Isonicotinamide co-crystals

A spectacular series of ID assemblies based on three different components has been recently described by Aakeroy21 Specifically, 1 1 1 assemblies involving 3,5-di-nitrobenzoic acid and isonicotinamide co-crystallized with either 3-methylbenzoic acid, 4-(dimethylamino)benzoic acid, or 4-hydroxy-3-methoxycinnamic acid have been described (Fig. 25).21 In each case, the components produced a linear three-component assembly with isonicotinamide at the center. The pyridyl group formed a... 

Three of the four polymorphic compounds examined in this study [107] readily form co-crystals e.g. 2-hexeneoic acid isonicotinamide, 2-amino-5-nitropyrimi-dine 2-amino-3-nitropyridine, and 3-dimethylaminobenzoic acid 4-chlorobenza-mide. The structural behavior of 1-3 supports the suggestion that polymorphs make good co-crystallizing agents (provided that solubility differences are not too large). However, no co-crystals with maleic hydrazide were obtained, despite the fact that it exists in three different polymorphs. 

Figure 2.5.1 Primary motif typical of the majority of 1 1 isonicotinamide carboxylic acid co-crystals [93].

Co-crystal 5, 3-methylbenzoic acid isonicotinamide 3,5-dinitrobenzoic acid (1 1 1), contains the desired three-component supermolecule with the expected connectivity. The stronger acid (pKa=2.8) [145] interacts with the pyridine nitrogen atom, and the weaker acid (pKa=4.3) competes successfully for the amide moiety and forms a heteromeric hydrogen-bonded motif, Fig. 2.5.2. 

Co-crystal 6, 4-(N,N-dimethyl)aminobenzoic acid isonicotinamide 3,5-dinitro-benzoic acid (1 1 1), is also a ternary co-crystal with the intended three-component supermolecule. The acid-pyridine nitrogen interaction persists, and the weaker acid (pKa=6.5) forms a heteromeric motif with the amide moiety, Fig. 2.5.3. 

Dinitrobenzoic acid isonicotinamide 4-hydroxy-3-methoxycinnamic acid 7, is also a 1 1 1 ternary co-crystal with the same primary supramolecular connectivity... 

Figure 5.4 Hierarchic hydrogen bonding between acid, pyridine and amide groups in ternary co-crystals strongest acid- -pyridine and next best acid- - -amide heterosyn-thons. (a) 4-Dimetbylaminobenzoic acid isonicotinamide 3,5-dinitrobenzoic acid and (b) 3,4-dimethoxycinnamic acid isonicotinamide 3,5-dinitrobenzoic acid...

Figure 5.5 Very different hydrogen bondsynthons in isomeric co-crystals containing COOH, pyridine, CONHz, and OH functional groups, (a) Hierarchic hydrogen bonding in m-hydroxybenzoic acid isonicotinamide and (b) nonhierarchic hydrogen bonding in p-bydrox-ybenzoic acid isonicotinamide...

Figure 5.6 Acid-pyridine and amide dimer synthons in 1 2 co-crystals of giutaric acid and adipic acid with isonicotinamide (a and b), and acid-pyridine and acid-amide synthons in 1 1 co-crystals (c and d)...

Figure 2.10 Hydrogen-bonded units within the ternary co-crystals (a) 3,5-dinitro-benzoic acid isonicotinamide 3-methylbenzoic acid (1 1 1), (b) 3,5-dinitrobenzoic acid isonicotinamide 4-(V,iV-dimethylamino)benzoic acid (1 1 1), and (c) 3,5-dinitrobenzoic acid isonicotinamide 4-hydroxy-3-methoxycinnamic acid (1 1 1), incorporating isonicotinamide and carboxylic acids with different hydrogen-bond donor strengths. ...

The aforesaid methodology was used (Habgood et al. 2010) to compute crystal energy landscapes and consequently predict the co-crystallization of carbamazepine (an anticonvulsant drug used in the treatment of epilepsy) with pyridine carboxamides (Figure 5. Id to f). Experimentally, while isonicotinamide (INA) co-crystallizes with carbamazepine (CBZ), picolinamide (PA)—despite its similarity to other pyridine carboxamides in the homologous series—does not appear to form a... 

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