Cocrystals

Other hand, when an equimolar mixture of 2,5-DSP and l OEt is recrystallized from benzene, yellow crystals, comprising 2,5-DSP and l OEt in a molar ratio of 1 2, deposit. In the DSC curve of this crystal, a single endothermic peak is observed at 166°C, which is different from the melting point of either 2,5-DSP (223°C) or l OEt (156°C). Furthermore, the X-ray powder diffraction pattern of the crystal is quite different from those of the homocrystals 2,5-DSP and l OEt. Upon irradiation the cocrystal 2,5-DSP-l OEt affords a crystalline polymer (77i h = 1.0 dl g in trifluoroacetic acid). The nmr spectrum of the polymer coincides perfectly with that of a 1 2 mixture of poly-2,5-DSP and poly-1 OEt. In the dimer, only 2,5-DSP-dimer and l OEt-dimer are detected by hplc analysis, but the corresponding cross-dimer consisting of 2,5-DSP and l OEt is not detected at all (Hasegawa et al., 1993). These observations by nmr and hplc indicate that the photoproduct obtained from the cocrystal 2,5-DSP-l OEt is not a copolymer but a mixture of poly-2,5-DSP and poly-l OEt in the ratio 1 2. 

Trask AV, Jones W (2005) Crystal Engineering of Organic Cocrystals by the Solid-State Grinding Approach. 254 41-70 Tuntulani T, see Suksai C (2005) 255 163-198... 

Plummer MS, Holland DR, Shahripour A, Lunney EA, Fergus JH, Marks JS, McConnell P, Mueller WT, Sawyer TK. Design, synthesis, and cocrystal structure of a nonpeptide Src SH2 domain ligand. J Med Chem 1997 40 3719-3725. 

Diphenylurea Crystallization. 1,3-hfsphenylurea (13) is the parent compound of a large family of derivatives, most of which do not cocrystallize with guest molecules (Etter et al. 1990). Even when put into solution with strong hydrogen bond acceptors, e.g., dimethyl sulfoxide (DMSO), triphenylphosphineoxide (TPPO) and tetrahydrofuran (THF), most diphenyl ureas crystallize with other molecules of the same kind in a connectivity pattern viewed as is shown below (14), instead of forming cocrystals (e.g., 15). 

The crystal structures of DtxR and IdeR provide a detailed picture of this protein family (Figure 3.7, Plate 5). The N-terminal domain (residues 1-73) containing a helix-turn-helix motif binds a recognition nucleotide sequence of about 21 base pairs, as is nicely shown in a cocrystal of DNA and DtxR (Pohl et al., 1999). The central domain (74-140) has a function in dimerization the role of the third carboxy-terminal domain (141-230) is uncertain. Although metal-binding sites have been defined in these crystal structures, the mechanism by which metal binding causes the structural changes between apo- and holo-repressor is not clear. 

Figure 1 Schematic diagram of key PHD2/1 interactions based on x-ray cocrystal.

Relatively high molecular weight is a feature of the chemotype exemplified by 4-11 and this can require creative formulation techniques. Pharmacokinetic properties of a lead candidate (structure unknown) from the same series that provided 10 were inadequate to provide sufficient exposures at high doses to support preclinical safety studies. However, cocrystal formulations with saccharin or gentisic acid improved water solubility by 50-fold and increased oral exposures up to 10-fold relative to traditional formulations at 20mg/kg [64]. 

The cocrystal adduct TTF[Hg3(C6F4)3]2 crystallizes as orange needles by combining 1 1 carbon disulfide methylene chloride solutions of TTF and Hg3(C6F4)3 [56]. As illustrated in Fig. 5, the crystal structure is stabilized by multiple Hg—S secondary interactions which cause the TTF molecules to be sandwiched between two Hg3(C6F4)3 molecules. Spectroscopic and structural results indicate that charge transfer does not occur in this adduct and minimal conductivity is expected. 

One example of a cocrystal containing BEDT-TTF and ferrocene has been reported [104]. The [(BEDT-TTF Cgob lferrocene) adduct was crystallized from a carbon disulfide solution. The unit cell has been determined by single crystal X-ray diffraction but the crystal structure was not reported. An infrared spectroscopic analysis indicates that the charge transfer between the BEDT-TTF and C6o molecules is quite small. It has been suggested that such complexes may offer a means to introduce iron into the fullerene lattice. 

Bochtler, M., Song, H. K, Hartmann, C., Ramachandran, R., and Huber, R. The quaternary arrangement of HslU and HslV in a cocrystal a response to Wang, Yale. J Struct Biol 2001, 335, 281-293. 

Wang, J. A corrected quaternary arrangement of the peptidase HslV and atpase HslU in a cocrystal structure. J Struct Biol 2001, 334, 15-24. 

A. Jayasankar, D.J. Good and N. Rodriguez-Homedo, Mechanisms by which moisture generates cocrystals. Mol. Pharmaceutics, 4, 360-372 (2007). 

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