Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling.

Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier-a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility-diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction.

Synthetic analogues of memantine as neuroprotective and influenza viral inhibitors: in vitro and physicochemical studies.

Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aß toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC50 and IC50 were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aß toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula.

Identification of a previously unreported co-crystal form of acetazolamide: a combination of multiple experimental and virtual screening methods.

In the search for new co-crystal forms, many studies only consider one method of co-crystallisation which may lead to incorrect results. In this work, we demonstrate the efficiency of applying multiple experimental and virtual screening methods for a more comprehensive search for co-crystals of acetazolamide. A new co-crystal of acetazolamide with 4-aminobenzoic acid ([ACZ + PABA] (1 : 1)) was discovered, although previously, it had been found in the blind spot of the liquid-assisted grinding (LAG) screening method. The new co-crystal was investigated by different analytical techniques, including the powder and single crystal X-ray diffraction, differential scanning calorimetry, dissolution and solubility methods. The specific features of the mechanochemical formation process for [ACZ + PABA] (1 : 1) were studied. It was found that the appearance of the blind spot of the LAG screening method can be caused by a number of reasons; among those are the high sensitivity to the solvent choice and the low rate of the reagent conversion into the reaction product. A comparison of the ACZ co-crystals with 4-aminobenzoic and 4-hydroxybenzoic acids revealed their close resemblance in terms of the packing energy gain and the driving force of co-crystallization. Therefore, the experimental problems in the formation of the [ACZ + PABA] (1 : 1) co-crystal were associated with a number of kinetic reasons, e.g. the high energy barrier of the nucleation process and the low growth rate of the co-crystal. Using the co-crystal screening of acetazolamide as an example, the effectiveness of five different virtual methods for predicting co-crystal formation was assessed. In order to carry out the virtual screening based on the formation thermodynamics of a hypothetical co-crystal, for the first time ever we studied the ACZ sublimation process. Four out of the five virtual screening methods confirm the formation of the new [ACZ + PABA] (1 : 1) co-crystal.

Sublimation thermodynamics aspects of adamantane and memantine derivatives of sulfonamide molecular crystals.

A number of new sulfonamide compounds with adamantane and memantine fragments were synthesized and characterized. Thermodynamic functions of sublimation processes have been determined on the basis of experimental values of saturated vapor pressures measured by the transpiration method in a wide temperature range. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the considered substances were studied using the DSC method. Correlation equations linking the thermodynamic characteristics of sublimation with melting points and packing densities of crystals have been proposed.

Understanding of Relationship between Phospholipid Membrane Permeability and Self-Diffusion Coefficients of Some Drugs and Biologically Active Compounds in Model Solvents.

In this work we measured self-diffusion coefficients of 5 drugs (aspirin, caffeine, ethionamide, salicylic acid, and paracetamol) and 11 biologically active compounds of similar structure in deuterated water and 1-octanol by NMR. It has been found that an increase in the van der Waals volume of the molecules of the studied substances result in reduction of their diffusion mobility in both solvents. The analysis of the experimental data showed the influence of chemical nature and structural isomerization of the molecules on the diffusion mobility. Apparent permeability coefficients of the studied compounds were determined using an artificial phospholipid membrane made of egg lecithin as a model of in vivo absorption. Distribution coefficients in 1-octanol/buffer pH 7.4 system were measured. For the first time the model of the passive diffusion through the phospholipid membrane was validated based on the experimental data. To this end, the passive diffusion was considered as an additive process of molecule passage through the aqueous boundary layer before the membrane and 1-octanol barrier simulating the lipid layer of the membrane.

Novel 1,2,4-thiadiazole derivatives as potent neuroprotectors: approach to creation of bioavailable drugs.

Novel 1,2,4-thiadiazole derivatives as potent neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca uptake was measured. Permeation experiments on the phospholipid membranes were conducted, and the apparent permeability coefficients were obtained. The partition coefficients in n-octanol/buffer (pH 7.4) and n-hexane/buffer (pH 7.4) immiscible phases (as model systems for characterizing gastrointestinal tract membranes and BBB) were determined. A classification of the studied compounds from the standpoint of "permeability-activity" properties was proposed.

Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated ß-Cyclodextrin Solid Dispersion.

The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-ß-CD) and acetylated (Ac-ß-CD) ß-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-ß-CD as compared to Me-ß-CD was revealed. The solid dispersion of BCL with Ac-ß-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-ß-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-ß-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers-polyvinylpyrrolidone (PVP, Mn = 58,000) and hydroxypropylmethylcellulose (HPMC, Mn ~ 10,000)-were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-ß-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the AUCC(t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-ß-CD (HPMC), BCL/Ac-ß-CD (PVP), BCL/Ac-ß-CD (buffer), and the BCL/Ac-ß-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-ß-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing.

