Annotation of the results obtained in 2021
Novel potential antifungal compound of 1,2,4-triazole class - 3,3`-(piperazine-1,4-diyl)bis(2-(2,4-difluorophenyl)-1-(1H-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 (pH2.0 and 7.4) two-phase systems were obtained and considered from the thermodynamic point. The delta(logD) 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. (Volkova T.V., Simonova O.R., Levshin I.B., Perlovich G.L. Physicochemical profile of new antifungal compound: pH-dependent solubility, distribution, permeability and ionization assay. J. Mol. Liq. 2021, 336, 116535. https://www.sciencedirect.com/science/article/abs/pii/S0167732221012599) 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-beta-cyclodextrin 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 1-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 ∆logD parameter coming from the difference between the distribution coefficient in octanol/water and hexane/water systems was evaluated. The permeability coefficients through the PermeapadTM 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. (Volkova T.V., Simonova O.R., Perlovich G.L. Thiazolidine-2,4-dione derivative in 2-hydroxypropyl-β-cyclodextrin solutions: Complexation/solubilization, distribution and permeability. J. Mol. Liq. 2021, 333, 115931. https://www.sciencedirect.com/science/article/abs/pii/S0167732221006589). 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, beta-CD, 2-HP-beta-CD, 6-O-Maltosyl-beta-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. 2-HP-beta-CD and 6-O-Maltosyl-beta-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-beta-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 of the permeability coefficient. According to the PermeaPad, S-119 was classified as highly permeated substance. Addition of 1.5 w/v% CDs in donor solution moves it to low-medium permeability class. (Volkova T.V., Simonova O.R., Perlovich G.L. New antifungal compound: Impact of cosolvency, micellization and complexation on solubility and permeability processes. Pharmaceutics, 2021, 13, 1865-1882. https://doi.org/10.3390/pharmaceutics13111865). The temperature dependence of the saturated vapour pressure of the antifungal drugs – tioconazole (TCZ), miconazole (MCZ) and climbazole (CLZ) – was determined by the inert gas carrier transfer method. The standard molar enthalpies of sublimation at T = 298.15 K calculated from these data were 117.2 ± 0.5 kJ∙mol-1 for TCZ 106.2 ± 0.9 kJ∙mol-1 and for MCZ 113.3 ± 1.0 kJ∙mol-1 for CLZ. The vaporization and sublimation enthalpies of the compounds were found by the Langmuir and Clausius-Clapeyron equations without determining the vapour pressures of the drugs. Sublimation enthalpies derived by both these methods were in good agreement. It was shown that it was possible to estimate the thermodynamic sublimation functions by applying the space clusterization approach to the studied and structurally related compounds. In addition, the temperature and enthalpy of fusion of the compounds were measured by differential scanning calorimetry. (Blokhina, S., Ol'khovich, M., Sharapova, A., Perlovich,G.Sublimation thermodynamics of antifungal drugs: Tioconazole, miconazole and climbazole, Fluid Phase Equil., 2021, 544-545, 113098. https://www.sciencedirect.com/science/article/pii/S0378381221001606) New thiazolo[4,5-d]pyrimidine derivatives were synthesized as potential antifungal agents. The amorphous nature of the obtained compounds was verified by DSC and PXRD. The kinetic and equilibrium solubilities of the derivatives were studied by the shake-flask method in pharmaceutically relevant solvents: buffer pH 2.0, buffer pH 7.4 and 1-octanol. It has been found that within the temperature range of (293.15–313.15) K the solubility of the compounds does not exceed 5х10E-4 mol•L-1 in aqueous solvents and 6х10E-2 mol•L-1 in alcohol. The solubility values were correlated by van't Hoff and modified Apelblat equations. Based on the partition coefficients in the system 1-octanol/ buffer pH 7.4 the lipophilicity of the compounds has been estimated. The thermodynamic functions of dissolution and partition for the compounds studied in the solvents selected were calculated. It has been established that the transfer process of compounds from the aqueous phase to the organic is endothermic and entropy-controlled. The efficiency of the some computer's programs to predict partition coefficients has been tested using experimental data. It was shown