Racher Florian, Petrick Tom L, Braun Doris E
Institute of Pharmacy, University of Innsbruck, Innrain 52c, Innsbruck 6020, Austria.
Cryst Growth Des. 2023 May 3;23(6):4638-4654. doi: 10.1021/acs.cgd.3c00387. eCollection 2023 Jun 7.
The application of computational screening methodologies based on H-bond propensity scores, molecular complementarity, molecular electrostatic potentials, and crystal structure prediction has guided the discovery of novel cocrystals of dapsone and bipyridine (DDS:BIPY). The experimental screen, which included mechanochemical and slurry experiments as well as the contact preparation, resulted in four cocrystals, including the previously known DDS:4,4'-BIPY (2:1, CC-B) cocrystal. To understand the factors governing the formation of the DDS:2,2'-BIPY polymorphs (1:1, CC-A and CC-B) and the two DDS:4,4'-BIPY cocrystal stoichiometries (1:1 and 2:1), different experimental conditions (such as the influence of solvent, grinding/stirring time, etc.) were tested and compared with the virtual screening results. The computationally generated (1:1) crystal energy landscapes had the experimental cocrystals as the lowest energy structures, although distinct cocrystal packings were observed for the similar coformers. H-bonding scores and molecular electrostatic potential maps correctly indicated cocrystallization of DDS and the BIPY isomers, with a higher likelihood for 4,4'-BIPY. The molecular conformation influenced the molecular complementarity results, predicting no cocrystallization for 2,2'-BIPY with DDS. The crystal structures of CC-A and CC-A were solved from powder X-ray diffraction data. All four cocrystals were fully characterized by a range of analytical techniques, including powder X-ray diffraction, infrared spectroscopy, hot-stage microscopy, thermogravimetric analysis, and differential scanning calorimetry. The two DDS:2,2'-BIPY polymorphs are enantiotropically related, with form B being the stable polymorph at room temperature (RT) and form A being the higher temperature form. Form B is metastable but kinetically stable at RT. The two DDS:4,4'-BIPY cocrystals are stable at room conditions; however, at higher temperatures, CC-A transforms to CC-B. The cocrystal formation enthalpy order, derived from the lattice energies, was calculated as follows: CC-B > CC-A > CC-A.
基于氢键倾向得分、分子互补性、分子静电势和晶体结构预测的计算筛选方法的应用，指导了氨苯砜与联吡啶（DDS:BIPY）新型共晶体的发现。实验筛选包括机械化学和浆料实验以及接触制备，得到了四种共晶体，包括先前已知的DDS:4,4'-BIPY（2:1，CC-B）共晶体。为了理解控制DDS:2,2'-BIPY多晶型物（1:1，CC-A和CC-B）以及两种DDS:4,4'-BIPY共晶体化学计量比（1:1和2:1）形成的因素，测试了不同的实验条件（如溶剂的影响、研磨/搅拌时间等），并与虚拟筛选结果进行了比较。尽管对于相似的共形成物观察到了不同的共晶体堆积，但计算生成的（1:1）晶体能量景观以实验共晶体为最低能量结构。氢键得分和分子静电势图正确地表明了DDS和BIPY异构体的共结晶，4,4'-BIPY的可能性更高。分子构象影响了分子互补性结果，预测2,2'-BIPY与DDS不会共结晶。从粉末X射线衍射数据解析出了CC-A和CC-A的晶体结构。所有四种共晶体都通过一系列分析技术进行了全面表征，包括粉末X射线衍射、红外光谱、热台显微镜、热重分析和差示扫描量热法。两种DDS:2,2'-BIPY多晶型物是对映变体相关的，B型在室温（RT）下是稳定的多晶型物，A型是较高温度形式。B型是亚稳的，但在室温下动力学稳定。两种DDS:4,4'-BIPY共晶体在室温条件下是稳定的；然而，在较高温度下，CC-A会转变为CC-B。根据晶格能计算得到的共晶体形成焓顺序如下：CC-B > CC-A > CC-A。