Physicochemical Profile of Antiandrogen Drug Bicalutamide: Solubility, Distribution, Permeability.

The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15−313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van't Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability.

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay.

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-ß-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. AL- and AL--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.

Formation Thermodynamics of Carbamazepine with Benzamide, Para-Hydroxybenzamide and Isonicotinamide Cocrystals: Experimental and Theoretical Study.

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].

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.

New Antifungal Compound: Impact of Cosolvency, Micellization and Complexation on Solubility and Permeability Processes.

Poor solubility of new antifungal of 1,2,4-triazole class (S-119)-a structural analogue of fluconazole in aqueous media was estimated. The solubility improvement using different excipients: biopolymers (PEGs, PVP), surfactants (Brij S20, pluronic F-127) and cyclodextrins (α-CD, ß-CD, 2-HP-ß-CD, 6-O-Maltosyl-ß-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. Additionally, 2-HP-ß-CD and 6-O-Maltosyl-ß-CD were proposed as promising solubilizers for S-119. According to the solubilization capacity and micelle/water partition coefficients in buffer pH 7.4 pluronic F-127 was shown to improve S-119 solubility better than Brij S20. Among biopolymers, the greatest increase in solubility was shown in PVP solutions (pH 7.4) at concentrations above 4 w/v%. Complex analysis of the driving forces of solubilization, micellization and complexation processes matched the solubility results and suggested pluronic F-127 and 6-O-Maltosyl-ß-CD as the most effective solubilizing agents for S-119. The comparison of S-119 diffusion through the cellulose membrane and lipophilic PermeaPad barrier revealed a considerable effect of the lipid layer on the decrease in the permeability coefficient. According to the PermeaPad, S-119 was classified as a highly permeated substance. The addition of 1.5 w/v% CDs in donor solution moves it to low-medium permeability class.

Comparative analysis of solubilization and complexation characteristics for new antifungal compound with cyclodextrins. Impact of cyclodextrins on distribution process.

From a pharmaceutical standpoint, cyclodextrin-based products have deservedly gained substantial market share due to their ability to improve undesirable physicochemical properties of drugs. In this study the solubility of a potenial antifungal compound (L-173) has been improved essentially by addition of ß-cyclodextrin (ß-CD), 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD) in aqueous solutions (pH 2.0 and pH 7.4) at 298.15-313.15 K. The phase solubility diagrams were constructed. The stoichiometric ratio of the complexes was determined as 1:1. The stability constants of L-173 with all three CDs in acidic medium belong to the range optimal for the improvement of the bioavailability of hydrophobic drugs. DM-ß-CD was assigned as the best solubilizer for L-173. The driving forces of the solubilization and complexation process were revealed by evaluating the thermodynamic parameters. The distribution behavior of L-173 in the 1-octanol/buffer and 1-hexane buffer systems at pH 2.0 and pH 7.4 in the presence of different CDs concentrations was studied. The reduction of the distribution coefficients with the increasing of CD concentration was detected due to complex formation. Based on the analysis of the solubility-distribution relationship, the L-173 partitioning between the biological tissues and penetration through the biological membranes in case when cyclodextrins are used as solubilizers was evaluated, and the optimal CD concentrations were proposed.

Sulfonamides as a subject to study molecular interactions in crystals and solutions: sublimation, solubility, solvation, distribution and crystal structure.

Crystal structures of 4-amino-N-(4-chlorophenyl)-benzene-sulfonamide (IV), 4-amino-N-(2,3-dichlorophenyl)-benzene-sulfonamide (V), 4-amino-N-(3,4-dichlorophenyl)-benzene-sulfonamide (VI) and 4-amino-N-(2,5-dichlorophenyl)-benzene-sulfonamide (VII) were solved by X-ray diffraction method. Temperature dependencies of saturated vapour pressure and thermodynamic functions of sublimation process were calculated (IV: delta Gsub298=74.0 kJ mol(-1), delta Hsub298=134.1+/-1.2 kJ mol(-1), delta Ssub298=202+/-3 J mol(-1)K(-1); V: delta Gsub298=61.7 kJ mol(-1), delta Hsub298=141.1+/-0.7 kJ mol(-1), delta Ssub298=266+/-2 J mol(-1)K(-1); VI: delta Gsub298=85.8 kJ mol(-1), delta Hsub298=167.5+/-3.6 kJ mol(-1), delta Ssub298=274+/-8 J mol(-1)K(-1); VII: delta Gsub298=75.7 kJ mol(-1), delta Hsub298=155.4+/-1.6 kJ mol(-1), delta Ssub298=268+/-4 J mol(-1)K(-1)). Thermochemical parameters of fusion and evaporation processes for the compounds were obtained. Temperature dependencies of the solubility in water, n-octanol were measured. The thermodynamic functions of solubility and solvation processes were deduced. The transfer processes of the molecules from water to n-octanol were analysed by diagram method and main driven forces were established.

