Homosynthons

Fig. 7 Strategies used in the formation of cocrystals of carbamazepine which may be applicable to APIs with carboxamide groups. Strategy I maintains the carboxamide homosynthon and uses the exterior hydrogen bond donor and acceptor sites. Strategy II forms a heterodimer by hydrogen bonds between the carboxamide and carboxylic groups. (Reproduced from Ref " l)...

Other elegant examples on the use of homosynthons have been reported by Wheeler and co-workers, using flexible chiral sulphonamide cinnamic acids, which form dimers via self-complementary hydrogen bonds and via formation of carbojgrlic acids homosynthons. These compounds are reminiscent of the /-shaped dicarbojgrlic acid reported by Feldman and Campbell, which form similar dimers via the same homosynthons (Scheme 7). In such assemblies, the double bonds are oriented in a parallel fashion at suitable distances for the photo-dimerisation upon UV irradiation. 

As outlined by Desiraju, crystal engineering strategies rely on the use of supramolecular synthons , or structural units within supermolecules that can be assembled using known synthetic operations , in order to achieve favourable erystal packings. Specifically, regarding organic-based moleeules, the supramolecular synthons can exist in two main types namely, homosynthons and heterosynthons (Scheme l). 

Homosynthons are composed of identical functional groups that are complementary to one another and often referred to as self-association motifs / Heterosynthons, on the other hand, are composed of different functional groups - usually from different molecules - that are also self-complementary/ ... 

Fig. 5 X-ray structure of co-crystals of p-PTE with (a) GA and (b) AA (red box highlights COOH- -N heterosynthon and blue box highlights COOH- HOOC homosynthon." " ...

Figure 1 Supramolecular association in tetrolic acid with the carboxylic acid carrying no additional functional groups, (a) Dimer formation via the eight-membered -HOCO 2 homosynthon and (b) catemer formation in the crystal structure of a second form of tetrolic acid. The 0-H- -O hydrogen bonds are shown as orange dashed lines. In each of the motifs, the carboxylic acids are syn-syn. It is noted that for the catema- motif, anti-anti and, more rarely, alternating syn-anti carboxylic acids are known.

Figure 2 Supramoiecuiar association in the neutrai forms of cionixin, 2-(2-methyi-3-chioroaniiino)-nicotinic acid, (a) Chemicai structure of cionixin and (b) dimer formation via the eight-membered HOCO 2 homosynthon. The O-H- O and N-H O hydrogen bonds are shown as orange dashed iines.

Figure 7 Chemical structure of (a) l-(3-methylsulfonylphenyl)-3-pyridin-2-ylurea and (b) dimaic aggregate sustained by the eigk-membered amide - - -HNC=0 2 homosynthon. Hydrogen bonds are shown as orange dashed lines.

The most successful approach to the design of cocrystals is based on the identification of reliable snpramolec-nlar heterosynthons that will form in preference to any possible homosynthon. The CSD is an essential tool for finding these synthons and assessing synthon com-petition. Nevertheless, molecules that could form identical supramolecular synthons often differ in their tendency toward cocrystal formation. The low success rate of synthon-based screening experiments (about 20%) indicates that factors other than synthon complementarity should be considered. Known cocrystals contain information about these additional influences, and statistical analysis of cocrystal structures in the CSD has been used to identify them. 

Figure 2.2 Some synthons referred to in this chapter. The term homosynthon is frequently used as the complement to heterosynthon,...

There are two types of supramolecular synthons (Formula 5.1) supramolecular homosynthons, which are formed by self-eomplementary funetional groups e.g., carboxylic add dimers) and supramoleeular heterosynthons, which are formed by different, but complementary functional groups e.g., carboxylic acids and pyridine rings). Supramolecular heterosynthons that... 

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