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Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM]. [ABSTRACT FROM AUTHOR]

Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0–0.05 M CD concentration range for pH 2.0 and pH 7.4. A L - and A L − -type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances. [ABSTRACT FROM AUTHOR]

[Display omitted] • Distribution of nortryptiline hydrochloride (NTT) was studied at several temperatures. • Permeability of NTT through three membranes was investigated at three pH of solution. • Both the distribution and permeability coefficients were increased with the pH growth. • A 4.7-fold enhancing effect of isopropylmyristate was demonstrated on PDS membrane. Partitioning/distribution and permeability are key parameters determining successful drug absorption. In the present work the distribution thermodynamics of nortryptiline hydrochloride (NTT) - an antidepressant drug of BCS II class was studied in the three partition systems: 1-octanol/buffer, n-hexane/buffer and isopropyl myristate (IPM)/buffer (pH 2.0, pH 4.0, and pH 6.8). The studies revealed rather low values of D app Org / b u f attributed to the ionized state of the majority of the NTT molecules. The following sequence of the distribution coefficients in all the systems was estimated: D app Org / b u f (p H 6.8) > D app Org / b u f (p H 4.0) > D app Org / b u f (p H 2.0) . Thermodynamic calculations disclosed the entropy as the main driving force for the buffer → 1-octanol and buffer pH 6.8 → IPM transfer. In order to select the optimal membrane for simulating the cells of different tissues, three artificial barriers were tested for NTT permeability: cellulose (RC), PermeaPad (PP) and polydimethylsiloxane-polycarbonate (PDS). A 4.7-fold enhancing effect of IPM as a known "percutaneous permeability enhancer" was demonstrated on PDS membrane. The distribution-permeability interrelations were discussed. We expected the results to be applicable for the improvement of tricyclic antidepressants peroral and transdermal use. [ABSTRACT FROM AUTHOR]

[Display omitted] • Solubility, distribution and permeability of nadolol were studied at several temperatures. • Apparent thermodynamics parameters were calculated. • Energy of activation and permeability enhancement factor were disclosed. • Good linear correlation between the distribution and permeability coefficients was derived. The dissolution (buffer solutions pH 2.0, pH 7.4, 1-octanol and n-hexane), distribution (1-octanol/buffer pH 7.4 system, n-hexane/buffer pH 7.4 system) and permeation (buffer pH 7.4, PermeaPad barrier) of nadolol (NDL) - a beta-blocker BCS Class III drug with antianxiety potential - were studied at different temperatures. The apparent thermodynamic parameters of the outlined processes were derived from the temperature dependences of the experimental solubilities, distribution and permeability coefficients. Comparative analysis of the driving forces was used to disclosing the behavior of the compound in different biologic media. Estimation of the influence of experimental temperature on the permeability of nadolol allowed to evaluate the energy of activation and the permeability enhancement factor equaling to EF = 2.16 upon 15 °C temperature rise. A good linear correlation (R = 0.9988, F = 831.66) between the distribution and permeability coefficients has been derived and would be applied to the prediction of the permeability from the distribution at a specific temperature. Comparison of the enthalpy contributions to the transferring from buffer pH 7.4 to 1-octanol and to the permeability through the lipophilic PermeaPad barrier showed the similar trends in these two processes. The present study has the perspectives for the application in the design of the drug formulations for the complex therapy of cardiovascular and depressive-like disorders. [ABSTRACT FROM AUTHOR]

Drug-likeN-substituted 1-selena-3-azaspiro[5,5]undec-2-en-2-aminehydrobromides (1:1) have been synthesized. Phenyl, isopropylphenyl,and fluorophenyl substituents were used. The solubility of the obtainedcompounds in pharmaceutically relevant solvents within the temperaturerange from (298.15 to 318.15) K has been measured using the isothermalsaturation technique. All of the compounds studied appear to havepoor solubility of ∼10–6mole fraction inphosphate buffer pH 7.4 and hexane. The solubility values enlargesubstantially to ∼10–2and 10–4mole fraction, respectively, in octanol and muriatic buffer solutionpH 2.0. The solubility of the selenazines in aqueous media was shownto increase as the number of protonated forms grew. The high solubilityof the compounds in octanol was found to depend on the formation ofintermolecular solvent–solute hydrogen bonds. Thermodynamicsolubility functions for the substances in the solvents studied havebeen calculated. The solubility in all of the systems with the predominantenthalpy term of Gibbs energy was proved to increase as the dissolutionenthalpy decreased. [ABSTRACT FROM AUTHOR]

