Co-crystallisation of benzoic acid derivatives with N-containing bases in solution and by mechanical grinding: stoichiometric variants, polymorphism and twinning

Abstract

Benzoic acid, salicylic acid and o-acetylsalicylic acid (aspirin) have been co-crystallised with diazabicyclo[2.2.2]octane (DABCO), piperazine, phenazine and 2-aminopyrimidine, using solution and solvent-drop grinding methods. Two of the resulting co-crystals, benzoic acid/DABCO (2 : 1) and benzoic acid/2-aminopyrimidine (2 : 1), form different polymorphs using the two distinct preparative techniques. In both systems, the polymorph obtained by grinding has a higher crystal density and packing coefficient than the polymorph obtained from solution. For benzoic acid/piperazine (2 : 1), salicylic acid/DABCO (2 : 1), salicylic acid/phenazine (2 : 1) and salicylic acid/N,N′-diacetylpiperazine (2 : 1) (derived from reaction between aspirin and piperazine), the same crystal form is obtained in bulk from solution and by solvent-drop grinding. For salicylic acid/N,N′-diacetylpiperazine (2 : 1), rapid cooling of an acetone solution produces single crystals of a different polymorph. Benzoic acid/2-aminopyrimidine also forms a 1 : 1 co-crystal from methanol solution on seeding with the material produced by grinding. For aspirin/DABCO (2 : 1), co-crystallisation was achieved only using solvent-drop grinding. Interactions between benzoic acid molecules in the co-crystals frequently resemble those in benzoic acid itself. For salicylic acid, two of the co-crystals have a layered structure in which the hydroxyl group is isolated within the layer, and the interlayer interactions also resemble those in benzoic acid. For aspirin, co-crystallisation with DABCO disrupts the layered structure and intermolecular interactions between acetyl groups. In benzoic acid/2-aminopyrimidine (2 : 1), insertion of base induces twinning based on two possibilities for the arrangement of adjacent hydrogen-bonded layers.