Synthesis and Structural Characterization of Cocrystals and Pharmaceutical Cocrystals: Mechanochemistry vs Slow Evaporation from Solution

The reliability of solvent drop grinding (SDG), also referred to as liquid assisted grinding, wet cogrinding, or mechanochemistry, to facilitate cocrystal formation is addressed with a series of model cocrystals and pharmaceutical cocrystals. The synthesis and single crystal structures of 17 new cocrystals that are sustained by COOH···Narom and OH···Narom supramolecular heterosynthons are presented. These cocrystals were prepared by both slow evaporation from solution and SDG. We also investigated whether or not SDG could be used to prepare previously reported carbamazepine (CBZ) pharmaceutical cocrystals. The following eight cocrystal formers were investigated in this context: 4,4′-bipyridine, 4-aminobenzoic acid/H2O, 2,6-pyridinedicarboxylic acid, benzoquinone, terephthalaldehyde, saccharin, nicotinamide, and aspirin. Our results reveal that all of the cocrystals that were grown from solution and characterized by single crystal X-ray crystallography can also be prepared by SDG. SDG therefore appears to be a cost-effective, green, and reliable method for discovery of new cocrystals as well as for preparation of existing cocrystals.

本研究针对溶剂滴磨法（solvent drop grinding, SDG，又称液体辅助研磨、湿共研磨或机械化学）促进共晶（cocrystal）生成的可靠性展开探讨，采用一系列模型共晶与药用共晶作为研究对象。本文报道了17种由COOH···Narom与OH···Narom超分子异合成子（supramolecular heterosynthons）稳定的新型共晶的合成方法与单晶结构，上述共晶可通过溶液缓慢挥发法与SDG法两种途径制备。本研究同时探究了SDG法能否用于制备已有文献报道的卡马西平（carbamazepine, CBZ）药用共晶，共考察了8种共晶形成剂：4,4'-联吡啶、4-氨基苯甲酸/水、2,6-吡啶二羧酸、苯醌、对苯二甲醛、糖精、烟酰胺与阿司匹林。研究结果表明，所有通过溶液法生长并经单晶X射线衍射分析表征的共晶，均可通过SDG法制备得到。由此可见，SDG法是一种经济高效、绿色环保且可靠的方法，可用于新型共晶的发现与现有共晶的制备。