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.
Human malaria, one of the most striking, reemerging infectious diseases, is caused by several types
of Plasmodium parasites. As the parasite digests hemoglobin in human red blood cells, the heme byproduct crystallizes
into micron-sized malaria-pigment (hemozoin). Making use of a recently reported powder-crystal structure
determination of synthetic hemozoin (β-hematin), we describe here its theoretical growth form and show it to be
similar in habit and form to that of natural hemozoin. With this information, we propose a noncovalent binding site
for the quinoline drug family at the end face of the fastest-growing direction of β-hematin. This adsorption mechanism
is examined in terms of crystal growth inhibition vis-à-vis published data. The surface binding site elucidates the
difference in activity of various quinolines, revealing the importance of the different quinoline functionalities. The
interplay between molecular chirality of quinolines and the chirality of centrosymmetric β-hematin crystal faces is
analyzed in terms of crystal growth inhibition. We additionally propose a molecular isomerism of the crystalline
building blocks, with implications on quinoline surface binding, as well as on nucleation and size of β-hematin crystals.
The elusive form II of aspirin has been obtained during co-crystallization experiments with levetiracetam or acetamide, and it has been characterized by IR, DSC, HPLC, and single-crystal X-ray diffraction.
We describe the use of ternary, isothermal phase diagrams of co-crystal-forming systems as a basis for understanding current crystallization methodologies and for experimental design in the preparation of co-crystals.
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