[Display omitted] • Solubility of mebendazole and flubendazole in buffers, octanol and hexane has been determined at five temperatures. • Distribution coefficients in octanol/buffer and hexane/buffer systems have been measured. • Thermodynamic parameters have been derived and compared for the dissolution and transfer processes. • Permeability through PermeaPad has been measured and discussed. • Relationships between the determined parameters have been disclosed. The solubility of mebendazole and flubendazole was measured in aqueous buffers (pH 2.0 and pH 7.4), hexane, and octanol in the temperature range of 293.15–313.15 K by the shake flask method. The molecule ionization state effect on the solubility was investigated. The ionization constants of the compounds at different temperatures were derived from the solubility data. The distribution coefficients in the octanol/buffer (pH 2.0) system at (293.15–313.15 K) and in the hexane/buffer (pH 2.0) system at 298.15 K were measured. The hydrogen bonding potential of the compounds was evaluated using the Δlog D parameter. The thermodynamic functions of the dissolution and transfer process between the organic and aqueous phases were calculated and discussed. The permeability coefficients through the PermeaPad barrier were determined. The dependences between the distribution and permeability parameters and structural descriptor ΣC ad /α were analyzed to obtain the correlation equations. [ABSTRACT FROM AUTHOR]

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: Δ G =60.0 kJ mol−1; Δ H =117.9±0.7 kJ mol−1; Δ S =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, Δ H (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 Δ H (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 (Δ G =56.1 kJ mol−1; Δ H =115.9±0.9 kJ mol−1; Δ S =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. [ABSTRACT FROM AUTHOR]

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: ΔGsub298 = 60.0 kJ/mol; ΔHsub298 = 117.9 ± 0.7 kJ/mol; ΔSsub298 = 190 ± 2 J/mol · K; acetanilide: ΔGsub298 = 40.5 kJ/mol; ΔHsub298 = 99.8 ± 0.8 kJ/mol; ΔSsub298 = 197 ± 2 J/mol · K; phenacetin: ΔGsub298 = 52.3 kJ/mol; ΔHsub298 = 121.8 ± 0.7 kJ/mol; ΔSsub298 = 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. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2158–2169, 2006 [ABSTRACT FROM AUTHOR]

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: ΔGsub298 = 38.5 kJ/mol; ΔHsub298 = 96.6 ± 0.8 kJ/mol; ΔSsub298 = 191 ± 3 J/mol · K; 3-hydroxybenzoic acid: ΔGsub298 = 50.6 kJ/mol; ΔHsub298 = 105.2 ± 0.8 kJ/mol; ΔSsub298 = 180 ± 2 J/mol · K; 4-hydroxybenzoic acid: ΔGsub298 = 55.0 kJ/mol; ΔHsub298 = 113.3 ± 0.7 kJ/mol; ΔSsub298 = 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 Dmol3 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. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1448–1458, 2006 [ABSTRACT FROM AUTHOR]

A novel potential antifungal compound of 1,2,4-triazole class - ((5Z)-5-[(4-chlorophenyl)methylidene]-3-(2-{4-[2-(2,5-difluorophenyl)-2-hydroxy-3-(1,2,4-triazol-1-yl)propyl]piperazin-1-yl}-2-oxoethyl)-1,3-thiazolidine-2,4-dione) (L-173) - has been synthesized and characterized. Some pharmacologically relevant physicochemical properties have been determined for the first time. Solubility in buffer solutions (pH 1.2, 2.0, and 7.4), ethanol, hexane, and octanol was measured by the shake flask method in the temperature range of 293.15–313.15 K. L-173 was shown to be poor soluble in buffer solutions and hexane, at the same time, better solubility in alcohols was revealed. The Van't Hoff and Apelblat equations gave good correlations when used for modeling the experimental solubility results. The solubility evaluation in different solvents with the help of Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen showed the consistency with the experimental data and revealed good potential adsorption of the investigated drug. The thermodynamic parameters of solubility and transfer processes were calculated and discussed in view of solute-solvent interactions. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of lipophilic delivery pathways for L-173 in the biologic media. • Solubility of antifungal compound in buffers, hexane, and alcohols was assessed. • Good adsorption in the GIT by Hansen solubility parameters was proposed. • Analysis of transfer solubility thermodynamics approved the Hansen results. • Parameter ∆logD showed the preference of lipophilic delivery pathways for the drug. [ABSTRACT FROM AUTHOR]

