Insights into salts/cocrystals formation of polyhydroxy natural products as well as their separation behavior via cocrystallization

According to in-depth research on cocrystals of polyhydroxylated natural products, we previously summarized the substitution model to elucidate the formation mechanism of cocrystals. However, when refers to salt formation of natural products, the substitution model reveals numerous deficiencies. To compensate for the shortcomings of substitution model in predicting salt formation, this study conducts a comprehensive exploration of natural product salts. By supplementing the energy difference rule to the substitution model, it endows the modified model with broader applicability. Simultaneously, the transfer of protons within salts structures is verified by this modified model. Furthermore, we apply competitive cocrystallization technique to separate flavonoid natural products (quercetin, hesperetin, and naringenin). In view of the characteristics of various natural products as well as their cocrystals/salts, numerous separation processes are developed, and the separation effects of these processes are analyzed in detail. The purity of the products obtained from separation process all reaches above 70%, strongly demonstrating the feasibility of using cocrystallization for the binary separation of flavonoids. This work not only refines the substitution model for predicting cocrystals/salts formation of natural products but also indicates the promising application prospects of cocrystallization in industrial separation of natural products.