Grinding cocrystallization

A.V. Trask, W.D.S. Motherwell, W. Jones, Solvent-drop grinding green polymorph control of cocrystallization, Chem. Commun. (2004) 890-891. 

Characterization of the cocrystals obtained using [58] solution crystallization, high-throughput cocrystallization, dry grinding, and solvent-drop grinding... 

On the other hand, cocrystallization or grinding together of 12a and S-ethyl 4-[2-(2-pyrazinyl)ethenyl]thiocinnamate (12b) forms a 45 55 molar mixed crystal (a solid solution), which upon UV irradiation gave a crystalline random copolymer (Scheme 10) [14]. 

The cocrystallization method consists in the incorporation of the molecule of interest in a saturated sucrose solution, followed by the formation of sucrose microcrystals, containing the molecule in a crystallized or amorphous state. After a drying step and a grinding operation, the encapsulated molecule contained in the resulting granular solid presents improved solubility and stability. 

Upon mixing of the two colourless co-crystal constituents in the solid state, the formation of a yellow co-crystal phase is rapidly (within 1 min) observed at the interface of the two solids. Microscopic observation of the interface between two macroscopic single crystals of diphenylamine and benzophenone revealed melting of the surface which proceeds until most of the material is converted to a liquid at room temperature. Subsequent nucleation of the co-crystal phase results in the solidification of the entire melt to form the solid co-crystal. Consequently, the role of grinding in a eutectic-mediated cocrystallization is most likely two-fold first, it provides agitation to expose fresh reactant surfaces for eutectic formation and second, it enhances cocrystal formation by inducing co-crystal nucleation in the eutectic phase (Figure 8.13(c)). 

In the course of this work, an interesting observation arose variation of the total quantity of material in the grinding jar affected the outcome of the cocrystallization experiment. On the other hand, total grinding time did not appear to be a factor, as the observation held for total grinding times of 30, 60, and 90 min. 

Childs and Hardcastle [99] cocrystallized piroxicam with 23 different carboxylic acids by crystallization from solution and also by grinding, affording in total 50 unique piroxicam acid cocrystals. Where possible, the structure of cocrystals was determined from diffraction experiments (eight cocrystals), while the entire collection of cocrystals was additionally characterized by PXRD, infrared (IR) spectroscopy, and Raman spectroscopy. The structural study showed that the piroxicam is indeed present in both tautomeric forms in obtained cocrystals, as nonionized and zwitterionic form, and showed unique synthons for each tautomeric form (Scheme 13.16). These tautomeric forms were evident in Raman spectra, where the zwitterionic forms have a characteristic peak at 1410cm . The Raman spectroscopy further divided nonionized piroxicam cocrystals into two classes. This division was ascribed to different hydrogen bond interactions with the amide N-H group, which was also confirmed by structural investigations. 

---