorimetry and thermogravimetric analysis), gravimetric moisture sorption/desorption studies and variable humidity powder X-ray diffraction, along with computational modeling (crystal structure prediction and pair-wise intermolecular energy calculations). Depending on the relative humidity the hydrate contains between 0 and 0.33 molecules of water per molecule DDS. The crystal structure is retained upon dehydration indicating that DDS hydrate shows a non-stoichiometric (de)hydration behavior. Unexpectedly, the water molecules are not located in structural channels but at isolated-sites of the host framework, which is counterintuitively for a hydrate with non-stoichiometric behavior. The water-DDS interactions were estimated to be weaker than water-host interactions that are commonly observed in stoichiometric hydrates and the lattice energies of the isomorphic dehydration product (hydrate structure without water molecules) and (form ) differ only by ~1 kJ mol. The computational generation of hypothetical monohydrates confirms that the hydrate with the unusual DDS:water ratio of 3:1 is more stable than a feasible monohydrate structure. Overall, this study highlights that a deeper understanding of the formation of hydrates with non-stoichiometric behavior requires a multidisciplinary approach including suitable experimental and computational methods providing a firm basis for the development and manufacturing of high quality drug products.
所观察到的氨苯砜（4,4'-二氨基二苯砜，DDS）0.33水合物随湿度和温度的转变与其结构以及水 - DDS分子间相互作用的数量和强度相关。使用了多种表征技术，包括热分析（热台显微镜、差示扫描量热法和热重分析）、重量法水分吸附/解吸研究以及可变湿度粉末X射线衍射，同时还进行了计算建模（晶体结构预测和成对分子间能量计算）。根据相对湿度的不同，水合物中每分子DDS所含的水分子数在0至0.33之间。脱水后晶体结构得以保留，这表明DDS水合物呈现出非化学计量的（脱）水行为。出乎意料的是，水分子并非位于结构通道中，而是位于主体骨架的孤立位点，这对于具有非化学计量行为的水合物来说有悖常理。据估计，水 - DDS相互作用比化学计量水合物中常见的水 - 主体相互作用要弱，同构脱水产物（无水分子的水合物结构）和（形式）的晶格能仅相差约1 kJ/mol。对假设的一水合物的计算生成证实，具有不寻常的DDS:水比例为3:1的水合物比一种可行的一水合物结构更稳定。总体而言，这项研究强调，要更深入地理解具有非化学计量行为的水合物的形成，需要采用多学科方法，包括合适的实验和计算方法，为高质量药品的开发和生产提供坚实基础。
