Synthesis, characterization, and molecular modeling of a pharmaceutical co-crystal: (2-Chloro-4-nitrobenzoic acid):(Nicotinamide)

Andreas Lemmerer, Catharine Esterhuysen, Joel Bernstein

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


The active pharmaceutical ingredient 2-chloro-4-nitrobenzoic acid (2c4n) is a potentially novel therapy for immunodeficiency diseases as an anti-viral and anti-cancer agent, and exists as a dimorph in the solid state. The Kofler hot stage contact method was employed to investigate the potential of preparing a co-crystal with nicotinamide (nic), a GRAS compound. The 1:1 co-crystal 1 was made using liquid-assisted grinding and solution crystallization experiments. The crystal structure determination of 1 reveals that the two molecules are associated via a carboxylic acid - pyridine hydrogen bond, while the nic forms a centrosymmetric R22(8) dimer to ultimately form a ribbon architecture which is compared to other known co-crystals of nic. The melting point of the co-crystal is higher than the melting points of either of the pure components, indicating that the pharmaceutical co-crystal is thermally more stable than the pure pharmaceutical compound. The relative stability of the interactions in the co-crystal over the pure compounds is further supported by molecular modeling calculations.

Original languageEnglish
Pages (from-to)4054-4071
Number of pages18
JournalJournal of Pharmaceutical Sciences
Issue number9
StatePublished - 1 Jan 2010


  • Calorimetry
  • Cambridge crystallographic database
  • Crystal engineering
  • Crystal structure
  • Crystallography
  • Hydrogen bonding
  • Liquid-assisted grinding
  • Molecular modeling
  • Pharmaceutical co-crystals
  • X-ray powder diffractometry

ASJC Scopus subject areas

  • Pharmaceutical Science


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