IMPACTIVE researchers have successfully synthesised a new cocrystal lenalidomide and quercetin. The former is an anticancer drug and the latter a potent antioxidative – together the synergic solid crystal makes the active molecule stay stable for longer.
In pharmaceutical science, developing co-crystals (solid crystalline forms made by two or more compounds connected by non-covalent bonds) is an excellent way to modulate the properties of the active pharmaceutical ingredients (APIs) without changing their chemical structure. It’s like adding spices to an already delicious dish, it only improves the flavour. Therefore, by carefully choosing good companions to our APIs, we may increase interesting properties, including stability.
Quercetin is a flavonoid, a potent antioxidative compound found in fruits and vegetables. It has attracted significant interest because of its potential therapeutic activities, including anticancer, anti-inflammatory, antiviral and cardioprotective effects. Our researchers in IMPACTIVE decided to investigate whether combining quercetin with the API lenalidomide could lead to a new crystal form with properties relevant to the drug’s anticancer activity.
“The idea was to use one of the molecules from our work package to find a different solid-state, multicomponent crystal form that could affect its final properties and, ultimately, its behaviour within the body,” explains Vânia André, researcher at Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID), Portugal.
As expected, mechanochemistry played a central role in this work. The new cocrystal was successfully synthesised using liquid-assisted grinding in a ball mill and liquid-assisted resonant acoustic mixing (RAM). For comparison, it was also prepared using conventional solution-based methods.
“In the end, we obtained the same final compound using all synthetic routes. However, mechanochemistry offers a much greener approach,” says André.
Before carrying out the synthesis, the team used crystal-engineering tools and data mining from the Cambridge Structural Database to identify molecular groups capable of forming the desired hydrogen-bond interactions. This rational design approach helped predict the likelihood of cocrystal formation.
“To form these multicomponent crystal forms, or cocrystals, we need to identify functional groups from the different molecules we want to combine and determine whether they are likely to interact through non-covalent interactions such as hydrogen bonds. This allows us to identify suitable groups and design new compounds based on these interactions,” says André.
As cocrystals are held together by non-covalent interactions rather than covalent chemical bonds, the chemical structure of lenalidomide remains unchanged. This is an important advantage from a pharmaceutical perspective. In simple terms, a cocrystal is like two compounds “glued” together temporarily. While they are combined in the solid state, each molecule retains its original identity and properties. Once the cocrystal dissolves in the body, the molecules separate and behave normally.
This means that it is possible to modify certain physical properties of the drug, such as its stability or solubility, without creating a new active compound. As a result, the development pathway may be more straightforward than that required for an entirely new drug molecule.
André concludes: “For IMPACTIVE, we have disclosed a new crystal form of lenalidomide synthesised through mechanochemistry that presents advantages over conventional solution-based techniques. Based on what we know so far, it appears to be pharmaceutically acceptable, and we have used a coformer that is suitable for pharmaceutical applications.”