Crystal Structure of Polymorph II and the Pressure–Temperature Phase Diagram of the Dimorphic Anesthetic Butamben

The crystal structure of the low-temperature form II of butamben has been solved in a P2₁/c space group very similar to that of form I. Form II possesses virtually the same packing as that of the high-temperature form I, and the dimorphism is mainly represented by a small discontinuous change in the size of the unit cell and by a difference in the enthalpy. Because of the small enthalpy difference between the two polymorphs of 375 J·mol^–1, it will be difficult to predict the change in the stability hierarchy by computer-aided methods. The pressure–temperature phase diagram, constructed using volume and enthalpy differences between the two phases at ordinary pressure, corresponds to a case of overall enantiotropy, as the I–II and I–L equilibrium lines diverge with increasing pressure. This conclusion is confirmed by the experimental pressure–temperature phase diagram obtained with differential thermal analysis measurements under pressure.