An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The 2:1 co-crystal of 4-cyanopyridine and 4,4‘-biphenol exists in at least two polymorphic forms. Single-crystal X-ray crystallographic analysis of forms I and II revealed conformational differences in the 4,4‘-biphenol molecules, but O−H···N(pyridine) supramolecular heterosynthons sustain both forms, suggesting that O−H···N(pyridine) interactions are favored over competing O−H···N(cyano) interactions. These conformational polymorphs crystallize concomitantly, and conformational isomorphism is also observed in this co-crystal. Experimental conditions that induce transformations between form I and form II are described. The structural differences between form I and II are discussed in the broader context of conformational polymorphism.

Crystal engineering has evolved in such a manner that it is now synonymous with the paradigm of supramolecular synthesis, that is, it invokes self-assembly of existing molecules to generate a wide range of new solid forms without the need to break or form covalent bonds. This review addresses how crystal engineering has been applied to active pharmaceutical ingredients, API's, with emphasis upon how pharmaceutical co-crystals, a long known but little explored alternative to the four traditionally known forms of API, can be generated in a rational fashion. Case studies on Carbamazepine (CBZ) and Piracetam are presented which illustrate the relative ease with which pharmaceutical co-crystals can be prepared and their diversity in terms of composition and physical properties.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A Cambridge Structural Database study of supramolecular synthons involving primary amides reveals that 84% form amide-amide dimers, whereas 14% form catemers in the absence of other competing hydrogen bond donors and/or acceptors. However in the presence of chemically different but complementary functional groups, e.g., carboxylic acids or aromatic nitrogen moieties, primary amides tend to form supramolecular heterosynthons. Supramolecular heterosynthons represent an opportunity for design of multi-component crystals (co-crystals) in which one molecule contains a primary amide and a second molecule (the co-crystal former) contains the functional group that is complementary to the primary amide. The results of the CSD analysis facilitated the selection of components for seven new primary amide co-crystals: A. Isonicotinamide/2-hydroxybenzoic acid (1: 1); B. Nicotinamide/3-hydroxybenzoic acid (1: 1); C. Pyrazinamide/2,5dihydroxybenzoic acid (1: 1); D. Carbamazepine (CBZ)/ 4,4'-bipyridine (2: 1); E. CBZ/4-arrrinobenzoic acid (2: 1); E CBZ/4-aminobenzoic acid/H2O (2: 1: 1); G. CBZ/2,6-pyridinedicarboxylic acid (1: 1). The molecular recognition events involving the amide moieties are discussed in the context of our experimental results and their implications for crystal engineering of pharmaceutical co-crystals.

An analysis of the Cambridge Structural Database reveals that 77% of compounds that contain both 2-aminopyridine and carboxylic acid moieties generate 2-aminopyridine-carboxylic acid supramolecular heterosynthons rather than carboxylic acid or 2-aminopyridine supramolecular homosynthons. In the absence of other competing functionalities, the occurrence of heterosynthons increases to 97%. This observation is supported by the determination of single-crystal structures of 10 new compounds that contain both a 2-aminopyridine and a carboxylic acid moiety: 2-aminopyridinium 4-aminobenzoate, 1; 2-aminopyridinium isophthalate, 2; bis(2-aminopyridinium) terephthalate, 3; 2-amino-5-methylpyridinium benzoate, 4; bis(2-amino-5-methylpyridinium) 5-tertbutylisophthalate, 5; 2-amino5-methylpyridinium terephthalate, 6; bis(2-amino-5-methylpyridinium) 2,6-naphthalenedicarboxylate, 7; bis(2-amino5-methylpyridinium) adipate adipic acid, 8; bis(2-amino-5-methylpyridinium) 2,5-thiophenedicarboxylate 2,5-thiophenedicarboxylic acid, 9; and indomethacin 2-amino-5-methylpyridinium, 10. All 10 compounds are ionic, with proton transfer occurring to the aromatic nitrogen of the 2-aminopyridine moiety. Analysis of the supramolecular synthons and their effect upon crystal packing is presented in the context of crystal engineering and host-guest chemistry.