Nikita Vasilev | G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences (original) (raw)
Papers by Nikita Vasilev
125793, 2024
In this study, we have analyzed the thermodynamic formation functions for four multi-component cr... more In this study, we have analyzed the thermodynamic formation functions for four multi-component crystals based on the solubility data in the range of 293.15-313.15 K. The investigation was performed for the cocrystals of fluconazole (FLZ) with 4-hydroxybenzoic (4OHBA) and vanillic (VA) acids, and salts of fenbendazole (FNB) with maleic (Mal) and oxalic (Ox) acids. A database on the thermodynamic parameters of the multi-component molecular crystals (Gibbs free energy, enthalpy, and entropy) obtained in this study and borrowed from the literature was created. These parameters were determined using the experimental data on the solubility of the individual components and the product of the solubilities of the multi-component crystals at 298.15 K. A regression model was proposed to estimate the solubility product of the two-component crystals using the intrinsic solubility of the individual components as an independent variable. A detailed analysis of the database disclosed the relationship between the entropy term and the molecular volume of the multi-component crystal formation.
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Olaparib (OLA) is an insoluble targeting antitumor drug for the treatment of ovarian cancer. Here... more Olaparib (OLA) is an insoluble targeting antitumor drug for the treatment of ovarian cancer. Herein, polyamorphism of OLA was systematically studied aiming to improve its solubility and dissolution properties. Three amorphous forms of OLA were prepared by ball milling (form I), rotary evaporation (form II), and melting (form III) methods, and the effects of polyamorphism on the morphology, thermodynamic properties, dissolution and gelation phenomenon, and the stability of OLA were studied for the first time. The results indicate that morphology has an impact on the gelation process of amorphous forms and thereby affects the dissolution of the drug. Among them, form II shows the best solubility and dissolution rate due to its slightest gelation, as well as relatively good stability and tabletability, which exhibits good application prospects in the amorphous solid formulation development of OLA.
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Two new multicomponent crystalline phases of fenbendazole (FNB), a benzimidazole anthelmintic age... more Two new multicomponent crystalline phases of fenbendazole (FNB), a benzimidazole anthelmintic agent, with maleic and oxalic acids have been prepared, and their structural and physicochemical properties carefully investigated. The crystal structures of the solid forms have been determined from powder X-ray diffraction data. The positions of dynamic hydrogen atoms have been further refined via dispersioncorrected density functional theory calculations, which validated the salt nature of the resulting solid forms by demonstrating proton transport from the corresponding acids to the FNB molecule. The in vitro dissolution performance of the solid forms in aqueous media at different pH values, as well as the in vivo anthelmintic efficacy of fenbendazole on the laboratory model of Trichinella spiralis infection in mice have been evaluated and compared to that of the previously reported salt of FNB with p-toluenesulfonic acid. A relationship between the in vitro dissolution characteristics and the in vivo therapeutic action has been revealed and discussed.
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Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole, 2023
In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the... more In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the formation of two novel solid forms of FluBZ with l-phenylalanine (Phe) and l-tryptophan (Trp). A variety of physicochemical techniques have been used to describe new systems, including powder X-ray diffraction, thermal methods, infrared spectroscopy, and scanning electron microscopy. Co-amorphization has been shown to suppress crystallization tendency and considerably increase the shelf-life storage of amorphous flubendazole solid across a wide range of relative humidities. The dissolution behavior of the amorphous forms in biorelevant media at pH = 1.6, pH = 6.5, and 37 °C has been studied in terms of Cmax (maximum FluBZ concentration), Tmax (time to attain peak drug concentration), and AUC (concentration area under the curve during dissolution). At pH = 6.5, a continuous supersaturation and the highest AUC value of all examined systems were observed for the FluBZ-Phe (1:1) system. The phase solubility diagrams revealed that the reason for the better dissolution performance of FluBZ-Phe (1:1) at pH = 6.5 is a complexation between the components in a solution. This work highlights the applicability of co-amorphous systems in improving the physical stability and dissolution performance of drug compounds with poor biopharmaceutical characteristics.
