Tableting-induced mechanochemical matrix crosslinking: Towards non-disintegrating chitosan-based sustained delivery tablets

Background: Mechanochemistry involves the application of mechanical force to induce chemical changes in the material solid state. Mechanochemistry promises to overcome many drawbacks in pharmaceutical formulation. Chitosan (CS), a semisynthetic polymer obtained by N-deacetylation of chitin, has attracted attention in various biomedical and pharmaceutical applications. Methods: CS was grafted with 2,4-dichlorophenoxyacetic acid (2,4-D), a significantly hydrophobic and safe substituent, to promote facile adsorption of CO2. Physical mixtures and corresponding tablets comprised of model drugs and CS-2,4-D were prepared and characterized by DSC, XRD, and IR, and were compared with pure drugs and their mixtures with unmodified CS. Tensile strength and drug-release profiles of CS-2,4-D tablets were evaluated and compared with counterparts prepared from unmodified CS. Results: Adsorbed CO2 promoted the formation of powerful and extensive carbamate crosslinks within CS-2,4-D upon mechanochemical stress induced by mixing the new polymer with model drugs followed by tableting. Corresponding tablets showed increased tensile strength, sustained drug release and resistance to disintegration over 72 h of exposure to dissolution media. MTT bioassay indicated CS-2,4-D to be less cytotoxic than un-modified CS. Conclusions: the current study provided a proof-of-principle on tableting mediated mechanochemical matrix crosslinking.

Automated summary

Mechanochemistry involves the application of mechanical force to induce chemical changes in the material solid state. In this study, chitosan (CS) was grafted with 2,4-dichlorophenoxyacetic acid (2,4-D) to promote CO2 adsorption. The resulting tablets showed increased tensile strength, sustained drug release, and resistance to disintegration.