Polymorphism of paracetamol

Abstract

The thermodynamic relationship between crystal modifications of paracetamol was studied by alternative methods. Temperature dependence of saturated vapor pressure for polymorphic modifications of the drug paracetamol (acetaminophen) was mea sured and thermodynamic functions of the sublimation process calculated. Solution calorimetry was carried out for the two modifications in the same solvent. Thermodynamic parameters for sublimation for form I (monoclinic) were found: ΔG ²⁹⁸_sub =60.0 kJ mol⁻¹; ΔH ²⁹⁸_sub =117.9±0.7 kJ mol⁻¹; ΔS ²⁹⁸_sub =190±2 J mol⁻¹ K⁻¹. For the orthorhombic modification (form II), the saturated vapor pressure could only be studied at 391 K. Phase transition enthalpy at 298 K, ΔH ²⁹⁸_tr (I→II)=2.0±0.4 kJ mol⁻¹, was derived as the difference between the solution enthalpies of the noted polymorphs in the same solution (methanol). Based on ΔH ²⁹⁸_tr (I→II), differences between temperature dependencies of heat capacities of both modifications and the vapor pressure value of form II at 391 K, the temperature dependence of saturated vapor pressure and thermodynamic sublimation parameters for modification II were also estimated (ΔG ²⁹⁸_sub =56.1 kJ mol⁻¹; ΔH ²⁹⁸_sub =115.9±0.9 kJ mol⁻¹; ΔS ²⁹⁸_sub =200±3 J mol⁻¹ K⁻¹). The results indicate that the modifications are monotropically related, which is in contrast to findings recently reported found by classical thermochemical methods.