that the in vitro antifungal activity of the studied compounds increases with growth solubility in aqueous solvents. (Blokhina, S.V., Ol'khovich, M.V., Sharapova, A.V., Levshin, I.B., Perlovich, G.L. Study of dissolution and transfer processes of new bioactive thiazolo[4,5-d]pyrimidine derivatives in modeling biological systems, J. Mol. Liq., 2021, 337, 116395. https://www.sciencedirect.com/science/article/pii/S0167732221011193). A new series of hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole containing different linker skeleton and a variety of substituents (methyl-, methoxy-, chloro- and fluoro- ones) in the phenyl ring has been designed and synthesized to be used as antifungal agents. The pharmaceutically significant properties of the obtained substances - solubility and lipophilicity - were determined. The compounds with piperazine in the linker fragment exhibited the significant antifungal activity, comparable to fluconazole, against filamentous and yeast fungi: C. parapsilosis ATCC 22019, C. albicans ATCC 24433, C. albicans 8R, C. albicans CBS 8837, C. albicans 604M, C. utilis 84, C. tropicalis 3019, C. glabrata 61 L, C. krusei 432M, Cryptococcus neoformans, A.niger 37a, M. canis B-200 and T. rubrum 2002 . (Blokhina, S.V., Sharapova, A.V., Ol'khovich, M.V., Doroshenko, I.A., .Levshin, I.B., Perlovich, G.L. Synthesis and antifungal activity of new hybrids thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole. Bioorg. Med. Chem. Lett., 2021, 40, 127944. https://www.sciencedirect.com/science/article/pii/S0960894X21001700); (https://iz.ru/1166836/olga-kolentcova/konetc-sporam-v-rossii-sozdan-proryvnoi-protivogribkovyi-preparat); (https://rscf.ru/news/chemistry/konets-sporam-v-rossii-sozdan-proryvnoy/) Novel (5Z)-3-(3-(4-acetylpiperazin-1-yl)-2-hydroxypropyl)-5-(4-chlorobenzylidene) thiazolidine-2,4-dione was synthesized as a potent antimicrobial agent. Its melting enthalpy and melting point temperature were measured to be 44.4 kJ/mol and 433.9 K, respectively. The solubility of the compound studied was determined in pharmaceutically and industrially relevant organic solvents within the temperature range of 293.15–313.15 К. The solubility was found to increase in the systems with the following solvents: hexane, buffer рН 7.4, buffer рН 2.0, 1-octanol, 1-propanol, ethanol, and methanol. The compound solubility values were correlated by the modified Apelblat equation, two-suffix Margules and Wilson models with good agreement. The activity coefficients at infinite dilution and excess thermodynamic functions of the compound in eaсh solvent were calculated. The compound ability to disperse, polar and hydrogen interactions were described using Hansen solubility parameters. The temperature dependences of the distribution coefficients of the compound in 1-octanol/buffer (pH 2.0 and 7.4) two-phase systems were determined. The distribution process was characterized as thermodynamically favorable, endotermic and entropy-driven. (Blokhina, S.V., Sharapova, A.V., Ol'khovich, M.V., Levshin, I.B., Perlovich, G.L. Solid–liquid phase equilibrium and thermodynamic analysis of novel thiazolidine-2,4-dione derivative in different solvents, J. Mol. Liq., 2021, 326, 115273, https://www.sciencedirect.com/science/article/pii/S0167732220375152). A temperature dependence of saturated vapor pressure of isavuconazole (IVZ), an an-timycotic drug, was found by using the method of inert gas-carrier transfer and the thermodynamic functions of sublimation were calculated at a temperature of 298.15 K. The value of the compound standard molar enthalpy of sublimation was found to be 138.1±0.5 kJ/mol. The IVZ thermophysical properties - melting point and enthalpy equaled 302.7 K and 29.9 kJ/mol, respectively. The isothermal saturation method was used to determine the drug solubility in seven pharmaceutically relevant solvents within the temperature range from 293.15 to 313.15 K. The IVZ solubility in the studied solvents increased in the following order: buffer pH 7.4, buffer pH 2.0, buffer pH 1.2, hexane, 1-octanol, 1-propanol, ethanol. Depending on the solvent chemical nature, the compound solubility varied from 6.7х10E-6 to 0.3 mol/L. The Hansen’s approach was used for evaluating and analyzing the solubility data of drug. The results show that this model well-described intermolecular interactions in the solutions studied. It was established that in comparison with the van’t Hoff model, the modified Apelblat one ensured the best correlation with the experimental solubility data of the studied drug. The activity coefficients at infinite dilution and dissolution excess thermodynamic functions of IVZ were calculated in each of the solvents. Temperature dependences of the compound partition coefficients were obtained in a binary 1-octanol/buffer pH 7.4 system and the transfer thermodynamic functions were calculated. The drug distribution from the aqueous solution to the organic medium was found to be spontaneous and entropy-driven.