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The present study reports the effects of two pharmaceutical excipients of differing natures—non-ionic surfactant pluronic F127 (F127) and anionic sulfobutylether-β-cyclodextrin (SBE-β-CD)—on the permeation of the model compound, carbamazepine (CBZ). The permeability coefficients of CBZ at three concentrations of the excipients were measured through two different artificial barriers: hydrophilic cellulose membrane (RC) and lipophilic polydimethylsiloxane–polycarbonate membrane (PDS). The equilibrium solubility of CBZ in F127 and SBE-β-CD solutions was determined. The micellization, complexation, and aggregation tendencies were investigated. Systemically increasing the solubility and the reduction of permeation upon the excipients' concentration growth was revealed. The quantitative evaluation of the permeability tendencies was carried out using a Pratio parameter, a quasi-equilibrium mathematical mass transport model, and a correction of permeability coefficients for the free drug concentration ("true" permeability values). The results revealed the mutual influence of the excipient properties and the membrane nature on the permeability variations. [ABSTRACT FROM AUTHOR]

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-β-CD and SBE-β-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-β-CD due to the charge–charge attraction and electrostatic interactions between NTT and SBE-β-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT's association with SBE-β-CD than that with HP-β-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers. [ABSTRACT FROM AUTHOR]

The main aims of the study were to disclose the influence of the structure on the solubility, distribution and permeability of the parent substances, iproniazid (IPN), isoniazid (INZ) and isonicotinamide (iNCT), at 310.2 K and to evaluate how the presence of cyclodextrins (2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and methylated β-cyclodextrin (M-β-CD)) affects the distribution behavior and diffusion properties of a model pyridinecarboxamide derivative, iproniazid (IPN). The following order of decreasing the distribution and permeability coefficients was estimated: IPN > INZ > iNAM. A slight reduction of the distribution coefficients in the 1-octanol/buffer pH 7.4 and n-hexane/buffer pH 7.4 systems (more pronounced in the first system) was revealed. The extremely weak IPN/cyclodextrins complexes were estimated from the distribution experiments: KC(IPN/HP-β-CD) > KC(IPN/M-β-CD). The permeability coefficients of IPN through the lipophilic membrane—the PermeaPad barrier—were also measured with and without cyclodextrins in buffer solution. Permeability of iproniazid was increased in the presence of M-β-CD and reduced by HP-β-CD. [ABSTRACT FROM AUTHOR]

This study describes the influence of pluronic F-127 (F-127) and ethanol (EtOH) on the solubility of umifenovir (UMF) in buffer solutions of pH 2.0 and pH 7.4, and its permeability through cellulose membranes. A 44.4-fold greater UMF solubility in acidic medium as compared to an alkaline one was estimated at 310.15 K. The concentration of UMF in the saturated solution was enhanced by the interaction with F-127 micelles. The combined positive effect of EtOH and F-127 on the solubility was estimated. The aggregation number of F-127 micelles in the presence of 10% and 20% ethanol appeared to be reduced by 2.1-fold and 4.1-fold, respectively, as compared to buffer pH 7.4. The presence of ethanol in buffer pH 7.4 solution provided better solvent conditions but inhibited the formation of F-127 micelles. The impact of UMF on the aggregation number of F-127 was not pronounced and was expressed only by a slight increase of 1 and 3 units in 10% and 20% EtOH, respectively. According to the values of zeta potential, addition of EtOH reduced the stability of the system. The permeation of UMF in buffer pH 7.4 measured through the cellulose membrane MWCO 12–14 kDa was increased 1.4-fold by 10% EtOH. An increase in EtOH content to 20% reduced this effect to 1.2-fold. Decreasing effect of 1.5% F-127 on the permeability was inhibited by using 10% EtOH. The solution containing 1.5% F-127 and 10% EtOH was shown to be an advantageous system for UMF in view of the solubility–permeability balance. The authors suppose the findings of the study to be useful for the design of pharmaceutical formulations based on UMF antiviral drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-β-CD) and acetylated (Ac-β-CD) β-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-β-CD as compared to Me-β-CD was revealed. The solid dispersion of BCL with Ac-β-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-β-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-β-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-β-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 A U C C (t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-β-CD (HPMC), BCL/Ac-β-CD (PVP), BCL/Ac-β-CD (buffer), and the BCL/Ac-β-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-β-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. [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]

