Multicomponent crystals can help optimize the solid-state properties and performance of active pharmaceutical ingredients (APIs), including their solubility, stability, and bioavailability. According to a recent paper published in Crystal Growth & Design, strides have been made in developing crystal engineering principles for simple, binary co-crystals. However, a similar toolkit for engineering higher-order molecular ionic co-crystals (ICCs) remains lacking. In this paper, the researchers present a set of guiding principles to aid the crystallization of molecular ICCs sustained by charge-assisted hydrogen bonding interactions. Here, we talk to corresponding author, Dr Sharmarke Mohamed (Assistant Professor of Chemistry, Khalifa University) about his team’s work and what it might mean for drug discovery.
Was there anything about the results you found especially surprising?
I was surprised to learn that molecular ICCs (i.e. those derived from molecular organic compounds) exist within a narrow range of the property landscape. For example, our work has shown that the conformation of the molecules used to target ICCs is critical, with molecules displaying comparable conformational degrees of freedom, more likely to form ICCs. The CSD system has been really useful in not only helping us retrieve a database of published ICC structures, but also analyzing a range of properties for ICCs, including the conformations adopted by the molecular fragments and the synthons of the resulting crystal forms.
The final surprising thing from our study was that it really is difficult to crystallize higher-order co-crystals comprising more than three chemical fragments (i.e. ternary solids). This was illustrated by the fact that approximately 90% of all the ICC solid forms surveyed were ternary solid forms. This suggests that the crystal engineering of higher-order co-crystals beyond ternary solids may be the exception rather than the norm due to a number of poorly understood factors that limit the self-assembly of more than three chemical fragments in the crystal.
What kinds of risks in solid forms are associated with ICCs—especially regarding pharmaceutically relevant molecules?
There are currently a number of pharmaceutical drugs on the market that can be categorized as ionic co-crystals (ICCs). A large fraction of these solid forms comprise inorganic metal ions, which are highly polarizing. As a consequence, it is not uncommon to see unexpected solvent inclusion behavior in ICC solid dosage forms either during manufacturing or post-marketing. This is a major risk profile for ICCs and computational methods can play a role in minimizing this risk by carefully mapping the structures and properties of putative ICC polymorphs using crystal structure prediction methods.
In the paper, you use full interaction maps to illustrate the importance of avoiding synthon competition. Can you elaborate on that?
Synthon competition appears to be an important parameter to consider in targeting higher-order ICCs. Our work suggests that as you attempt to incorporate more chemical fragments into the crystal, the new chemical entities should not compete for hydrogen bonds with the existing chemical fragments. Instead, there should be sufficient pendant hydrogen bond donors and acceptors on the existing fragments to support the formation of new intermolecular interactions. The full interaction maps in Mercury were very useful in understanding this.
Read the full paper: “Expanding the Supramolecular Toolkit: Computed Molecular and Crystal Properties for Supporting the Crystal Engineering of Higher-Order Molecular Ionic Cocrystals,” (Cryst. Growth Des. 2022, 22, 1, 485–496.)
Learn how researchers at Tianjin University used the CSD and the CSD-Materials software suite to identify coformers to prevent hydrate conversion.
Read about CCDC’s collaboration with Pfizer demonstrating how to use CSD-Materials to reduce polymorph risk and select the most stable form across three different APIs.