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

✍ Scribed by German L. Perlovich; Tatyana V. Volkova; Annette Bauer-Brandl

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 236 KB
• Volume: 95
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20674

✦ Synopsis

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: DG sub 298 ¼ 60.0 kJ/mol; DH sub 298 ¼ 117.9 AE 0.7 kJ/mol; DS sub 298 ¼ 190 AE 2 J/mol Á K; acetanilide: DG sub 298 ¼ 40.5 kJ/mol; DH sub 298 ¼ 99.8 AE 0.8 kJ/mol; DS sub 298 ¼ 197 AE 2 J/mol Á K; phenacetin: DG sub 298 ¼ 52.3 kJ/mol; DH sub 298 ¼ 121.8 AE 0.7 kJ/mol; DS sub 298

Analysis of packing energies based on geometry optimization of molecules in the crystal lattices using diffraction data and the program Dmol 3 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. ß 2006