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Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.

The crystal engineering design strategy facilitates supramolecular synthesis of 13 new crystalline phases of carbamazepine (CBZ), an analgesic and anticonvulsant with known problems related to solubility and polymorphism. CBZ forms supramolecular complexes with the following molecules, all of which are complementary to CBZ in terms of hydrogen bonding and can therefore act as cocrystal formers:  acetone (1a); DMSO (1b); benzoquinone (1c); terephthalaldehyde (1d); saccharin (1e); nicotinamide (1f); acetic acid (1g); formic acid (1h); butyric acid (1i); trimesic acid (1j); 5-nitroisophthalic acid (1k); adamantane-1,3,5,7-tetracarboxylic acid (1l); and formamide (1m). Two distinct strategies based upon selection of complementary hydrogen-bond functionalities and previously known supramolecular synthons were utilized:  strategy I exploits the exofunctional nature of the carboxamide dimer as either a hydrogen-bond donor or a hydrogen-bond acceptor and thereby retains the carboxamide dimer that is present in all previously isolated forms of CBZ; strategy II perturbs the carboxamide homosynthon by forming a heterosynthon between the carboxamide moiety of CBZ and the carboxylic acid moieties. The latter approach profoundly modifies crystal packing and should therefore affect the physical and pharmaceutical properties of CBZ. A full analysis of crystal packing and a discussion of what these results might mean in the broader context of crystal engineering and pharmaceutical solids is presented.