CRYSTAL ENGINEERING OF MULTICOMPONENT SOLID FORMS OF ANTICANCER DRUGS: CO-CRYSTALS, PHARMACEUTICAL SALTS, SOLVATES, AND THEIR PHYSICOCHEMICAL OPTIMIZATION

Abstract

Anticancer active pharmaceutical ingredients (APIs) comprise a diverse and expanding catalogue of small-molecule therapeutics that, despite remarkable pharmacological sophistication, share a common physicochemical liability: poor aqueous solubility classified predominantly within BCS Class II or Class IV. Crystal engineering — the rational design of crystalline materials through deliberate exploitation of non-covalent intermolecular interactions — provides a scientifically rigorous, intellectually coherent, and regulatory-tractable strategy for improving solid-state performance without altering the covalent structure of the drug molecule. This review delivers a systematic and critically evaluated examination of multicomponent solid forms (MCSFs) of fourteen anticancer drugs — imatinib, 5-fluorouracil, erlotinib, gefitinib, sorafenib, lapatinib, cabozantinib, venetoclax, palbociclib, dasatinib, tamoxifen, and nilotinib — prepared by crystal engineering approaches spanning solution crystallization, mechanochemistry, hot-stage methods, spray drying, and hot-melt extrusion. Structural data from the Cambridge Structural Database (CSD) are analyzed in depth, with single-crystal X-ray diffraction (SCXRD) crystallographic parameters (unit cell, space group, density, R-factors) compiled for eight benchmark co-crystal systems (Table 2), alongside hydrogen-bond geometry and Etter graph-set notation (Table 3). Five comprehensive tables provide CSD refcodes and CCDC deposit numbers, solubility, intrinsic dissolution rates (IDR), coformer physicochemical criteria, and regulatory or stability data. Six annotated figure panels describe crystal packing motifs, ORTEP diagrams, Hirshfeld surface analyses, supramolecular synthon hierarchies, physicochemical performance comparisons, and continuous manufacturing schematics. The ΔpKa rule for salt/co-crystal assignment, the thermodynamic basis of dissolution enhancement, hydrogen-bond propensity analysis, crystal structure prediction (CSP), and machine-learning-based coformer selection are addressed. Regulatory frameworks from the FDA (2018) and EMA (2018) are evaluated against clinical development evidence for gefitinib fumarate (NMPA approval, 2019) and palbociclib fumarate (Phase II, US). This review serves as a comprehensive reference for pharmaceutical scientists, crystallographers, formulation chemists, and regulatory scientists engaged in the solid-state optimisation of oncology medicines.