ACS Omega 2025 May 27;1020:20661-20673. doi: 10.1021/acsomega.5c01538.

Crystal Structure of Melphalan Hydrochloride and Its Association with Caffeine Improves Its Antineoplastic Action.

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Melphalan hydrochloride (MEH) is a chemotherapy drug with antitumor activity, recognized for its classification as an alkylating agent. Over the past few decades, the drug has been administered to patients undergoing treatment for breast and ovarian cancers, and it is also intended for the treatment of multiple myeloma. It is commercially available in tablet and injection forms; however, its oral administration presents some limitations, including presystemic elimination and incomplete absorption. This study employs a simulated annealing approach and powder X-ray diffraction data to determine its crystal structure. The structure is confirmed by Rietveld refinement, which reveals good visual agreement between the generated model and experimental data. Given that MEH has low solubility in water, a screening conducted in the Mercury program (utilizing the CSD-Materials module) indicates the potential use of various molecular synthons to enhance the drug's efficacy. Grinding processes (manual and mechanochemical) are conducted with MEH and a coformer, caffeine (CAF), to form stoichiometric mixtures. The vibrational characteristics associated with MEH and CAF show low energy levels. The effects on cell viability of the MEH-CAF combination are studied at different concentrations and reveal more significant cytotoxicity against the HeLa cell line (cervical tumor) compared to healthy MRC-5 cells (human fetal lung fibroblasts).

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