title: Crystal structures of the pyrazinamide-p-aminobenzoic acid (1/1) cocrystal and the transamidation reaction product 4-(pyrazine-2-carboxamido)benzoic acid in the molten state.
abstract: The synthesis of pharmaceutical cocrystals is a strategy to enhance the performance of active pharmaceutical ingredients (APIs) without affecting their therapeutic efficiency. The 1:1 pharmaceutical cocrystal of the antituberculosis drug pyrazinamide (PZA) and the cocrystal former p-aminobenzoic acid (p-ABA), C7H7NO2·C5H5N3O, (1), was synthesized successfully and characterized by relevant solid-state characterization methods. The cocrystal crystallizes in the monoclinic space group P2₁/n containing one molecule of each component. Both molecules associate via intermolecular O-H···O and N-H···O hydrogen bonds [O···O = 2.6102 (15) Å and O-H···O = 168.3 (19)°; N···O = 2.9259 (18) Å and N-H···O = 167.7 (16)°] to generate a dimeric acid-amide synthon. Neighbouring dimers are linked centrosymmetrically through N-H···O interactions [N···O = 3.1201 (18) Å and N-H···O = 136.9 (14)°] to form a tetrameric assembly supplemented by C-H···N interactions [C···N = 3.5277 (19) Å and C-H···N = 147°]. Linking of these tetrameric assemblies through N-H···O [N···O = 3.3026 (19) Å and N-H···O = 143.1 (17)°], N-H···N [N···N = 3.221 (2) Å and N-H···N = 177.9 (17)°] and C-H···O [C···O = 3.5354 (18) Å and C-H···O = 152°] interactions creates the two-dimensional packing. Recrystallization of the cocrystals from the molten state revealed the formation of 4-(pyrazine-2-carboxamido)benzoic acid, C12H9N3O3, (2), through a transamidation reaction between PZA and p-ABA. Carboxamide (2) crystallizes in the triclinic space group P1̅ with one molecule in the asymmetric unit. Molecules of (2) form a centrosymmetric dimeric homosynthon through an acid-acid O-H···O hydrogen bond [O···O = 2.666 (3) Å and O-H···O = 178 (4)°]. Neighbouring assemblies are connected centrosymmetrically via a C-H···N interaction [C···N = 3.365 (3) Å and C-H···N = 142°] engaging the pyrazine groups to generate a linear chain. Adjacent chains are connected loosely via C-H···O interactions [C···O = 3.212 (3) Å and C-H···O = 149°] to generate a two-dimensional sheet structure. Closely associated two-dimensional sheets in both compounds are stacked via aromatic π-stacking interactions engaging the pyrazine and benzene rings to create a three-dimensional multi-stack structure.
authors.affiliation: Center for Materials Characterization, CSIR-National Chemical Laboratory, Pune 411 008, India.
authors.forename: Shridhar H
authors.initials: SH
authors.lastname: Thorat
authors.affiliation: Center for Materials Characterization, CSIR-National Chemical Laboratory, Pune 411 008, India.
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Sahu
authors.affiliation: Center for Materials Characterization, CSIR-National Chemical Laboratory, Pune 411 008, India.
authors.forename: Rajesh G
authors.initials: RG
authors.lastname: Gonnade
mesh_terms: D062365:Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D019817:Benzoic Acid / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011718:Pyrazinamide / Q000737:chemistry* / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000605390:4-(pyrazine-2-carboxamido)benzoic acid; D062365:Aminobenzoates; D000995:Antitubercular Agents; D001565:Benzoates; D011719:Pyrazines; C000605391:pyrazinamide-p-aminobenzoic acid; D011718:Pyrazinamide; D019817:Benzoic Acid
keywords: acid–amide hetero-synthon; active pharmaceutical ingredient (API); cocrystal; crystal structure; hydrogen bonding; molten-state reaction; powder diffraction; transamidation reaction