Synthon Modularity in Crystal Structure Prediction: Designing Pomalidomide Polymorphs and Co-Crystals

Abstract

Synthon modularity is valuable for crystal structure prediction (CSP), allowing for the rationalization of polymorphs and co-crystals. This work used CSP to investigate the crystal structures of the pharmaceutical compound pomalidomide and its co-crystals with urea, gallic acid, and 3,4-dihydroxybenzoic acid (DHBA). By integrating crystal engineering (CE) principles and leveraging the concept of synthon modularity, we identified and characterized two polymorphs of pomalidomide (forms A and B) and proposed its co-crystal structures. Comparative analysis with analogous compounds like thalidomide and lenalidomide revealed shared synthon interactions, supporting the predictive reliability of the approach. These findings highlight the potential of synthon-guided CSP in advancing pharmaceutical crystallography and fostering the development of novel materials.