Towards the systematic crystallisation of molecular ionic cocrystals: insights from computed crystal form landscapes

The underlying molecular and crystal properties affecting the crystallisation of ionic cocrystals (ICCs) with the general formula A(-)B(+)N (A(-) = anion, B+ = cation and N = neutral acid molecule; 1:1:1 stoichiometry) are reported for a limited set of known crystal structures determined following the cocrystallisation of either 4-aminopyridine (which forms salts) or 4-dimethylaminopyridine (which forms salts and ICCs) with the same set of monoprotic acids with a single hydroxy or halogen substitution at the ortho or para position. Periodic density functional theory calculations (PBE + D2) on the energetic driving force for ICC crystallisation for a set of known crystal structures with well characterised acid, salt and ICC structures show that all but 1 of the 7 experimental ICC structures surveyed were more stable than the sum of their component salt and acid structures with 4 displaying relative stabilities (E-ICC) ranging from 2.47-8.02 kJ mol(-1). The majority of molecular ICCs that are more stable with respect to their component salt and acid structures display the formation of discrete intermolecular O-HacidOanion hydrogen bonds with the D11(2) graph set between the carboxylic acid OH donor and the carboxylate oxygen acceptor of the anion. Computed crystal form landscapes for model 1:1 salts derived from acid-base pairs (involving 4-dimethylaminopyridine) known to form molecular ICCs show that on average the most stable predicted polymorphs of the 1:1 salts have efficient packing of the ions with packing coefficients in the range 65-80% and this is comparable to the packing coefficients of the most stable predicted polymorphs of 1:1 salts (involving 4-aminopyridine) that have no ICCs reported. This suggests that the cocrystallisation of equimolar amounts of the 1:1 salt and the acid to form a 1:1:1 molecular ICC is a complicated phenomenon that cannot be explained on the basis of inefficiencies in the crystal packing of the salt ions.