(Ol’khovich, M., Sharapova, A., Blokhina, S., Perlovich, G. Isavuconazole: Thermodynamic evaluation of processes sublimation, dissolution and partition in pharmaceutically relevant media. Molecules, 2021, 26(16), 4759. https://www.mdpi.com/1420-3049/26/16/4759). Solubility of antifungal drug miconazole in pharmaceutically relevant solvents were measured by the shake-flask method in the temperature range between 293.15 –313.15 K. The solubility of compound in selected solvents increases in the following order: buffer pH 7.4, buffer pH 2.0, hexane, 1-octanol. It is shown that the modified Apelblat equation give better correlation results with the experimental data than Hoff equation and Two-Suffix Margules model. The HSPs were employed to study the miscibility of drug with all of tested solvents. The calculation of the thermodynamic functions of drug solubility and solvation in the selected solvents was performed. The excess Gibbs energy and the activity coefficients of MCZ were also calculated. The temperature dependence of the partition coefficients of the compound studied in the 1-octanol/buffer pH 7.4 system was determined and thermodynamic quantities for the transfer of this drug from water phase to organic one were obtained. (Sharapova A., Blokhina S., Ol’khovich M., Perlovich G. Thermodynamic analysis of solubility, distribution and solvation of antifungal miconazole in relevant pharmaceutical media, J. Mol. Liq. 2021.) Based on the literature analysis, we have built a database containing fusion temperatures and enthalpies of two-component molecular co-crystals and individual compounds (2170 co-crystals). The distribution functions of two-component crystals have been analysed using their fusion temperatures, both for the database as a whole and separately for Drug-Drug, Drug-GRAS, Drug-CF, and CF1-CF2 databases. A comparative analysis has been done of the co-crystal distribution by classes of compounds - I (“Between”), II (“Higher”) and III (“Low”) - for the general database and six small databases. Correlation equations connecting the melting points of the co-crystals and individual components have been obtained, which has enabled us to design co-crystals with predictable melting temperatures. It has been analyzed how the difference between the melting temperatures of individual co-crystal components affects the probability of formation of co-crystals of different groups (I, II, III). An approach has been developed for evaluating the ideal solubility of co-crystals based on the knowledge of the ideal solubility of one of the co-crystal individual components only. (Perlovich G.L. Two-Component Molecular Crystals: What Is the Difference between Drug−Drug, Drug−GRAS, and CF−CF Databases? Evaluation of Melting Points and Ideal Solubility of Unknown Co-crystals. Crystal Growth & Design, 2021. 21(9), 5058-5071. https://doi.org/10.1021/acs.cgd.1c00477) Isavuconazole (ISV) is a systemic antifungal agent which is used to treat invasive aspergillosis, mucormicosis and candidiasis. Although both oral and intravenous dosage forms of this drug exist on the market, the crystal structure and physicochemical properties of ISV as well as possible alternative solid forms are yet unexplored in the literature. In the present work, the solid form landscape of isavuconazole including solvate, polymorph and salt screening was studied systematically. The solid-state properties of initial crystalline ISV and newly obtained forms (ISV monohydrate, two amorphous forms obtained by different means and two pharmaceutical salts with p-toluenesulfonic and phosphoric acids) were described for the first time. The structures of all crystalline forms were solved based on the single crystal X-Ray diffraction data, and the packing forces in the considered solids were studied using different theoretical approaches. The transformation pathways between the ISV solid forms were investigated experimentally and rationalized based on the DFT computations