Influence of position and size of substituents on the mechanism of partitioning: a thermodynamic study on acetaminophens, hydroxybenzoic acids, and parabens.

The objective of the present investigation was to study the influence of size, nature, and topology of substituents on the thermodynamic characteristics of sublimation, fusion, solubility, solvation, and partitioning processes of some drug and druglike molecules. Thermodynamic functions of sublimation process 2-acetaminophen and 3-acetaminophen were obtained on the basis of temperature dependencies of vapor pressure by the transpiration method. Thermodynamic characteristics of solubility processes in water, n-octanol, and n-hexane were calculated from the temperature dependencies of solubility using the solubility saturation method. For evaluation of fusion parameters, differential scanning calorimetry was used. A new approach to distinguishing specific and nonspecific energetic terms in the crystal lattice was developed. Specific and nonspecific solvation terms were distinguished using the transfer from the "inert" n-hexane to the other solvents. For the acetaminophen compounds and for some related drug molecules, the correlation between melting points and a parameter describing the ratio between specific and nonspecific interaction in the crystal lattices was obtained. A diagram enabling analysis of the mechanism of the partitioning process was applied. It was found that for isomers of benzoic acids and for acetaminophens, the position of substituents affects the mechanism of the partitioning process but not the extent of partitioning (DeltaG(tr)(0) values). In contrast to this, an increased size of substituents (parabens) leads to essential changes in DeltaG(tr)(0) values, but the mechanism of the partitioning process stays the same.

Studying thermodynamic aspects of sublimation, solubility and solvation processes and crystal structure analysis of some sulfonamides.

Crystal structures of N-(2-chlorophenyl)-benzene-sulfonamide (I), N-(2,3-dichlorophenyl)-benzene-sulfonamide (II), N-(4-chlorophenyl)-benzene-sulfonamide (III) were solved by X-ray diffraction method. Temperature dependencies of saturated vapor pressure and thermodynamic functions of sublimation process were calculated (I: DeltaG(sub)(298)=50.4kJmol(-1); DeltaH(sub)(298)=114+/-1kJmol(-1); DeltaS(sub)(298)=213+/-3Jmol(-1)K(-1); II: DeltaG(sub)(298)=54.1kJmol(-1); DeltaH(sub)(298)=124.9+/-1.6kJmol(-1); DeltaS(sub)(298)=237+/-5Jmol(-1)K(-1); III: DeltaG(sub)(298)=49.9kJmol(-1); DeltaH(sub)(298)=98.6+/-1.9kJmol(-1); DeltaS(sub)(298)=163+/-5Jmol(-1)K(-1)). Thermochemical parameters of fusion process for the compounds were obtained. Enthalpies of evaporation were estimated from enthalpies of sublimation and fusion. Temperature dependencies of the solubility in water, n-octanol and n-hexane were measured. The thermodynamic functions of solubility and solvation processes were deduced. Specific and non-specific solvation terms were distinguished using the transfer from the "inert"n-hexane to the other solvents. The transfer processes of the molecules from water to n-octanol were analyzed and main driven forces were established.

Cocrystal formation, crystal structure, solubility and permeability studies for novel 1,2,4-thiadiazole derivative as a potent neuroprotector.

The cocrystallization approach has been applied to modify the poor solubility profile of the biologically active 1,2,4-thiadiazole derivative (TDZ). Extensive cocrystal screening with a library of coformers resulted in formation of a new solid form of TDZ with vanillic acid in a 1:1 molar ratio. The cocrystalline phase was identified and characterized by thermal and diffraction analyses including single-crystal X-ray diffraction. The energies of intermolecular interactions in the crystal were calculated by solid-state DFT and PIXEL methods. Both calculation schemes show good consistency in terms of total energy of the intermolecular interactions and suggest that the cocrystal is mainly stabilized via hydrogen bonds, which provide ca. 44% of the lattice energy. Since the cocrystal contained the hydroxybenzoic acid derivative as a coformer, the solubility profile of the cocrystal was investigated at different pHs using eutectic concentrations of the components. Furthermore, the influence of the cocrystallization on the permeability performance of the 1,2,4-thiadiazole through an artificial regenerated cellulose membrane was also evaluated. In addition, the thermodynamic functions of the cocrystal formation were estimated from the solubility of the cocrystal and the corresponding solubility of the pure compounds at various temperatures. The cocrystal formation process was found to have a relatively small value of the driving force (-5.3kJ·mol-1). The most significant contribution to the Gibbs energy was provided by the exothermic enthalpy of formation.

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%)

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, biological activity, distribution and membrane permeability of novel spiro-thiazines as potent neuroprotectors.

New spiro-derivatives of 1,3-thiazine - potential neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor-acceptor properties.