Leflunomide, an immunosuppressive disease-modifying antirheumatic drug, is sparingly soluble in aqueous solutions. The aim of this work was to propose the suitable excipients for the enhancement of aqueous solubility of leflunomide. The ability of different cyclodextrins, biopolymers and (hydroxypropyl-β-cyclodextrin + biopolymer) mixtures to improve the leflunomide solubility due to complex formation was examined by phase solubility and spectroscopy methods. It was found that β-cyclodextrin and its hydroxypropylated and methylated derivatives form stable 1:1 complexes with leflunomide and considerably increase the drug solubility. Influence of cyclodextrin structure on the thermodynamics of binding with leflunomide was analyzed. In comparison with cyclodextrins, solubilizing effect of polymers such as polyvinylpyrrolidone (PVP K16-18 and K29-32), polyethylene glycol (PEG 1000) and hydroxypropylmethylcellulose was considerably lower. Among polymers under consideration only PVP K29-32 displays a noticeable solubilizing efficiency due to its ability to complex formation with leflunomide through hydrogen bonding. It was demonstrated that formation of the ternary complexes cyclodextrin/leflunomide/polymer does not occur and synergetic effect of cyclodextrins and polymers is rather weak. [ABSTRACT FROM AUTHOR]

Influence of a structural modification on thermodynamic aspects of solubility and solvation processes of the 1,2,4-thiadiazole drug-like compounds in pharmaceutically relevant solvents n -hexane and 1-octanol was investigated. The solubility of the compounds in 1-octanol does not substantially depend on the nature and position of the substituent in the phenyl moiety. In n -hexane, however, the introduction of any substituent in the phenyl ring of the 1,2,4-thiadiazole molecule reduces the solubility in the solvent. In order to rationalize the relationships between the structure of 1,2,4-thiadiazoles and their solubility, the latter was considered in terms of two fundamental processes: sublimation and solvation. It was found that for the most of the compounds the solubility change in both solvents is a consequence of competition between the sublimation and solvation contributions, i.e. the introduction of substituents leads to growth of the sublimation Gibbs energy and increase in the solvation Gibbs energy. Thermodynamic parameters of the transfer process of the compounds from n -hexane to 1-octanol, which is a model of the blood–brain barrier (BBB), were also analyzed. [ABSTRACT FROM AUTHOR]

Three biologically active selenium bicyclic compounds – N-aryl-(3-seleno-azabicyclo[3.3.1]non-2-ylidene)amines were synthesized. The effect of the substances structure on their protolytic properties was investigated. The substance solubility in hexane and pharmaceutically relevant buffer solutions (pH 2.0 and pH 7.4) was measured in the temperature range of 293.15–313.15 K by the saturation shake-flask method. Temperature dependences of the distribution coefficients of the compounds in the two-phase systems “organic solvent (octanol, hexane)/buffer solution” were obtained. Thermodynamic parameters of distribution process were calculated. [ABSTRACT FROM AUTHOR]

Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1 H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives. [ABSTRACT FROM AUTHOR]

Aqueous solubility and distribution of ciprofloxacin, enrofloxacin, norfloxacin and levofloxacin antimicrobials drugs in octanol/buffer system has been measured by the isothermal saturation method using buffer solutions pH 2.0 and 7.4 in the temperature range of 293.15–313.15 K. Thermophysical characteristics for the compounds have been determined by the DSC method. It has been established that the solubility of levofloxacin in these buffers is higher than that of the other fluoroquinolones. HYBOT descriptors for biologically active compounds have been calculated and the impact of the donor-acceptor capacity of the molecules on drugs solubility has been studied. According to the lipophilicity parameter fluoroquinolones are ranged in the following order: enrofloxacin > levofloxacin > ciprofloxacin > norfloxacin. The thermodynamic solubility and distribution functions of the studied compounds have been obtained. The permeability coefficients of the substances through an artificial phospholipid membrane were determined. The drugs with a lower aqueous solubility were estimated to have higher distribution coefficients and membrane permeability. [ABSTRACT FROM AUTHOR]

The solubility values of pyrazinamide, isoniazid, and p -aminobenzoic acid in buffers (рН 2.0 and 7.4) and octanol were measured in the temperature range of 293.15 to 313.15 K. The dissolution Gibbs energy, enthalpy, and entropy were calculated. The dissolving process was endothermic and enthalpy-determined. The activity coefficients of the compounds at infinite dilution were determined based on the solubility data and thermophysical parameters. A positive deviation from the ideality was observed in all the solutions. A common tendency of the solubility increase with a decrease in the activity coefficients at T = 298.15 K was revealed for the investigated solute-solvent systems. The excess thermodynamic solubility functions were calculated from the temperature dependences of the activity coefficients. The solvation processes were found to have a considerable influence on the solubility of the substances in solutions studied. [ABSTRACT FROM AUTHOR]