and non-covalent interaction analysis. It was observed that crystalline isavuconazole does not transform into the hydrate upon dissolution, in contrast to other solid forms. The amorphous and salt forms of ISV were found to demonstrate a spring-like increase of the drug concentration in pharmaceutically relevant buffer media. The tableting of the pharmaceutical salts leads to slower phase transformation into the ISV hydrate and prolonged drug supersaturation. (Voronin A.P., Vasilev N.A., Surov A.O., Churakov A.V., Perlovich G.L. Exploring the solid form landscape of antifungal drug Isavuconazole: crystal structure analysis, phase transformation behavior and dissolution performance. CrystEngComm, 2021, DOI: 10.1039/D1CE01353J) In this work, the cocrystallization approach was applied to itraconazole (ITR), a very slightly soluble triazole antifungal drug, which led to the formation of two new solid forms of ITR with 4-aminobenzoic acid (4AmBA) and 4-hydroxybenzamide (4OHBZA). A thermodynamic analysis of the solid-liquid binary phase diagrams for the (ITR+4AmBA) and (ITR+4OHBZA) systems provided conclusive evidence of the cocrystal stoichiometry: 1:1 for the cocrystal with 4-aminobenzoic acid, and 1:2 for the cocrystal with 4-hydroxybenzamide. In addition, two distinct polymorphic forms of the [ITR+4OHBZA] (1:2) cocrystal were obtained either through solution or melt crystallization and the latter process was investigated in detail by the DSC and HSM methods. The thermodynamic functions of cocrystal formation were estimated from the solubility of the cocrystals and the corresponding solubility of the pure compounds at different temperatures. The combination of ITR and 4OHBZA was found to be more favorable than the reaction between ITR and 4AmBA in terms of both Gibbs energy and enthalpy. The pH-solubility behavior of the cocrystals was investigated at different pH values using eutectic concentrations of the components and the cocrystal solubility advantage was estimated. The cocrystal dissolution behavior in biorelevant media was analyzed in terms of Cmax, σmax parameters (maximum ITR concentration and supersaturation), and AUC (concentration area under the curve during the dissolution – supersaturation – precipitation process). The cocrystals had similar σmax values during the dissolution and sustained supersaturation for up to 6 hours, which gave them an advantage in the AUC values over the drug (13 to 37 times higher). The differences in the dissolution profiles of the cocrystals were rationalized in terms of their dissolution rate values. (Vasilev, N.A., Surov, A.O., Voronin, A.P., Drozd, K.V., Perlovich, G.L. Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility. Int. J. Pharm., 2021. 599, 120441. quartile 1; IF = 5.875; DOI: 10.1016/j.ijpharm.2021.120441). https://minobrnauki.gov.ru/press-center/news/?ELEMENT_ID=31770 https://yandex.com/turbo/glasnarod.ru/h/nauka/386228-preparaty-ot-gribkovyx-zabolevanij-stanut-luchshe-blagodarya-sokristallam?utm_source=yxnews&utm_medium=desktop https://www.ivanovonews.ru/news/1079666/ https://nauka.tass.ru/nauka/11036675?utm_source=yxnews&utm_medium=desktop https://new.iluki.ru/news/Uchenyye-iz-Ivanovo-pridumali-kak-effektivneye-lechit-gribok https://sm.news/ijp-ivanovskie-uchenye-pridumali-effektivnyj-sposob-lecheniya-gribka-70968/?utm_source=yxnews&utm_medium=desktop https://rossaprimavera.ru/news/c053b744?utm_source=yxnews&utm_medium=desktop The thermophysical characteristics and decomposition of pyrazinoic (POA), dipicolinic (DPA), and quinolinic (QNA) acids have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The transpiration method has been used to measure the vapour pressures as a function of the POA, DPA or QNA temperature. It has been found that QNA remains thermally stable in the solid form up to the temperature of 367.15 K, and further heating causes its decarboxylation and irreversible conversion to nicotinic acid. The standard molar enthalpies, entropies, and Gibbs energies of sublimation for POA, DPA and QNA have been calculated. A comparative study of five calculation schemes for sublimation enthalpy estimation (periodic Density Functional Theory computations (DFT-D3), Quantum Theory of Atoms in Molecules (QTAIM), Gavezzotti’s Coulomb-London-Pauli model (CLP and PIXEL) and CrystalExplorer CE-B3LYP) has been conducted. The sublimation thermodynamic functions of the compounds studied by the correlation method have been estimated. When applied to the