Amide N-oxide heterosynthon and amide dimer homosynthon in cocrystals of carboxamide drugs and pyridine N-oxides

Abstract

The carboxamide-pyridine N-oxide heterosynthon is sustained by syn(amide)-N-H⋯O-(oxide) hydrogen bond and auxiliary (N-oxide)C-H⋯O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide-N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide-N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine-quinoxaline N,N′-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N- H⋯O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius2, COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30°C up to four weeks. Amide-N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H2O functional groups. © 2007 American Chemical Society.