An Elusive Drug–Drug Cocrystal Prepared Using a Heteroseeding Strategy

Both sorafenib (SOR) and regorafenib (REG), which are structurally similar, can form drug–drug cocrystals with 5-fluorouracil (FU). However, while SOR-FU could be prepared easily by the slurry approach, the elusive REG-FU could not be prepared without the seeds of SOR-FU. The influence of the fluoro substitution of SOR on the cocrystal formation is understood by considering the phase solubility diagrams (PSD) in methanol and acetonitrile and changes in free energy and lattice energy upon cocrystallization using experimental and computational approaches. On the basis of the value of the free energy change upon cocrystal formation, the cocrystallization of REG-FU is less thermodynamically favored than that of SOR-FU. Additionally, the REG-FU formation also faces a higher kinetic barrier due to conformational differences, which lead to the failure of spontaneous cocrystallization from REG and FU. Thus, a subtle molecular structure modification of one coformer significantly influenced the ease of cocrystallization. The heteroseeding strategy was used to overcome both thermodynamic and kinetic barriers for REG-FU synthesis. This strategy may be useful to prepare new pharmaceutical cocrystals of structurally similar compounds in the drug discovery pipeline.