The difference between partitioning and distribution from a thermodynamic point of view: NSAIDs as an example.

Solubility and solvation of some NSAIDs were studied in their non-ionic (aqueous buffers of pH 2.0) and ionic molecular form (pH 7.4) over a wide temperature interval. Absolute scale values for the thermodynamic terms (Gibbs energy, enthalpy and entropy) were obtained. Thermodynamic parameters of the transfer of the molecules from one buffer to the other (representing protonation/deprotonation) were derived. It has been found that the thermodynamic characteristics of solvation (hydration) of (+)- and (+/-)-IBP in the buffers show a difference, which is larger than the experimental error. This may be explained by differences in the association states of the molecules in solution. For the other NSAIDs studied, a correlation between the Gibbs energy of transfer, deltaG(tr) (pH 7.4-->pH 2.0) and the pK(a)-value, and a compensation effect between the enthalpic and entropic terms have been revealed. Thermodynamic aspects of the transfer process from the buffers to n-octanol were analysed. The two types of the transfer processes (non-dissociated molecule to octanol (partitioning), and dissociated form to octanol (distribution)) have essentially different driving forces: partitioning is enthalpy driven, whereas the transfer of the ionic form is entropy driven. The following points are discussed: (a) significance of using water-octanol systems (logP as a measure of drug lipophilicity) to describe biological membranes (lipid systems); (b) differences in thermodynamic aspects of the partitioning/distribution processes of these systems; (c) advantages of the present transfer method approach in comparison with temperature dependencies of logP to analyse the driving forces of partitioning/distribution.     

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

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%)相似文献   

Thermodynamic properties of flufenamic and niflumic acids--specific and non-specific interactions in solution and in crystal lattices, mechanism of solvation, partitioning and distribution

Temperature dependency of saturated vapour pressure and the thermochemical characteristics of the fusion process were measured for flufenamic acid and niflumic acid, and thermodynamic functions of sublimation, fusion and evaporation calculated. An approach to split specific and non-specific energetic terms in crystal lattices is developed. The melting points of the considered molecules correlate with the ratio between specific and non-specific interactions in crystal lattices. Temperature dependencies of the solubility in buffers with pH 2.0 and 7.4, in n-octanol and in n-hexane were measured. The thermodynamic functions of solubility, solvation and transfer processes were deduced. Specific and non-specific solvation terms were distinguished by the transfer from "inert"n-hexane to the other solvents. Comparison of the ratio between specific and non-specific interactions in solid state and in the solutions was carried out. A diagram to analyse energetic terms of partitioning and distribution processes is introduced.     

Thermodynamic study of sublimation, solubility, solvation, and distribution processes of atenolol and pindolol

Temperature dependency of saturated vapor pressure, thermochemical, and thermodynamic characteristics of sublimation, as well as fusion and vaporization processes, for atenolol and pindolol was studied. Specific and nonspecific energetic terms in the crystal lattices were estimated. Temperature dependencies of solubility in buffer (pH 7.4), in n-octanol, and in n-hexane were measured. Thermodynamic functions of solubility, solvation, and transfer processes were deduced. It was found that transfer processes for the drugs moving from water into n-octanol are determined mainly by the entropy term. Distribution coefficients of the compounds in the water/n-octanol system were derived and compared with analogous coefficients calculated from saturation solubility data in the individual solvents. The impact of mutual dissolution of water and n-octanol molecules in the water/n-octanol system on distribution coefficients is discussed.     

Thermodynamics of Solutions I: Benzoic Acid and Acetylsalicylic Acid as Models for Drug Substances and the Prediction of Solubility

Purpose. To investigate the solution process of drug substances (exemplified by benzoic acid, BA, and acetylsalicylic acid, ASA), particularly the interrelation between enthalpic and entropic terms of Gibbs energy, in different solvents. To develop an approach for the estimation of standard solution enthalpies based on a self-consistent thermochemical scale. Method. Two independent methods, solubility experiments (concentrations of saturated solutions) and solution calorimetry (standard solution enthalpies) in aliphatic alcohols and individual organic solvents were used. Correlation between the thermodynamic functions in various solvents were analyzed by standard statistical methods. Multiple regression analysis between H ⁰ _sol values and the parameters of the solvents was run on the Koppel-Palm equation. Results. Based on experimental data, a compensation effect between thermodynamic functions was observed. Correlation was found between H ⁰ _sol (BA) and H ⁰ _sol (ASA) [where the H ⁰ _sol (BA)-values were used as a self-consistent thermochemical scale]. Furthermore, H ⁰ _sol correlated with the Koppel-Palm basicity of the solvents. Conclusions. The model based on solubility and solution experiments might be useful for the prediction of solubility or solvation of drug substances in different media. The regression equation based on the self-consistent thermochemical scale makes it possible to approximate the ability to solvate a drug substance in comparison with structure-relative substances.     

Thermodynamic aspects of solubility process of some sulfonamides

The thermodynamic aspects of solubility process of sulfonamides with the general structures C₆H₅–SO₂NH–C₆H₄–R (R = 4-NO₂; 4-Cl) and 4-NH₂–C₆H₄–SO₂NH–C₆H₄–R (R = 4-NO₂; 4-CN; 4-Cl; 4-OMe; 4-C₂H₅) in water, phosphate buffer with pH 7.4 and n-octanol (as phases modeling various drug delivery pathways) were studied using the isothermal saturated method.     

