Enhancing the stability of active pharmaceutical ingredients by the cocrystal strategy

Cocrystallization has been recognized as one of the most successful approaches to address the stability problems of active pharmaceutical ingredients (APIs) in the past few decades. However, scant attention has been paid to the molecular mechanism of the enhanced stability, primarily due to the complicated degradation pathway and insufficient structural analysis. In this review, we would like to demonstrate that stable cocrystals have their roots in tailored design, delicate modification, and ingenious construction rather than luck. It is not only possible but also necessary to propose an individual cocrystal strategy to minimize the disadvantageous influence of environmental factors (heat, moisture, light, and oxygen). Therefore, a multidimensional structural understanding of the improved stability, including the manipulation of interaction strength, molecular conformation, packing styles, and electronic effect, has been provided here. Prominent examples of cocrystals that had successfully dealt with the same kinds of stability problems are summarized separately, revealing the vital structural factors in different scenarios and further paving the way for future stable cocrystal design.

Automated summary

This review discusses the successful application of cocrystallization in addressing the stability issues of active pharmaceutical ingredients (APIs) and the molecular mechanism behind it. By tailored design, delicate modification, and ingenious construction of cocrystals, the stability of APIs can be enhanced. A multidimensional structural understanding is necessary to manipulate interaction strength, molecular conformation, packing styles, and electronic effect. Prominent examples of cocrystals that have successfully dealt with stability problems are summarized, providing insights into vital structural factors in different scenarios and guiding future stable cocrystal design.