A Cambridge Structural Database (CSD) analysis was conducted in order to evaluate the hierarchy of supramolecular heterosynthons that involve two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids and alcohols, in competitive environments. The study revealed that 34% of the 5690 molecular carboxylic acid entries and 26% of the 25 035 molecular alcohol entries form supramolecular homosynthons, whereas the remaining entries form supramolecular heterosynthons with other functional groups, in particular Narom, CONH2, C−O−C, CO, and chloride anions. Further refinement of this raw data revealed the following: 98% occurrence of the COOH···Narom supramolecular heterosynthon in the 126 crystal structures that contain acid and pyridine moieties in the absence of other hydrogen bond donors or acceptors; and 78% occurrence of the OH···Narom supramolecular heterosynthon in 228 crystal structures that contain hydroxyl and pyridine moieties (excluding intramolecular hydrogen bonding). Such high frequencies indicate that these supramolecular heterosynthons are strongly favored over their respective COOH···COOH and OH···OH supramolecular homosynthons. However, the CSD does not contain enough information to evaluate the predictability of even common supramolecular heterosynthons in the presence of competing hydrogen bonding moieties; for example, there are only 15 entries when -COOH, -OH, and Narom moieties are present exclusively (no other hydrogen bond donors and acceptors groups) in a molecule. We have addressed the competition between the COOH···Narom and the OH···Narom supramolecular heterosynthons by analyzing these 15 entries in CSD and characterizing 15 new compounds (cocrystals 1−13; salts 14 and 15) that are composed of cocrystal formers which contain a permutation of -COOH, -OH and Narom functional groups. Analysis of this group of compounds reveals that supramolecular heterosynthons are favored over the respective supramolecular homosynthons. We also address the methodologies that can be used to prepare 1−15 in the context of solvent evaporation, solvent-drop grinding, and slurrying.

The reliability of solvent drop grinding (SDG), also referred to as liquid assisted grinding, wet cogrinding, or mechanochemistry, to facilitate cocrystal formation is addressed with a series of model cocrystals and pharmaceutical cocrystals. The synthesis and single crystal structures of 17 new cocrystals that are sustained by COOH · · · N arom and OH · · · N arom supramolecular heterosynthons are presented. These cocrystals were prepared by both slow evaporation from solution and SDG. We also investigated whether or not SDG could be used to prepare previously reported carbamazepine (CBZ) pharmaceutical cocrystals. The following eight cocrystal formers were investigated in this context: 4,4′-bipyridine, 4-aminobenzoic acid/H 2 O, 2,6-pyridinedicarboxylic acid, benzoquinone, terephthalaldehyde, saccharin, nicotinamide, and aspirin. Our results reveal that all of the cocrystals that were grown from solution and characterized by single crystal X-ray crystallography can also be prepared by SDG. SDG therefore appears to be a cost-effective, green, and reliable method for discovery of new cocrystals as well as for preparation of existing cocrystals.

The carboxylic acid-primary amide supramolecular heterosynthon is exploited for the generation of pharmaceutical co-crystals that contain two active pharmaceutical ingredients that are polymorphic in their pure forms.

A Cambridge Structural Database study of supramolecular synthons involving primary amides reveals that 84% form amide-amide dimers, whereas 14% form catemers in the absence of other competing hydrogen bond donors and/or acceptors. However in the presence of chemically different but complementary functional groups,

The 2:3 co-crystal of trimesic acid and 1,2-bis(4-pyridyl)ethane (2) exhibits concomitant polymorphism. Form II of 2 is the expected hexagonal (6,3) network, whereas form I is a (10,3)-a network that exhibits an unprecedented 18-fold level of interpenetration.