Crystal structure determination and DFT analysis of doxorubicin hydrochloride for controlled-release drug formulations

Doxorubicin hydrochloride (DOX) is a widely used chemotherapeutic drug that inhibits the growth of cancer cells. Many DOX-based controlled-release systems have been proposed to reduce toxicity. However, knowledge of its crystal structure is essential for optimizing drug release processes and designing co-crystals or salts with different release properties. Although DOX has been extensively studied, no crystal structure is available in the Cambridge Structural Database or literature. In this work, we determine the crystal structure of DOX using a simulated annealing approach based on powder X-ray diffraction data. We confirm its validation by Rietveld refinement and molecular cohesion by using a molecular geometry check tool. We also use density functional theory to optimize the DOX structure and obtain the minimum energy conformation, H-bond donor/acceptor species, charge localization, and crystal structure parameters. This study provides essential structural information on DOX that can be used to rationalize new modified-release dosage forms and to design co-crystals or salts with different release properties.