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

## TL;DR

This paper investigates how combining melphalan hydrochloride with caffeine improves its cancer-fighting properties through structural analysis and cell studies.

## Contribution

The novel contribution is demonstrating that combining melphalan hydrochloride with caffeine enhances its antineoplastic efficacy through structural and cytotoxic studies.

## Key findings

- The crystal structure of melphalan hydrochloride was determined using simulated annealing and Rietveld refinement.
- Combining melphalan hydrochloride with caffeine increases cytotoxicity against HeLa cells compared to healthy cells.
- Molecular synthons identified via Mercury program suggest ways to improve drug efficacy.

## Abstract

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).