title: Thermodynamic and structural aspects of sulfonamide crystals and solutions.
abstract: The crystal structures of three sulfonamides with the general structure 4-NH(2)-C(6)H(4)-SO(2)NH-C(6)H(4/3)-R (R = 4-Et; 4-OMe; 5-Cl-2-Me) have been determined by X-ray diffraction. On the basis of our previous data and the results obtained a comparative analysis of crystal properties was performed: molecular conformational states, packing architecture, and hydrogen bond networks using graph set notations. The thermodynamic aspects of the sulfonamide sublimation process have been studied by investigating the temperature dependence of vapor pressure using the transpiration method. A regression equation was derived describing the correlation between sublimation entropy terms and crystal density data calculated from X-ray diffraction results. Also correlations between sublimation Gibbs energies and melting points, on the one hand, and between sublimation enthalpies and fusion enthalpies at 298 K, on the other hand, were found. These dependencies give the opportunity to predict sublimation thermodynamic parameters by simple thermo-physical experiments (fusion characteristics). Solubility processes of the compounds in water, n-hexane, and n-octanol (as phases modeling various drug delivery pathways and different types of membranes) were investigated and corresponding thermodynamic functions were calculated as well. Thermodynamic characteristics of sulfonamide solvation were evaluated. For compounds with similar structures processes of transfer from one solvent to another one were studied by a diagram method combined with analysis of enthalpic and entropic terms. Distinguishing between enthalpy and entropy, as is possible through the present approach, leads to the insight that the contribution of these terms is different for different molecules (entropy- or enthalpy-determined). Thus, in contrast to interpretation of only the Gibbs energy of transfer, being extensively used for pharmaceuticals in the form of the partition coefficient (log P), the analysis of thermodynamic functions of the transfer process provides additional mechanistic information. This may be important for further evaluation of the physiological distribution of drug molecules and may provide a better understanding of biopharmaceutical properties of drugs.
authors.affiliation: Department of Computer-Aided Molecular Design, Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia. glp@isc-ras.ru
authors.forename: German L
authors.initials: GL
authors.lastname: Perlovich
authors.forename: Valery V
authors.initials: VV
authors.lastname: Tkachev
authors.forename: Nadezda N
authors.initials: NN
authors.lastname: Strakhova
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Kazachenko
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Volkova
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Surov
authors.forename: Klaus-Jürgen
authors.initials: KJ
authors.lastname: Schaper
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Raevsky
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D019999:Pharmaceutical Solutions; D012995:Solubility; D012997:Solvents; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D019999:Pharmaceutical Solutions; D012997:Solvents; D013449:Sulfonamides