Benzocaine (ethyl 4-aminobenzoate) is a common local anesthetic drug for topical use. It is a poorly soluble molecule and numerous studies have focused on benzocaine formulations to enhance delivery. Of particular interest is the crystal structure of benzocaine as it is known to exist in three different polymorphs with varying physical properties. Characterization of solid-state polymorphs continues to be an invaluable resource for formulation development regarding drug efficacy, but also for storage and shelf-life. Here, the crystalline polymorphs (I, II, and III) of benzocaine are investigated using low-frequency Raman spectroscopy (LFRS) and solid-state density functional theory (ss-DFT) to examine the lattice vibrations of these crystals and the energies involved with the polymorphic forms. The use of Raman vibrational spectroscopy in the 10-300 cm<sup>-1</sup> range enables measurement of material-specific vibrations that originate not only from individual molecules (e.g. torsional vibrations), but from motions between molecules in the solid-state (e.g. translational vibrations). Together, these vibrations yield unique LFRS profiles for compound detection and identification, and also provide insights into the conformation and cohesion energy factors that govern polymorph properties. Temperature-dependent LFRS data sets have been recorded of the benzocaine polymorphs from ambient to liquid-nitrogen temperatures. A reversible phase transition of Form II to Form III can clearly be seen in these temperature studies with a well-defined phase transition temperature at 250K and distinct LFRS peaks appearing for Form III below this threshold. Form I shows no phase transition over the same temperature range. The spectra have been completely assigned using ss-DFT simulations of the crystal structures and lattice vibrations, demonstrating the applied computational methods are able to accurately model the intermolecular forces within the solids. The ss-DFT analyses also establish the metastability of Form I at all temperatures, and the thermodynamic relationship between II and III.

Low-frequency Raman spectroscopy of phase transitions in benzocaine polymorphs

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