Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

Abstract

New virtual cocrystal screening was proposed taking advantage of the similarities between cocrystallization landscapes of different compounds. Assuming that cocrystallization propensities can be modeled by miscibility affinities of liquid components under supercooled conditions, the quantitative rules of likeness were formulated and validated for 45 aromatic and heteroaromatic amides interacting with a variety of coformers. The most important finding comes from the observed linear trends between the values of mixing enthalpies of amides with respect to a reference molecule. Particularly isonicotinamide was found as a very convenient comparative system since it constitutes 97 binary cocrystals. Many experimentally observed cocrystals were used for supporting the analogy hypothesis, which states that a properly selected reference molecule, for which cocrystals were experimentally documented, can provide practical information about cocrystallization propensities of another compound provided that two criterions are met, namely sufficiently high similarities and high enough affinities. Hence, it is not necessary to perform experimental cocrystallization of every pair of coformers since miscibility in the solid state of one compound can be transferred to another one at least in the case of aromatic or heteroaromatic amides.

In silico screening of dicarboxylic acids for cocrystallization with phenylpiperazine derivatives based on both cocrystallization propensity and solubility advantage

“…1 is that knowledge of the cocrystallization abilities of succinic acid allows us to infer the cocrystallization characteristics of other DCAs—a conclusion supported by the relatively high correlation coefficients observed ( R 2  > 0.9). This behavior has already been reported [40] for aromatic amides, when it was termed “the similarity of cocrystallization landscapes.” It appears that such behavior is exhibited many families of compounds. It is worth noting that this analogy is not based on a simple representation of the formal structure.…”

“…New solid forms of drugs are only useful if they offer an advantage over the single-component formulation. In order to successfully perform this final step, the newly proposed methodology [25, 40] of screening via analogy was validated and applied to the target group of drugs. The working paradigm for cocrystal screening is that miscibility in the solid state can be adequately predicted from the thermodynamics of the miscibility of liquids in the metastable supercooled state under ambient conditions.…”

“…The number of misclassified cases heavily depends on the selected threshold value of H mix . Thus, an additional condition was suggested [40], which takes advantage of similarities in the cocrystallization landscapes of different substances that belong to the same class of compounds. Thus, the similarities of the cocrystallization landscapes of the nine dicarboxylic acids are documented here, as are the similarities of the cocrystallization landscapes of the phenylpiperazine derivatives.…”

“…In particular, comparing values of the excess enthalpy of mixing ( H mix ) of coformers under supercooled conditions [36–38] has been found to be a very efficient way to screen for APIs that have a propensity to cocrystallize [25, 39–41]. Indeed, it has become possible to use this particular methodology [40] to rationalize the selection of pairs of coformers based on similarities in their affinities and cocrystallization landscapes. This approach takes into account linear relationships between the mixing enthalpies of components.…”

“…This approach takes into account linear relationships between the mixing enthalpies of components. As has been shown [40] for aromatic and heteroaromatic amides, the cocrystallization affinities of a set of chemical systems toward a group of coformers can be predicted after appropriate selection of a reference compound. This idea is in accord with chemical intuition, and can be very helpful when attempting to identify pairs with high probabilities of cocrystallization.…”