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

Abstract

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 (ΔEICC) 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.

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach

“…Comparison of the Kitaigorodsky packing coefficients ( ) of the molecular ICCs in our series with the packing coefficients of their respective molecular salts as reported in the CSD (see Table S3 in the Supporting Information for refcodes) show that only 5 , 6 , and 7 ‐ II display >1 % improvement (Table ) in upon switching from the salt to the ICC. The finding that 2 – 4 show little or no change (Table ) in the packing efficiency of the species in the crystal as we switch from the binary salt to the ternary ICC is consistent with previous observations that poor crystal packing of salt ions is not a satisfactory explanation for rationalizing ICC formation. CSP studies (rigid molecular conformations) on the set of ICCs with previously reported crystal structures ( 3 – 6 and 7 ‐ I ) have shown (see Tables S6–S10) that all experimentally determined solid forms could be predicted within an energy range of 20 kJ mol −1 with respect to the global minimum (GM) structure.…”

“…We use the predicted crystal form landscapes (CFLs) to assess the preferred packing modes of ternary molecular ICCs and the degree to which CSP methods can guide the selection of ICCs in crystallization screens. We also test the hypothesis that the crystallization of ternary molecular ICCs is under thermodynamic control, and that the use of dispersion‐corrected density functional theory (DFT‐D) energies is diagnostic enough to guide the experimental discovery of ternary molecular ICCs.…”

Living in the salt-cocrystal continuum: indecisive organic complexes with thermochromic behaviour

“…One route to modified properties is the formation of multicomponent complexes, where the introduction of a second molecule into the crystal lattice can facilitate the engineering of solid-state forms with significantly different properties. [16][17][18] In this work, we sought to develop switchable materials by creating and switching between neutral cocrystals and ionic salts. In cocrystals, both components are formally neutral and typically interact through designable intermolecular interactions such as hydrogen or halogen bonding.…”

Neutral, Zwitterion, Ionic Forms of 5‐Aminoisophthalic Acid in Cocrystals, Salts and Their Optical Properties

“…[19] Charge-assisted hydrogen bonds have definite scopes in the synthesis of non-covalent assemblies. [20][21][22][23][24] The electrostatic interactions in the noncovalent self-assemblies of inorganic complexes are common. [25][26][27][28] Among many examples of organic salts forming cocrystals the salts of active pharmaceutical ingredients, [25] carboxylic acid, [20][21][22][23][24] quaternary ammonium [29] and heterocycle containing oximes [30] are well studied.…”

“…[26] A mono-deprotonated dicarboxylic acid also may form cocrystal (BÀ H) + (B)(AH) À (Where B is a nitrogen based compound and AH is mono-anion of a dicarboxylic acid). [20][21][22][23][24] Some unsymmetrical dicarboxylic acids undergo preferential deprotonation [31] and certain acids form monodeprotonated salt. [32] A zwitterion has different complementarity for hydrogen bond than the conventional neutral form the changes in the hydrogen bonding patterns due to change in the ability to interact differently.…”