title: Towards an understanding of the molecular mechanism of solvation of drug molecules: a thermodynamic approach by crystal lattice energy, sublimation, and solubility exemplified by paracetamol, acetanilide, and phenacetin.
abstract: Temperature dependencies of saturated vapor pressure for the monoclinic modification of paracetamol (acetaminophen), acetanilide, and phenacetin (acetophenetidin) were measured and thermodynamic functions of sublimation calculated (paracetamol: DeltaGsub298=60.0 kJ/mol; DeltaHsub298=117.9+/-0.7 kJ/mol; DeltaSsub298=190+/-2 J/mol.K; acetanilide: DeltaGsub298=40.5 kJ/mol; DeltaHsub298=99.8+/-0.8 kJ/mol; DeltaSsub298=197+/-2 J/mol.K; phenacetin: DeltaGsub298=52.3 kJ/mol; DeltaHsub298=121.8+/-0.7 kJ/mol; DeltaSsub298=226+/-2 J/mol.K). Analysis of packing energies based on geometry optimization of molecules in the crystal lattices using diffraction data and the program Dmol3 was carried out. Parameters analyzed were: (a) energetic contribution of van der Waals forces and hydrogen bonding to the total packing energy; (b) contributions of fragments of the molecules to the packing energy. The fraction of hydrogen bond energy in the packing energy increases as: phenacetin (17.5%)<acetanilide (20.4%)<paracetamol (34.0%). Enthalpies of evaporation were estimated from enthalpies of sublimation and fusion. Activity coefficients of the drugs in n-octanol were calculated from cryoscopic data and by estimation of dilution enthalpy obtained from solubility and calorimetric experiments (for infinite dissolution). Solubility temperature dependencies in n-octanol and n-hexane were measured. The thermodynamic functions of solubility and solvation processes were deduced. Specific and nonspecific solvation terms were distinguished using the transfer from the "inert" n-hexane to the other solvents. The transfer of the molecules from water to n-octanol is enthalpy driven for paracetamol; for acetanilide and phenacetin, entropy driven.
authors.affiliation: University of Tromsø, Institute of Pharmacy, Breivika, N-9037 Tromsø, Norway.
authors.forename: German L
authors.initials: GL
authors.lastname: Perlovich
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Volkova
authors.forename: Annette
authors.initials: A
authors.lastname: Bauer-Brandl
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000082:Acetaminophen / Q000737:chemistry*; D000083:Acetanilides / Q000737:chemistry*; D003460:Crystallization; D010615:Phenacetin / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D000083:Acetanilides; D012997:Solvents; D014867:Water; D000082:Acetaminophen; D010615:Phenacetin; D020003:1-Octanol