An Approach for Stabilizing the Metastable Form II of Carbamazepine Using Cellulose Nanofiber Aerogels

Carbamazepine (CBZ) is a widespread polymorphic drug, with Form II being the metastable polymorph that exhibits higher solubility, making it more attractive for pharmaceutical applications. However, Form II is prone to rapidly converting into the thermodynamically stable Form III at ambient temperatures. In this study, CBZ was crystallized in an aerogel synthesized by crosslinking TEMPO-oxidized cellulose nanofibers (TOCNF) with citric acid, resulting in the formation of the metastable Form II polymorph. PXRD and DSC analyses demonstrated that the aerogel could stabilize Form II at both room and high temperatures. Further storage studies indicated that the carboxyl and hydroxyl groups within the aerogel formed hydrogen bonds with Form II, effectively inhibiting its transformation to the stable polymorph. Molecular dynamics simulations revealed the interaction between cellulose nanofibers and the crystal face of different CBZ polymorphs. The results indicated that the interaction with Form II was the strongest, followed by Form III, while Form I exhibited the weakest interaction. These findings not only provide experimental evidence supporting the stability of CBZ’s metastable polymorph but also offer insights into potential strategies for stabilizing metastable forms of other drugs. This research could pave the way for the development of more effective pharmaceutical formulations that leverage the benefits of metastable polymorphs.