Introducing Crystal Structure of Tetracaine: The High Lattice Energy versus Low Melting Point Paradox

It is undeniable that knowledge of the crystal structure is crucial for understanding the properties of crystalline materials and is one of the cores of crystal engineering. Surprisingly, there are still widely used compounds whose crystal structures remain unreported. In this work, the crystal structure of tetracaine─a well-known Active Pharmaceutical Ingredient─is revealed. Its crystals take the symmetry of the monoclinic space group P21 with one symmetry-independent molecule in the unit cell. Currently, there are very limited structural reports on its crystal forms, and despite being known for almost 100 years, the crystal structure of pure tetracaine remains unknown. It was shown that its aggregation is governed by the formation of N–H···O hydrogen bonds as in the case of other popular “caines”: benzocaine, procaine, and lidocaine; however, due to the imbalance between H-donors and acceptors, the preferred interaction landscape remains unfulfilled. Despite that, it was revealed that tetracaine has a surprisingly high lattice energy of −163.15 kJ·mol–1, largely due to the input of dispersive interactions. This correlates with the low water solubility of tetracaine, but contrasts with its relatively low melting point of approximately 40 °C (313 K). The crystal structure of tetracaine is analyzed in terms of intermolecular interactions and molecular conformation to understand its physicochemical properties. Additionally, the differences in the crystal structures of tetracaine free base and its hydrochloride are analyzed and compared in the context of the difference in the protonation of the nitrogen of the tertiary amine group.