An Elusive Drug-Drug Cocrystal Prepared Using a Heteroseeding Strategy

Chengyu Liu, Chenguang Wang, Shan Wan, Lei Liu, Changquan Calvin Sun, Feng Qian

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5659-5668
Number of pages10
JournalCrystal Growth and Design
Volume21
Issue number10
DOIs
StatePublished - Sep 7 2021

Bibliographical note

Funding Information:
We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported in this paper ( http://www.msi.umn.edu ). C.W. thanks Imanuel Bier at the Materials Science and Engineering department, Carnegie Mellon University, for his help in FHI-aims calculations. F.Q. thanks Beijing Advanced Innovation Center for Structural Biology for providing funding support.

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