Controlled release of dasatinib from cyclodextrin-based inclusion complexes by mechanochemistry: A computational and experimental study.

Dasatinib, a potent tyrosine kinase inhibitor, is widely used to treat chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, its poor aqueous solubility and high first-pass metabolism result in limited oral bioavailability and potentially severe side effects, such as cardiotoxicity, hepatotoxicity, and pulmonary complications, which are intensified by rapid concentration peaks in the bloodstream. To address these challenges, this study examines the development of a controlled-release formulation of dasatinib using cyclodextrins as macrocyclic receptors to form inclusion complexes. Cyclodextrins, known for their ability to form host-guest complexes, enhance drug solubility and stability while enabling controlled drug release and aligning with green chemistry principles when synthesized mechanochemically. Different solid-state and solution-based characterization methods confirmed successful complexation and drug amorphization. Additionally, molecular dynamics simulations provided valuable insights into the binding interactions between dasatinib and cyclodextrins in both gas-phase and aqueous medium, simulating experimental conditions in the absence of a solvent and a physiological environment. Formulated tablets exhibited enhanced solubility and improved in vitro release profiles, suggesting a potential reduction in adverse side effects and improved patient compliance. The results demonstrate the efficacy of cyclodextrins as carriers for dasatinib, highlighting their potential to improve the drug's therapeutic profile in leukemia treatment by facilitating a steady, controlled release and minimizing toxicity.