objects of this study, the method proved to be a quick, convenient and inexpensive way to evaluate the sublimation thermodynamic functions of molecular crystals using only the melting temperature of the compound. (Drozd, K.V., Manin, A.N., Voronin, A.P., Perlovich, G.L. Sublimation thermodynamics of pyrazinoic, dipicolinic and quinolinic acids: Experiment and theoretical prediction. J. Chem. Thermodynamics, 2021, 155, 106369. https://doi.org/10.1016/j.jct.2020.106369) Experimental and theoretical screening of multi-component crystal forms of miconazole (MCL), an antifungal drug, with ten aliphatic dicarboxylic acids was performed. Seven multi-component molecular crystals were isolated and identified by different analytical techniques, including the powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and solubility methods. The crystal structures of the MCL hemihydrate, two cocrystals with succinic ([MCL+SucAc] (2:1)) and fumaric acids ([MCL+FumAc] (2:1)) and one salt with maleic acid ([MCL+MleAc] (1:1)) were redetermined. The new cocrystal of MCL with adipic acid ([MCL+AdpAc] (2:1)) was investigated by single crystal X-ray diffractometer. The combination of periodic density functional theory (DFT) computations and quantum topology analysis confirmed the structure-directing role of the acid-imidazole heterosynthon for the considered crystals. The melting temperatures of all the studied multicomponent crystals are between the values of the corresponding individual components except [MCL+MleAc] (1:1). A thermal analysis has shown that the thermodynamic and thermophysical characteristics of the considered two-component molecular crystals are strongly dependent both on specific interactions (presence of sites of donor–acceptor interactions and hydrogen bond formation) and on nonspecific interactions – molecule polarizability. Based on the sublimation thermodynamics database of molecular crystals, the standard sublimation thermodynamic functions of MCL were evaluated. The thermodynamic functions of multi-component crystal formation based on MCL were calculated and analyzed. Solubility experiments on the MCL multi-component crystals were carried out in isotonic aqueous buffer solutions at pH 1.2 and 6.8 and compared with the solubility of the MCL free base and its nitrate salt. It was found that the salt/cocrystal formation of MCL with dicarboxylic acids considerably increased the MCL solubility in pH 6.8 buffer. The biggest MCL solubility enhancement was observed in the [MCL+TartAc] (1:1) salt. The solubility value of MCL in the [MCL+TartAc] (1:1) salt is commensurate with the commercial MCL nitrate salt. (Drozd, K.V., Manin, A.N., Voronin, A.P., Boycov, D.E., Churakov, A.V., Perlovich, G.L. A combined experimental and theoretical study of miconazole salts and cocrystals: crystal structures, DFT computations, formation thermodynamics and solubility improvement. Physical chemistry chemical physics, 2021, 23(21), 12456-12470. https://doi.org/10.1039/D1CP00956G) New multicomponent crystals of climbazole (CLB) with fumaric acid (FumAc) and tioconazole (TCL) with oxalic (OxlAc), malonic (MlnAc), fumaric and DL-tartaric (TartAc) acids were obtained by liquid-assisted grinding. The single crystals of climbazole were obtained for the first time and the crystal structure was characterized. The crystal structures of four studied multicomponent crystals ([CLB+FumAc] cocrystal (2:1), [TCL+MlnAc] salt (1:1), [TCL+FumAc] salt (1:1), [TCL+TartAc+H2O] salt (1:1:1)) for which single crystals were obtained by slow evaporation form solution, were determined. Influence of coformers structure of multicomponent crystals on CLB and TCL conformationally flexibility was discussed. Thermal analysis of studied multicomponent crystals was carried out. It was observed, that melting temperatures of CLB and TCL multicomponent crystals are between melting temperatures of coformers and APIs. The [TCL+TartAc+H2O] salt (1:1:1) dehydration mechanism was analyzed by thermogravimetric method, differential scanning calorimetry and thermomicroscopy. According to the thermal analysis data, it was determined, that after the completion of the [TCL+TartAc+H2O] salt (1:1:1) dehydration process follows the eutectic mixture melting and crystallization of anhydrous [TCL+TartAc] salt (1:1). Multicomponent crystals solubility study was carried out in phosphate buffer solution at pH 6.8. It was confirmed, that cocrystallization/salt formation of the studied APIs