Crystal Engineering for Sustainable Antimalarial Therapies: Combating Drug Resistance through Sulfadoxine–Ascorbic Acid Cocrystal Design

Malaria remains a leading cause of morbidity and mortality in sub-Saharan Africa, with Plasmodium falciparum increasingly resistant to existing antimalarial drugs. This study explores the use of crystal engineering to design sustainable, synergistic formulations aimed at mitigating drug resistance. Sulfadoxine (SAD), an antifolate used in sulfadoxine–pyrimethamine therapy, was co-crystallized with ascorbic acid (ACA) to form a redox-active cocrystal system designed to improve stability, bioavailability, and reduce environmental impact during production. Computational modelling using Density Functional Theory (DFT) was combined with experimental mechanochemical screening via liquid-assisted grinding (LAG). The SAD–ACA heterodimer showed a lower binding energy (–81.6 kJ mol⁻¹) than corresponding homodimers, indicating predicted cocrystal stability. The resulting solid form was characterised using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Findings confirm the formation of a novel cocrystal phase, evidenced by a distinct single melting endotherm and new PXRD peaks compared to the parent compounds. This work aligns with Sustainable Development Goals (SDGs) 3, 9, and 12, highlighting advances in health, innovation, and responsible production. The study demonstrates that green cocrystallization strategies can support the development of more stable, effective, and environmentally sustainable antimalarial therapies.