Co-crystals

Technical data. The Harshaw Chemical Co., Crystal and Electronics Dept., Solon, Ohio. 

Early biochemical studies supported the hypothesis that the HRl and the HR2 peptides would interact to form a helical structure (Chen et al. 1995 Lu et al. 1995). This hypothesis was strengthened when X-ray structures were resolved for co-crystals of HRl and HR2 peptides (Chan et al. 1997 Tan et al. 1997 Weissenhom et al. 1997). The results showed that in the six-helix bundle, three HRl domains were packed tightly together in the center of the bundle, with the HR2 domains bound in an antiparallel manner in grooves formed along the HRl core. 

Fig. 3.18 Nucleosome core particle (NCP)-polyamide co-crystal structures (PDB codes 1M18 and 1M19). (Top) Partial structure, viewed down the superhelical axis. Base pairs 58-145 (shown in white) and associated proteins (H3, blue H4, green H2A, yellow H2B, red) are shown for each complex. Superhelix locations (SHLs) are labeled as each major...

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

Figure 17.3 Anatomy of a redox enzyme representation of the X-ray crystallographic structure of Trametes versicolor laccase III (PDB file IKYA) [Bertrand et al., 2002]. The protein is represented in green lines and the Cu atoms are shown as gold spheres. Sugar moieties attached to the surface of the protein are shown in red. A molecule of 2,5-xyhdine that co-crystallized with the protein (shown in stick form in elemental colors) is thought to occupy the broad-specificity hydrophobic binding pocket where organic substrates ate oxidized by the enzyme. Electrons from substrate oxidation are passed to the mononuclear blue Cu center and then to the trinuclear Cu active site where O2 is reduced to H2O. (See color insert.)...

Zn -PDF, 37 pM versus E. coli Fe -PDF), it was successfully used to provide co-crystals bound in the active site of both Co - and Zn -E. coli PDF [58], These structures reveal that the H-phosphonate binds to the metal in a monodentate fashion, adopting a tetrahedral coordination state similar to that of the native resting state of the enzyme. This is in contrast to later co-crystal structures obtained with more potent hydroxamic acid or reverse hydroxamate inhibitors, which bind to the metal in a bidentate fashion vide infra). Presumably these bidentate inhibitors mimic the true transition state of the enzyme, in which the metal centre slips to a penta-coordinate geometry in order to activate the Wformyl carbonyl of the substrate [56, 67]. 

British Biotech has described co-crystal structures of both BB-3497 and actinonin bound in the active site of E. coli PDF [24]. The metal centre (Ni ) in both complexes adopts a pentacoordinate geometry, bound by the two oxygen atoms of the hydroxamate along with Cys-90, His-132 and His-136. This coordination pattern is consistent with the mechanism of de-formylation proposed by Becker et al. [56] and Jain et al. [67], in which a pentacoordinated metal centre stabilises the transition state during hydrolysis of the formamide bond. When compared to the co-crystal structure of a substrate hydrolysis product, Met-Ala-Ser, it is clear that the side chains of these two inhibitors bind into the active site pockets similarly to the substrate [56]. 

Even when co-crystallization is not feasible, if X-ray structures of the target are known, then there are opportunities to use computational techniques to try to understand the potential interactions of the compounds with their biological target... 

The remarkable strength of some XBs allows them to prevail over HBs in identifying the modules to be involved in self-assembly. For instance, in experiments of competitive co-crystal formation, a dipyridyl derivative prefers to co-crystallize with XB donors rather than HB donors and the same occurs for NjNjN jN -lclramclhylclhylcncdiaminc (TMEDA) [36]. In solution, solute-solute intermolecular HBs are considerably diminished if a strong XB donor co-solute is added. If haloperfluorocarbons (halo-PFCs) are used, the HB breaking potency increases moving from perfluorocarbons to chloro-, bromo-, and iodoperfluorocarbons [37-43], perfectly consistent with the order of the increasing XB donor ability of the halo-PFCs co-solutes, hi aque-... 

Fig. 6 XBs around ethers, thioethers and amines feature a tetrahedral arrangement with preferential axial directions for the XBs around hexacyclic amines (A, co-crystal between 1,4-dimethylpiperazine and 1,2-diiodotetrafluoroethane) and ethers (B, co-crystal between 1,4-dioxane and tetraiodoethene), and equatorial directions for hexacyclic thioethers (C, co-crystal between 1,4-dithiane and iodoform)...

When one, or both, the interactive modules are tridentate, bidimensional (2D) architectures can be formed. A frequently recurring pattern is the (6,3) network (honeycomb structure), which is sometimes formed when onium halides self-assemble with dihalocarbons. Halide anions work as tridentate XB acceptors and occupy the nodes while the dihalocarbons work as bidentate XB donors and form the sides that space the nodes. Such architectures are present in the co-crystals l,4-DITFB/Ph4P+Br , l,4-DITFB/Me4N+r [155], and a,oo-diiodoperfluoroalkanes/K.2.2.2.cKI [128,189]. The less planar the trigonal arrangement around the nodes, the more corrugated the honeycomb structure (Fig. 9). 

The self-assembly of tridentate modules with bi- or tridentate partners may afford architectures other than the (6.3) nets described above. For instance, in the co-crystal l,4-DITFB/Ph4P+r the iodide anions work as... 

T-shaped tridentate nodes, the diiodobenzenes as linear bidentate modules that space the nodes and ribbons compounded of consecutive rectangles are formed [155] (Fig. 11). A similar topology is present in the co-crystal CBr4/Ph4P+Br where bromide anions and carbon tetrabromide both work as tridentate notes that alternate in the ribbon [121]. 

Following Dehnicke s report in 1996 on the co-crystallization of diiodoacety-lene (DIA) with various halide anions to form two-dimensional networks through C-I X interactions [93], Kato et al. investigated these supramo-lecular anions in the electrocrystallization of classical TTFs such as BEDT-TTF. 

In addition to the challenges cited above, there are some special issues associated with steroid chemistry that should be noted. The steroidal impurities formed in the process are generally similar in structure to the desired product and, in some cases, co-crystallization with the product is a problem. It is, therefore, critical to limit the formation of steroidal impurities in the reactions. The structural similarity between product and impurities also creates challenges in developing assays for reaction monitoring and purity determination. Furthermore, the poor solubility of these compounds in the solvents typically used in a manufacturing process makes it very difficult to achieve practical volume productivity in process development. 

The catalytic preformance of Co crystals with two surface conditions were compared annealed crystals with large atomically flat terraces and Ar+ ion sputtered surfaces which produced a high population of surface defects. A sequence of PM-RAIRS spectra are shown in Figure 3.2 during exposure of a sputtered Co (0001) surface to mixtures of H2 and CO, with the temperature and pressure for each spectrum indicated in the figure. 

C62H85BrNi2Oie,2C1oH13N504-11 H20 7-BromoactinomycinDbis(2 -deoxyguanosine), undecahydrate (BRAXGU)306 P212121 Z = 4 Dx = 1.36 R = 0.094 for 4000 intensities. The co-crystals contain one actinomycin D (chromophore part, only, is shown in the... 

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