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. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Cyclodextrin's Effect on Permeability and Partition of Nortriptyline Hydrochloride" published in the journal Pharmaceuticals. The correction addresses an error in Figure 2 of the original publication, specifically the location of the diagrams in Figure 2a,b. The corrected figure has been provided, and the authors state that the scientific conclusions remain unaffected. The original publication has been updated to reflect this correction. [Extracted from the article]

5-Fluorouracil (5FU) is a BCS class III drug with good aqueous solubility and poor permeability, which severely limits its transdermal permeation through the stratum corneum. Herein, four cocrystals of 5FU with a series of isomeric hydroxybenzoic acids, including salicylic acid (2 : 1), 3-hydroxybenzoic acid (1 : 1) and 4-hydroxybenzoic acid (forms I and II, 1 : 1) were prepared and subjected to membrane permeation. They exhibited significantly improved membrane permeability due to the lipid solubility enhancement caused by cocrystallization. Solid-state DFT computations followed by Bader analysis based on single crystal structures were carried out to quantify the pattern of non-covalent interactions in the cocrystals. The lattice energy values were estimated as a sum of energies of non-covalent intermolecular interactions, which show a negative correlation with the lipid solubility of 1 : 1 cocrystals. This study has important implications for the use of the cocrystallization approach to improve the permeability of transdermal drugs. [ABSTRACT FROM AUTHOR]

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, β-CD, 2-HP-β-CD, 6-O-Maltosyl-β-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. Additionally, 2-HP-β-CD and 6-O-Maltosyl-β-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-β-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. [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] • Distribution and permeability of amitriptyline hydrochloride was studied at several temperatures and pH. • Distribution thermodynamics in 1 -octanol/ and n -hexane/buffer systems was disclosed. • Reduction of the permeability with the pH decrease was revealed. • Compound was shown to be highly permeated at pH 4.0 and pH 6.8. The partition and permeation processes for ionizable tricyclic antidepressant amitriptyline hydrochloride (AMT•HCl) were studied. The apparent distribution coefficients in 1 -octanol/aqueous buffer and n -hexane/aqueous buffer systems were determined at 6 temperatures (293.15–313.15 K). The thermodynamics and driving forces of the process were examined by calculating the main transfer thermodynamic parameters: Δ G tr 0 , Δ H tr 0 and Δ S tr 0. The distribution experiments were carried out at different pH of the aqueous phase: pH 2.0, pH 4.0 and pH 6.8 from which the impact of the ionization state on the compound transferring was disclosed. To help explaining the distribution behavior, the data on the solubility in n -hexane (determined herein) and 1 -octanol (from literature) were drawn into consideration. Two artificial membranes were used to investigate the permeability and to disclose the influence of the lipid layer in the content of the membrane. [ABSTRACT FROM AUTHOR]

[Display omitted] • Permeability of 34 diverse drug compounds through the PermeaPad was determined. • Reliable permeability correlations in the framework of the solubility-diffusion theory were estimated. • Impact of pH and cyclodextrin on the permeability was disclosed. Evaluation of permeability of drugs and drug-like compounds is a complicated task. In the present study in order to construct the predictive schemes of passive diffusion permeation for a set of drugs with diverse structure their permeability was determined using a lipophilic biomimetic membrane - PermeaPad barrier and the vertical-type Franz diffusion cell. Permeability coefficients were analyzed and correlated to physicochemical properties and structure descriptors. The best fitting equations were derived using the solubility of the studied compounds in 1-octanol and in the frameworks of the solubility-diffusion theory. The impact of pH and addition of 2-hydroxypropyl-β-cyclodextrin on the permeability of two selected amphiphilic compounds has been disclosed. [ABSTRACT FROM AUTHOR]

Since a majority of drug substances are poor soluble in aqueous solutions, suitable drug formulations are often used. Among others, the cyclodextrin-based pharmaceutical products have been shown to be successful for a large variety of drugs. In this study, based on the results of previous investigation on the solubility of novel potential antifungal compound (5Z)-3-(3-(4-acetylpiperazin-1-yl)-2-hydroxypropyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (TZD) in pure solvents, the overall physicochemical study of solubility, distribution and membrane permeability of this compound in the presence of 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD) was carried out in buffer solutions at pH 2.0 and pH 7.4. In order to estimate the driving forces of the solubilization, complexation and partition processes representing a particular importance for the prediction of drug behavior in biological media, the solubility and distribution experiments were performed in the range of 298.15–313.15 K. The distribution behavior of TZD in the 1-octanol/buffer and n-hexane buffer systems at pH 2.0 and pH 7.4 in the presence of 0.01 M 2HP-β-CD was studied. In order to elucidate a role of hydrogen bonding, the ∆ log D parameter coming from the difference between the distribution coefficient in octanol/water and hexane/water systems was evaluated. The permeability coefficients through the Permeapad™ barrier from buffer pH 2.0 and pH 7.4 to buffer pH 7.4 have been determined in the presence of 2HP-β-CD in order to evaluate the permeation of TZD across the stomach and intestine membranes, respectively. [Display omitted] • Thiazolidine-2,4-dione derivative (TZD) was studied in 2-HP-β-CD solutions. • Stability constant of TZD/CD complex belongs to the optimal bioavailability range. • Distribution experiments showed good potential gastrointestinal absorption. • Driving forces of the complexation, solubilization and distribution were revealed. • Optimal cyclodextrin concentrations were proposed by the permeability assay. [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]

