Solid multicomponent systems, such as salts and cocrystals, are critical for us at IMPACTIVE. These systems help to create medicines with improved properties, including solubility, stability, and bioavailability, bringing clear public health benefits. Within IMPACTIVE, several partners are involved in their development, and here we want to introduce one of them: Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID), in Portugal.
The best way to know what a multicomponent system is, is to see how it’s developed. At IST-ID, their work starts by looking at the molecules that the Work Package 2 (WP2) has selected. They then pair these molecules with carefully selected coformers upon noncovalent interactions. These interactions are weak, reversible forces that help to stabilise molecules together without forming actual chemical bonds. Some examples here are hydrogen bonds, van der Waals forces, and electrostatic attractions.
To identify the most promising combinations, our IST-ID use extensive data mining. Once they have selected the best candidates the pairs are then mechanochemically combined to yield new compounds, defining the optimal conditions—spoiler: not all candidates are always successful. To do so, our preferred instruments are mostly horizontal ball mills, but planetary or vertical mills are used when needed.
The next step is optimisation. We want the reactions to proceed as fast as possible and, if we cannot get rid of solvents altogether, to use the smallest amount of solvent. There’s a ton of parameters to adjust: milling time, ball size and material, milling frequency, jar composition. If everything is thoroughly optimised, the final bulk material is a pure multicomponent system.
Last, but definitely not least, comes structural characterisation, one of IST-ID’s greatest strengths. The team is responsible not only for characterising their own systems, but also for analysing the compounds synthesised by other WP2 partners.
This step is crucial as it reveals what the new system actually is. The best technique to do this is X-ray diffraction, which is based on analysing the characteristic diffraction pattern produced when X-rays interact with a crystalline sample. In the case of good quality single crystals, it is possible to elucidate the full structure, allowing us to “see” the atoms in the molecules and analyse how they are arranged in the space.
Their characterisation efforts have also helped guide the refinement of the final compounds and workflows within WP2. This is not the only WP this team collaborates with, though. IST-ID also assisted WP5, scale-up, with process optimisation. Although not formally stated, this team also maintain strong collaboration with WPs 4 and 6, as they contribute to kinetic studies, risk assessment, and life-cycle analysis. We do love to collaborate!
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