Pressure-induced modification of molecular aggregation in crystals of benzocaine

Benzocaine (BZC), a local anaesthetic and one of the best known representative of biologically active esters of 4aminobenzoic acid, is an Active Pharmaceutical Ingredient (API) of many commercially available drugs.Unfortunately, its water solubility of 0.131 mg/ml makes it unsuitable for enteral administration.Solubility of an API is an important aspect affecting properties and application of a final drug product.It strongly depends on intermolecular interactions present in the solid form of a given compound, making analysis of H-bonding pattern crucial for investigation of crystal properties.It was shown that BZC exhibits specific tendency for molecular aggregation and H-bonding pattern formation, common to all three polymorphs of BZC reported so far (Sinha & Pattabhi, 1987;Lynch & McClenaghan, 2002;Chan et al., 2009).In order to induce changes in BZC aggregation and synthons hierarchy a series of high-pressure experiments was performed.Pressure has proven to induce a phase transition in crystals of BZC, introducing its new polymorph.Herein, we present a thorough analysis and comparison of intermolecular interactions and molecular packing for all four polymorphs of BZC.