title: Co-crystallization with nicotinamide in two conformations lowers energy but expands volume.
abstract: A dispersion-corrected density functional theory method has been used to study the formation energies and volumes of cocrystals. For four cocrystals of nicotinamide (NIC) and (R)-mandelic acid, a broad agreement is found between experimental and computed values. We report that cocrystals containing NIC are anomalous as their formation generally decreases energy but expands volume. In this respect, the formation of NIC cocrystals is in contrast to most physical processes, but similar to water freezing. As in the case of water freezing, the cocrystallization with NIC leads to stronger hydrogen bonds and looser molecular packing, a combination that is likely responsible for the anticorrelation between energy and volume. NIC has two conformers 4 kJ/mol apart in energy and both can form cocrystals, with the resulting structures having comparable formation energies and volumes. These results are relevant for understanding the nature of cocrystallization and why NIC is a prolific cocrystal former.
authors.affiliation: School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705.
authors.forename: Si-Wei
authors.initials: SW
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.
authors.forename: John
authors.initials: J
authors.lastname: Kendrick
authors.affiliation: School of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.
authors.forename: Frank J J
authors.initials: FJJ
authors.lastname: Leusen
authors.affiliation: School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705. Electronic address: lyu@pharmacy.wisc.edu.
authors.forename: Lian
authors.initials: L
authors.lastname: Yu
mesh_terms: D003460:Crystallization / Q000379:methods; D004355:Drug Stability; D005615:Freezing; D006860:Hydrogen Bonding; D008333:Mandelic Acids / Q000737:chemistry; D008968:Molecular Conformation; D009536:Niacinamide / Q000737:chemistry*; D055585:Physical Phenomena; D014867:Water / Q000737:chemistry
chemical_list: D008333:Mandelic Acids; D014867:Water; D009536:Niacinamide; C037938:mandelic acid
keywords: cocrystal; crystal engineering; hydrogen bonding; lattice energy calculation; molecular modeling; molecular packing; nicotinamide; structure-property relationship; thermodynamics