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 (− 5.3 kJ·mol − 1 ). The most significant contribution to the Gibbs energy was provided by the exothermic enthalpy of formation. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

• New potential antifungal compound was synthesized and characterized. • Solubility in pharmaceutically relevant media was measured and modeled. • Distribution was evaluated using ΔlogD and thermodynamic parameters. • Permeability coefficient was determined and evaluated. Novel potential antifungal compound of 1,2,4-triazole class − 3,3'-(piperazine-1,4-diyl)bis(2-(2,4-difluorophenyl)-1-(1 H -1,2,4-triazol-1-yl)propan-2-ol) (S-119) - has been synthesized and characterized. Solubility in buffer solutions (pH 2.0 and 7.4), 1-octanol, n-hexane, and ethanol was measured by the isothermal saturation method in the temperature range (293.15–313.15 K). The following order of the solubility was revealed: ethanol > buffer pH 2.0 > 1-octanol > buffer pH 7.4 > n-hexane. The solubility was correlated by the Van't Hoff and Apelblat equations. The Hansen solubility parameters were applied to solubility evaluation and demonstrated the consistency with the experimental data. The thermodynamic parameters of solubility and transfer processes were calculated and discussed in view of solute–solvent interactions. The temperature dependences of the distribution coefficients of S-119 in 1-octanol/buffer and n-hexane/buffer (pH 2.0 and 7.4) two-phase systems were obtained and considered from the thermodynamic point. The ΔlogD parameter determined from the distribution experiment clearly demonstrated the preference of lipophilic delivery pathways for S-119 in the biologic media and unfavorable transition to the non-polar regions. Membrane permeability coefficient of S-119 was determined and evaluated with the assistance of the respective parameter for the structurally related drug fluconazole. [ABSTRACT FROM AUTHOR]

Four novel potential antifungal 1,2,4-triazole hybrids of thiazolopyrimidines with different - methyl-, methoxy-, chloro-, and fluoro- substituents in the molecule phenyl ring were synthesized and characterized by 1H NMR spectra. The PXRD and DSC techniques showed that the solid phases of the obtained compounds were amorphous. The kinetic solubility of the substances was studied in aqueous media of various acidity degrees. The equilibrium solubility of the derivatives was determined in buffers (pH 2.0 and 7.4) and 1-octanol at (293.15–313.15) K by the shake flask method. The compound solubility in the buffers did not exceed 9.0∙10−4 mol/L and decreased when the substituent was changed as follows: methoxy-, methyl-, chloro-, and fluoro-. The methoxy-derivative was found to have the more higher solubility in 1-octanol - 1.3∙10−2 mol∙L−1 at 298.15 K. The solubility behavior of the substances was studied based on Hansen solubility parameters. The solubility values were correlated by the modified van't Hoff and modified Apelblat equations. The best result was achieved with the modified Apelblat model. The partition coefficients of the compounds in the 1-octanol/buffer pH 7.4 system were determined at (293.15–313.15) K. The log P O/B values of the substances ranged from 0.80 to 1.27 at 298.15 K, depending on the chemical nature of the substituents that indicates to good balance between their solubility and permeability. The thermodynamic functions of dissolution and partition for the compounds studied in the solvents selected were calculated. A diagram approach was used to analyze the enthalpy and entropy contributions to the Gibbs energy of dissolution of the substances studied. • Solubility of four new bioactive compounds in 1-octanol, buffers (pH 2.0 and 7.4). • Correlations by the van't Hoff and modified Apelblat equations for solubility data. • Partition coefficients of compounds studied in 1-octanol/buffer pH 7.4 system. • Combination Hansen solubility parameter with solubility behavior. • Thermodynamic functions of dissolution and partition in model solvents. [ABSTRACT FROM AUTHOR]