Chitosan hydrogel for controlled crystallization of loaded drug: Role of interplay of assembly processes

The utilization of natural polymer gel to achieve drug polymorph control is usually a challenging issue, and the interplay of gelation and crystallization has been neglected in many studies. In this work, a modified chitosan (Cs) hydrogel was used to encapsulate drug Isonicotinamide (IN), where competitive crystallization and gelation was constructed for a better control of different assembly processes. It was found that the crystalline outcome of drug (cocrystals or IN Form I) depends on different crosslinking agents used. Spectral analysis and MD simulation reveal that the interplay of crosslinking effect of Cs, dimerization of crosslinking agents and aggregation of IN determines the crystalline outcome, among which the affinity to crosslinking agents of Cs chain plays the significant role. To our knowledge, it is the first time that Cs hydrogel acts as a template to regulate polymorphism of drug. This work offers a promising way for drug delivery system design.