with dicarboxylic acids allows not only to significantly improve their solubility, but also to maintain the level of supersaturation in solution for a sufficiently long time. Drozd K.V., Manin A.N., Boycov D.E., Churakov A.V., Perlovich G.L. Pharmaceutical multicomponent crystals of antifungal drugs with improved dissolution performance. Crystal Growth & Design, 2021, doi/10.1021/acs.cgd.1c01139. (quartile 1; IF = 4.076; https://pubs.acs.org/doi/10.1021/acs.cgd.1c01139) The influence of multicomponent crystals of miconazole with succinic, tartaric and maleic acids preparation methods on the dissolution parameters is analyzed. According to the time to reach and the value of the maximum concentration of miconazole in solutions, the synthesis methods can be arranged in the following order: liquid-assisted grinding method <slurry method <freeze-drying technique. The advantage in the dissolution parameters of the samples obtained by freeze drying is explained by the high dispersion of the system, the smallest crystallite size in comparison with the samples obtained by other methods. However, several days after the preparation of the samples, the degree of dispersion of the system decreases and the parameters of salt dissolution decrease. The most stable samples with the smallest particle size are salts prepared by the slurry method. Therefore, it was this preparation technology that was used to obtain the required quantities of samples for biological tests on rabbits. The obtained pharmacokinetic curves of the concentration of miconazole in the blood plasma of rabbits after intragastric administration of Miconazole and its co-crystal [Miconazole + Succinic acid] and salts [Miconazole + Tartaric acid], [Miconazole + Maleic acid] aqueous suspensions showed that the salt of miconazole with tartaric acid significantly increases the bioavailability of miconazole relative to the introduction of the pure miconazole substance.

 

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Annotation of the results obtained in 2019
Equilibrium solubility of clotrimazole, an important antimycotic drug, was measured between (293.15-313.15) K in four pharmaceutically relevant solvents including buffer pH 2.0, buffer pH 7.4, hexane and 1-octanol. The experimental solubility results were correlated by modified Apelblat and van’t Hoff equations. The compound melting temperature and enthalpy were determined. The activity coefficients at infinite dilution of clotrimazole in each solvent were calculated from experimental data on solubility and thermophysical properties. Substitution aqueous solvents for organic ones leads to lower activity coefficients and higher solubility of the drug. The limiting partial molar excess enthalpies, entropies and Gibbs energies of clotrimazole were evaluated. (S. Blokhina, A. Sharapova, M. Ol’khovich, G. Perlovich, Experimental solubility of clotrimazole and some thermodynamic aspects of dissolution in different solvents, Thermochimica Acta, Vol. 682, 2019, 178431. DOI:10.1016/j.tca.2019.178431) In this work, a database containing thermochemical and structural information about 208 monotropic polymorphic forms has been created and analyzed. Most of the identified compounds (77 cases) have been found to have two polymorphs, 14 compounds had three forms, and there were only three examples of systems with four polymorphs. The analysis of density distribution within the database has revealed that only 62 out of 114 metastable polymorphs (referred to as group I) obey the “density rule” proposed by Burger and Ramburger, while the rest 45% of the monotropic systems (group II) violate the rule. A number of physicochemical, structural and molecular descriptors have been used to find and highlight the differences between group I and group II of the polymorphs. Group II is characterized (on average) by higher values of descriptors, which are responsible for conformational flexibility of molecules. An algorithm has been proposed for carrying out bivariate statistical analysis. It implies partitioning the database into structurally related clusters based on Tanimoto similarity coefficients and subsequent analysis of each cluster in terms of the number of hydrogen bonds per molecule. (Perlovich G.L., Surov A.O. Polymorphism of Monotropic Forms: Relationships of Thermochemical and Structural Characteristics. Acta Cryst. B 2019, in press. (quartile 1; IF = 6.732 (2018);) Through cocrystallization of the broad-spectrum