Exploring the cocrystallization potential of urea and benzamide

Abstract

The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism.Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-016-2964-6) contains supplementary material, which is available to authorized users.

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

“…However, the expectation that a similar relationship will also be observed for H mix as a function of σ cannot be justified, as no such relationships have been found. Thus, while there is a simple relationship between the Hammett constants and the synthon stabilization energy [39], there is no similar relationship for H mix . This suggests that substituent effects make a nontrivial contribution to the total affinity of the coformers and it is not possible to infer the cocrystallization probability directly from the synthon energetics.…”

“…This is clearly demonstrated by the statistical analysis of existing cocrystals, which show that the formation of heterosynthon patterns is much preferred to the formation of homosynthon patterns [64, 65]. For example, a homosynthon formed from two carboxyl groups is far less common than a heterosynthon generated from amide and carboxyl groups, despite the fact that the energy of a pair of carboxyl groups is generally a few to several kcal/mol higher than the energy of the amide and carboxyl pair [39, 62, 63]. In this context, while the linear trends observed in Fig.…”

“…1 correlate well with chemical intuition, they are not a trivial representation of the synthon energetics. This is also supported by the lack of simple rules governing cocrystallization within such a coherent class of compounds as aromatic carboxylic acids—not every pair of aromatic acids forms an intermolecular complex in the solid state, even though the stabilization energies of all such pairs are actually very similar [39, 41]. Admittedly, there have been suggestions of a correspondence between Hammett constant values and the cocrystallization abilities of two aromatic acids [66, 67], but such a relationship is only qualitative and not suitable for general cocrystal prognostics.

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“…Alternatively, some methods that consider the electrostatic potential surface of the molecule have been used to identify the most likely contacts between components [24, 34, 35]. 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.…”

Selection of effective cocrystals former for dissolution rate improvement of active pharmaceutical ingredients based on lipoaffinity index

“…Improvement of dissolution profiles can be obtained by particle size reduction techniques (Choi and Park, 2017;Dizaj et al, 2015;Khadka et al, 2014;Sironi et al, 2017), crystal morphology/polymorphism modifications (Amodwala et al, 2017;Jain et al, 2017;Keraliya et al, 2010;Maghsoodi, 2015) or multicomponent A C C E P T E D M A N U S C R I P T crystals synthesis (Ross et al, 2016;Schultheiss and Newman, 2009;Yadav et al, 2009). The latter approach including bi-component cocrystallization deserves particular attention due to the variety of cocrystal preparation methods such as solvent evaporation techniques (Bag et al, 2011;Bag and Reddy, 2012;Cysewski et al, 2016;Przybyłek et al, 2016aPrzybyłek et al, , 2016b, antisolvent crystallization (Chun et al, 2014;Lee et al, 2015;Wang et al, 2013), mechanochemical co-grinding (Hasa et al, 2015;Karki et al, 2007;Li et al, 2016;Tröbs and Emmerling, 2014) or slurry methods (Apshingekar et al, 2017;Kojima et al, 2010;Takata et al, 2008). Furthermore, the variety of cocrystals formers applicable for pharmaceutical formulations offers fine tuning of physicochemical properties of new multicomponent solids ood and Rodr guez-Hornedo, 2009).…”