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In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with... more In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with isonicotinamide, picolinamide, 2-hydroxybenzamide, and 2-aminobenzamide have been obtained and thoroughly characterized by various analytical techniques. The crystal structures of the solid forms have been elucidated by single-crystal X-ray diffraction, and the energy distribution of intermolecular interactions has been further quantified on the basis of QTAIMC analysis. Eight distinct supramolecular heterosynthons of hydrogen bonding have been identified in the studied crystals, and their relative stability has been ranked in terms of total interaction energies. The thermodynamics of the cocrystallization reactions has been systematically investigated using two independent experimental techniques, namely solution calorimetry and phase solubility diagram, which allowed us to assess both the enthalpic and the entropic contributions to the cocrystal formation driving force. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components. Although all of the cocrystals reported here were found to be more soluble than the parent drug, their advantage in thermodynamic solubility did not translate into enhanced dissolution performance due to a rapid solution-mediated phase transformation in aqueous media. In addition, the effect of cocrystallization on other pharmaceutically relevant properties of nitrofurantoin, including photostability and membrane permeability, has been considered and analyzed.
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Isavuconazole (ISV) is a systemic antifungal agent and is used to treat invasive aspergillosis, m... more Isavuconazole (ISV) is a systemic antifungal agent and is used to treat invasive aspergillosis, mucormycosis 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 the initial crystalline ISV and newly obtained forms (ISV monohydrate, two amorphous forms obtained by different means and two pharmaceutical salts with p-toluenesulfonic acid and phosphoric acid) were described for the first time. The structures of all crystalline forms were solved based on 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 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.
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In this work, three new pharmaceutical salts of fenbendazole (FNB), a benzimidazole-based anthelm... more In this work, three new pharmaceutical salts of fenbendazole (FNB), a benzimidazole-based anthelmintic drug, with sulfonic acids have been obtained and thoroughly investigated by different analytical techniques, including thermal methods, infrared/Raman spectroscopy, and theoretical methods (periodic DFT computations and Bader analyses of the crystalline electronic density). Single-crystal and high-resolution synchrotron powder X-ray diffraction data for the first time made it possible to determine the crystal structures of mesylate and tosylate salts of the drug, which were further validated by dispersion-corrected density functional theory calculations. All the solid forms were stabilized by a robust R 2 2 (8) supramolecular motif formed by relatively strong N−H•••O hydrogen bonds. In the monohydrate of FNB tosylate, a considerable gain in the stabilization energy was due to the intermolecular interactions generated by the water molecules. A careful examination of the solubility−pH profile of the FNB salts revealed that, despite being thermodynamically unstable within the physiologically relevant pH range, the new solid forms demonstrated superior dissolution performance in terms of both the apparent solubility and the release rate in comparison to the parent drug. Since FNB has also been reported to possess anticancer activity, improving the drug's poor physicochemical properties through salt formation with the selected sulfonic acids is expected to promote further investigations toward repurposing of this potent compound.
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International Journal of Pharmaceutics, 599, 120441, 2021
In this work, the cocrystallization approach was applied to itraconazole (ITR), a very slightly s... more 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. Powder X-Ray diffraction analysis confirmed the formation of two different polymorphic forms of the [ITR + 4OHBZA] (1:2) cocrystal obtained either through solution or melt crystallization. Cocrystal formation and polymorphic transition processes were 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. It was found that the cocrystallization of itraconazole with 4OHBZA and 4AmBA can potentially increase the drug solubility at pH1.2 and 37 • C by 225 and 64 times, respectively. The cocrystal dissolution behavior in biorelevant media was analyzed in terms of C max , σ max parameters (the maximum ITR concentration and supersaturation), and AUC (the concentration area under the curve during the dissolution-supersaturation-precipitation process). The cocrystals had similar σ max values during the dissolution and sustained supersaturation for up to 6 h, which gave them an advantage in the AUC values (13-37 times higher) over the drug. The differences in the dissolution profiles of the cocrystals were rationalized in terms of their dissolution rate values.
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Symmetry. 13(3):425, 2021
Two new hydrated multicomponent crystals of zwitterionic 2-aminonicotinic acid with maleic and fu... more Two new hydrated multicomponent crystals of zwitterionic 2-aminonicotinic acid with maleic and fumaric acids have been obtained and thoroughly characterized by a variety of experimental (X-ray analysis and terahertz Raman spectroscopy) and theoretical periodic density functional theory calculations, followed by Bader analysis of the crystalline electron density) techniques. It has been found that the Raman-active band in the region of 300 cm−1 is due to the vibrations of the intramolecular O-H...O bond in the maleate anion. The energy/enthalpy of the intermolecular hydrogen bonds was estimated by several empirical approaches. An analysis of the interaction networks
reflects the structure-directing role of the water molecule in the examined multicomponent crystals. A general scheme has been proposed to explain the proton transfer between the components during the formation of multicomponent crystals in water. Water molecules were found to play the key role in this process, forming a “water wire” between the COOH group of the dicarboxylic acid and the COO–
group of the zwitterion and the rendering crystal lattice of the considered multicomponent crystals.