antifungal agent fluconazole (FLZ) with a number of nutraceuticals, we have isolated three distinct solid forms of the drug, namely anhydrous cocrystal with vanillic acid (VA), anhydrous and hydrated cocrystals of 4-hydroxybenzoic acid (4OHBA). The new cocrystals have been thoroughly investigated by different analytical techniques, including powder and single crystal X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), scanning electron microscopy (SEM), dissolution and solubility methods. Analysis of hydrogen bond patterns in the crystals has shown structural similarity in the packing of FLZ molecules between the new crystal forms and the structures taken from the CSD. Comparing the theoretical lattice energies of multicomponent crystals and their constituents, we have found that hydrated crystal forms are more energetically preferable than the anhydrous cocrystals. Analysis of non-covalent interaction energies performed within the framework of quantum theory of atoms in molecules and crystals (QTAIMC) has confirmed the structure-forming role of water molecules in the hydrated cocrystal of FLZ with 4OHBA. Thermal analysis and SEM investigations have shown that the dehydration behavior of FLZ monohydrate (FLZ•H2O) is highly sensitive to particle size and morphology of crystals. The pH-solubility behavior of the cocrystals has been investigated at different pHs using eutectic concentrations of the components, and the driving force of the cocrystal formation process for each solid phase has been estimated. Possible cocrystallization pathways between FLZ and 4OHBA have been examined under mechanochemical conditions. A two-step formation mechanism of cocrystallization reaction, which includes generation of an anhydrous [FLZ+4OHBA] (1:1) cocrystal as an intermediate, has been proposed. (Surov A.O., Voronin A.P., Vasilev N.A., Churakov A.V., Perlovich G.L. Cocrystals of fluconazole with aromatic carboxylic acids: competition between anhydrous and hydrated solid forms. Crystal Growth & Design, 2019, accepted (quartile 1; IF = 4.153))

 

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Annotation of the results obtained in 2020
Based on the literature analysis, we have built a database containing fusion temperatures of two-component molecular co-crystals and individual compounds (1947 co-crystals/salts). In order to estimate the thermodynamics of formation of two-component crystals, we have created a database on the basis of the values reported in the literature from 1900 till 2019 inclusive. The database includes the enthalpies and Gibbs energy values of individual molecular crystals obtained by various methods. A new algorithm for estimating the sublimation Gibbs energies of molecular crystals has been developed based on their sublimation enthalpies only. The algorithm divides the database into clusters including structurally related compounds. Using this approach, we have calculated the sublimation Gibbs energies for 269 crystals, whose sublimation enthalpies were obtained by the calorimetric method. The thermodynamic functions of the formation process of 509 co-crystals have been obtained and analyzed. The diagram method has been used to analyze the parameters under study. An analysis of the experimental data distribution in the diagram sectors has shown that the number of two-component crystals with enthalpy-driven processes of co-crystal formation corresponds to 70.8 %, whereas of those with entropy-driven processes – to 29.2 %. A detailed comparative analysis of the thermodynamic functions of co-crystal formation has been carried out for different monotropic polymorphic forms, two-component crystals with the same composition and different stoichiometry, and two-component crystals based on racemate and enantiomers. (Perlovich G.L. Formation thermodynamics of two-component molecular crystals: Polymorphism, stoichiometry and impact of enantiomers. Crystal Growth & Design, 2020, 20(8), 5526-5537. (https://dx.doi.org/10.1021/acs.cgd.0c00695 )) (https://www.kommersant.ru/doc/4458186) (https://www.gazeta.ru/science/news/2020/08/25/n_14844901.shtml ) (https://indicator.ru/chemistry-and-materials/baza-dvukhkomponentnykh-kristallov-pomozhet-sozdat-lekarstva-novogo-pokoleniya-22-08-2020.htm) ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Based on the review of the literature results the database of the fusion temperatures of two-component molecular crystals (1947 co-crystals) and individual components thereof