Towards an understanding of the molecular mechanism of solvation of drug molecules: a thermodynamic approach by crystal lattice energy, sublimation, and solubility exemplified by hydroxybenzoic acids

Temperature dependencies of saturated vapor pressure and heat capacities for the 2-, 3-, and 4-hydroxybenzoic acids were measured and thermodynamic functions of sublimation calculated (2-hydroxybenzoic acid: DeltaG(sub) (298) = 38.5 kJ/mol; DeltaH(sub) (298) = 96.6 +/- 0.8 kJ/mol; DeltaS(sub) (298) = 191 +/- 3 J/mol . K; 3-hydroxybenzoic acid: DeltaG(sub) (298) = 50.6 kJ/mol; DeltaH(sub) (298) = 105.2 +/- 0.8 kJ/mol; DeltaS(sub) (298) = 180 +/- 2 J/mol . K; 4-hydroxybenzoic acid: DeltaG(sub) (298) = 55.0 kJ/mol; DeltaH(sub) (298) = 113.3 +/- 0.7 kJ/mol; DeltaS(sub) (298) = 193 +/- 2 J/mol . K). Analysis of crystal lattice packing energies based on geometry optimization of the molecules in the crystal using diffraction data and the program Dmol(3) was carried out. The energetic contributions of van der Waals, Coulombic, and hydrogen bond terms to the total packing energy were analyzed. The fraction of hydrogen bond energy in the packing energy increases as: 3-hydroxybenzoic (29.7%) < 2-hydroxybenzoic (34.7%) < 4-hydroxybenzoic acid (42.0%). Enthalpies of evaporation were estimated from enthalpies of sublimation and fusion. Temperature dependencies of the solubility 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 process.     

Synthesis,Pharmacology, Crystal Properties,and Quantitative Solvation Studies from a Drug Transport Perspective for Three New 1,2,4-thiadiazoles

A novel 1,2,4-thiadiazoles were synthesized. Crystal structures of these compounds were solved by X-ray diffraction experiments and comparative analysis of molecular conformational states, packing architecture, and hydrogen bonds networks were carried out. Thermodynamic aspects of sublimation processes of studied compounds were determined using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. Solubility and solvation processes of 1,2,4-thiadiazoles in buffer, n-hexane and n-octanol were studied within the wide range of temperature intervals and thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. Distribution processes of compounds in buffer/n-octanol and buffer/n-hexane systems (describing different types of membranes) were investigated. Analysis of transfer processes of studied molecules from the buffer to n-octanol/n-hexane phases was carried out by the diagram method with evaluation of the enthalpic and entropic terms. This approach allows us to design drug molecules with optimal passive transport properties. Calcium-blocking properties of the substances were evaluated. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3754-3768, 2010     

Thermodynamic and structural study of tolfenamic acid polymorphs

The article deals with the study of two polymorphic modifications in the space groups P2₁/c (white form) and P2₁/n (yellow form) of the tolfenamic acid. It also describes how the white form vapor pressure temperature dependence was determined by using the transpiration method and how thermodynamic parameters of the sublimation process were calculated. We have estimated the difference between the crystal lattice energies of the two polymorphic forms by solution calorimetry and found that the crystal lattice energy of the yellow form is 6.7 ± 1.2 kJ mol⁻¹ higher than that of the white form, whereas Gibbs free energies of the forms obtained from the vapor pressure temperature dependence are practically the same. The modifications under consideration are monotropically related. From the practical point of view, the white form is more preferable due to its lower crystal lattice energy and better performing procedure. We have also studied the solubility, solvation and transfer processes of the tolfenamic acid white form in buffers (with various values of pH and ionic strengths), n-hexane and n-octanol. The thermodynamic parameters of the investigated processes have been discussed and compared with those determined for others fenamates. In the study we estimated specific and non-specific contributions of the solvation enthalpic term of the fenamate molecules with the solvents as well. The driving forces of the transfer processes from the buffers with pH 7.4 and different ionic strengths to n-octanol were analyzed. It was found that the relationship between the enthalpic and entropic terms depends essentially on the ionic strength. For the considered fenamates the transfer processes of the neutral molecules and the ionic forms are enthalpy-determined, whereas for the niflumic acid this process is entropy-determined.     

Thermodynamic and structural aspects of novel 1,2,4-thiadiazoles in solid and biological mediums

Novel 1,2,4-thiadiazoles were synthesized. Crystal structures of these compounds were solved by X-ray diffraction experiments, and comparative analysis of packing architecture and hydrogen bond networks was carried out. Thermodynamic aspects of sublimation processes of the compounds under study were analyzed using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. The melting points correlate with sublimation Gibbs energies. Moreover, an increase of donor-acceptor interactions in crystal structures leads to growth of Gibbs energy values. Relationships between the melting points and the fragmental contributions to the packing energies were established: R(1)-R(4) fragmental interactions are responsible for the fusion processes of this class of compounds. Solubility and solvation processes of 1,2,4-thiadiazoles in buffer, n-hexane and n-octanol were studied within a wide range of temperature intervals, and their thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. It was found that the melting points correlate with sublimation Gibbs energies. Distribution processes of compounds in buffer/n-octanol and buffer/n-hexane systems (describing different types of membranes) were investigated. Transfer processes of the studied molecules from the buffer to n-octanol/n-hexane phases were analyzed by the diagram method with evaluation of the enthalpic and entropic terms. This approach allowed us to design drug molecules with optimal passive transport properties. Calcium-blocking properties of the substances were evaluated. The trend between the ability to inhibit Glu-Ca uptake and the distribution coefficients in buffer/hexane system was observed.