Cocrystallization via planetary milling: enhancing throughput of solid-state screening methods.

The application of a novel modified planetary mill, with the capacity to process 48 samples in parallel, to the rapid screening of pharmaceutical cocrystals via grinding is demonstrated for carbamazepine/saccharin, caffeine/oxalic acid, and caffeine/maleic acid cocrystals. Milling is performed directly in standard glass vials therefore no vessel decontamination is needed or sample loss occurs. Furthermore, successive sample processing can be employed without the need for additional material, making the system suitable for screening compounds of limited availability. Use of the system in an automated screening workflow of dispensing, milling, and analysis with high-throughput is also discussed.

Hierarchy of supramolecular synthons: persistent hydroxyl...pyridine hydrogen bonds in cocrystals that contain a cyano acceptor.

An analysis of the Cambridge Structural Database reveals >99% occurrence of the hydroxyl...pyridine supramolecular heterosynthon in crystal structures that contain hydroxyl and pyridine moieties in the absence of other hydrogen-bonding moieties. The occurrence of the hydroxyl...cyano supramolecular heterosynthon in crystal structures that contain hydroxyl and cyano moieties is ca. 77%. Such high frequencies indicate that these heterosynthons are strongly favored over the competing hydroxyl...hydroxyl supramolecular homosynthon. However, the CSD does not contain enough information to evaluate which supramolecular heterosynthon prevails when only OH, pyridine, and CN moieties are present in a crystal structure. We have addressed the competition between the hydroxyl...pyridine and the hydroxyl...cyano supramolecular heterosynthons by characterizing a series of 17 cocrystals that are composed of cocrystal formers which contain a permutation of OH, pyridine, and CN functional groups. Structural analysis reveals that all cocrystals are sustained by the hydroxyl...pyridine heterosynthon.

Pharmaceutical co-crystals.

Crystal engineering has evolved in such a manner that it is now synonymous with the paradigm of supramolecular synthesis, that is, it invokes self-assembly of existing molecules to generate a wide range of new solid forms without the need to break or form covalent bonds. This review addresses how crystal engineering has been applied to active pharmaceutical ingredients, API's, with emphasis upon how pharmaceutical co-crystals, a long known but little explored alternative to the four traditionally known forms of API, can be generated in a rational fashion. Case studies on Carbamazepine (CBZ) and Piracetam are presented which illustrate the relative ease with which pharmaceutical co-crystals can be prepared and their diversity in terms of composition and physical properties.