was built up. To improve the design of co-crystals with predictable melting temperatures, the correlation equations connecting co-crystals and individual components melting points were deduced. These correlations were discovered for 18 co-crystals of different stoichiometric compositions. The correlation coefficients were analysed, and the conclusions about the main/determinative and slave components of co-crystal were made. The comparative analysis of the melting points of co-crystals composed from the same components but different stoichiometry showed a co-crystal melting temperature growth when increasing the content of a high-melting component. The differences in the melting temperatures were determined and discussed for the following: a) monotropic polymorphic forms; b) two-component crystals with the same composition and different stoichiometry, and c) two-component crystals based on racemates and enantiomers. The database analysis revealed the active pharmaceutical ingredients (APIs) and co-formers (CFs) more particularly used for co-crystal design. The approach based on an efficacy parameter allowing predicting co-crystals with melting points lower than those of individual compounds was developed. (Perlovich G.L. Melting points of one- and two-component molecular crystals as effective characteristics for rational design of pharmaceutical systems. Acta Cryst. 2020, B76, 696-706. (https://doi.org/10.1107/S2052520620007362 )) --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 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 beta-cyclodextrin (beta-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-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-beta-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. (Volkova T.V., Perlovich G.L. Comparative analysis of solubilization and complexation characteristics for new antifungal compound with cyclodextrins. Impact of cyclodextrins on distribution process. European Journal of Pharmaceutical Sciences 2020, 154, 105531. (https://www.sciencedirect.com/science/article/pii/S0928098720303195 )) (https://indicator.ru/chemistry-and-materials/sakharnaya-obolochka-uluchshila-rastvorimost-protivogribkovogo-preparata-05-10-2020.htm) (https://www.gazeta.ru/science/news/2020/10/05/n_15035941.shtml) -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 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 del(logD) parameter determined from the distribution experiment clearly demonstrated the preference of lipophilic delivery pathways for L-173 in the biologic media. (Volkova T.V., Levshin I.B., Perlovich G.L. New antifungal compound: Solubility thermodynamics and partitioning processes in biologically relevant solvents. J. Mol. Liq. 2020, 310, 113148 (https://www.sciencedirect.com/science/article/pii/S0167732220315786 )) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ 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 9.0x10E-4mol/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 - 1.3x10E-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 logPO/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. (Blokhina S.V., Ol'khovich M.V., Sharapova A.V., Levshin I.B., Perlovich G.L. Thermodynamic insights to solubility and lipophilicity of new bioactive hybrids triazole with hiazolopyrimidines. J. Mol. Liq. 2020, 114662 (https://www.sciencedirect.com/science/article/pii/S016773222036904X?dgcid=coauthor)) -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- The solubility of the antifungal drug fluconazole in buffer solutions of different acidity (рН 1.2, 2.0 and 7.4), 1-octanol and hexane in the temperature range (293.15-313.15) K is determined by the isothermal saturation method. The solubility of the compound in selected solvents increases as follows: hexane, buffer рН 7.4, buffer рН 2.0, 1- octanol, buffer рН 1.2, and does not exceed 0.2 mol•l-1. The temperature dependence of fluconazole saturated vapor pressure is obtained by the transpiration method. The sublimation enthalpy of the compound equals 131.4 ± 0.9 kJ∙mol-1. Based on the HYBOT descriptors, it is shown that it is possible to estimate the sublimation enthalpy of compounds structurally similar to fluconazole. (Blokhina S., Ol'khovich M., Sharapova A., Perlovich G. Experimental investigation of fluconazole: Equilibrium solubility and sublimation. J. Chem. Thermodyn. 2020, 151, 106243. (https://doi.org/10.1016/j.jct.2020.106243))

 

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