Green Mechanochemical Preparation of Cocrystal Polymorphs: Significant Effect of Intermediates and Solvents

Recently, green mechanochemical methods have received increasing attention. The fact that intermediates may exist during the milling process has also been gradually revealed. However, it is still unclear whether the modulation of the product polymorphs or the search for new polymorphs can be achieved by changing the intermediates. Herein, the modulation of the intermediates was successfully achieved by varying raw materials to explore the impact of intermediates on products, focusing on 4-chloro-3-sulfamoylbenzoic acid (CSBA), isonicotinamide (INA), and their cocrystals. The solvents and intermediates were revealed to have a decisive influence on the forms of products. A new CSBA–INA 1:1 cocrystal polymorph (form III) was discovered by changing intermediates, and its synthon was identified. The selected solvents were categorized into three groups based on the solubility data of CSBA and INA as well as the results of the milling experiments. When the second group of solvents was added, depending on the raw materials, CSBA–INA 1:1 form I could be obtained directly or form II/III could be obtained through the intermediate of a mixture of CSBA–INA 1:2 and 2:1. The mechanisms by which raw materials and solvents from different categories affect the intermediates and, consequently, the form of the products were elaborated. Ultimately, the alteration in the product form was attributed to a combination of the synthons in the intermediates and the stabilizing effect of the solvents on the crystals.