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Five new multicomponent solid forms of the biologically active 1,2,4-thiadiazole derivative (TDZH... more Five new multicomponent solid forms of the biologically active 1,2,4-thiadiazole derivative (TDZH) with dicarboxylic and hydroxybenzoic acids have been discovered by combined virtual/experimental cocrystal screening. The interplay between the intrinsic hierarchy of the donor/acceptor groups in the TDZH/coformer molecules and the hydrogen bond pattern in the multicomponent crystals was rationalized using quantitative analysis of molecular electrostatic potential (MEP) surfaces along with periodic DFT computations. All the TDZH cocrystals are based on a carboxy-aminothiadiazole heterosynthon which is stabilized by a combination of enthalpic factors and the “supramolecular chelating effect”. According to the analysis of the non-covalent interaction energies, the mean energy value of this heterosynthon equals ~77 kJ·mol-1, which is comparable to the well-known carboxyl-amide and carboxyl-pyridine synthons in terms of the dissociation energy. The thermal stability of the multicomponent crystals was investigated by the DSC and TG methods. The pH-solubility behavior of the cocrystals was investigated at different pH values using eutectic concentrations of the components. Three out of five co-crystals were found to be more soluble than the parent TDZH at low pH values (≈ 2.0). However, cocrystallization significantly alters the solubility-pH dependence of TDZH, increasing the compound solubility at neutral pH values.
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In this work, three new pharmaceutical hydrated salts of ciprofloxacin with selected derivatives ... more In this work, three new pharmaceutical hydrated salts of ciprofloxacin with selected derivatives of benzoic acid, namely 4-hydroxybenzoic acid, 4-aminobenzoic acid and gallic acid, were obtained and systematically investigated by several solid-state analytical techniques. In situ Raman spectroscopy was applied to elucidate the alternative pathways of the solid forms' formation under mechanochemical conditions. Crystal structure analysis and a CSD survey allowed us to establish a distinct supramolecular motif formed by infinite columnar stacks of ciprofloxacin dimers arranged in the "head-to-tail" manner. An alternative "head-to-head" packing arrangement was only observed in the crystal of the hydrated ciprofloxacin salt with 4-aminobenzoic acid. In addition, the pH-solubility behavior of the solid forms was thoroughly investigated. Furthermore, a distinct structure-property relationship between the specific features of the supramolecular organization of the hydrated salts and their solubility was observed and discussed.
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Through cocrystallization of the broad-spectrum antifungal agent fluconazole (FLZ) with a number ... more 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) and 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), thermogravi-metric analysis (TG), scanning electron microscopy (SEM), and 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 noncovalent 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·H 2 O) is highly sensitive to particle size and morphology of crystals. The pH-solubility behavior of the cocrystals has been investigated at different pH values 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.
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The crystallization of ciprofloxacinan antibacterial fluoroquinolone compoundwith salicylic aci... more The crystallization of ciprofloxacinan antibacterial fluoroquinolone compoundwith salicylic acid resulted in the isolation of five distinct solid forms of the drug, namely, an anhydrous salt, two polymorphic forms of the salt monohydrate, methanol and acetonitrile solvates, and the salt-cocrystal hydrate. The salicylate salts were investigated by different analytical techniques ranging from powder and single crystal X-ray diffractometry, differential scanning calorimetry, thermogravimetric analysis, variable temperature powder X-ray diffraction, dynamic vapor sorption analysis, dissolution, and solubility investigations. Real-time in situ Raman spectroscopy was used to investigate the mechanochemical formation pathways of the different solid polymorphs of ciprofloxacin salicylate. The mechanism of the phase transformation between the crystalline forms was evaluated under mechanochemical conditions. It was found that the formation pathway and kinetics of the grinding process depend on the form of the starting material and reaction conditions. The analysis of the solid-state thermal evolution of the hydrated salts revealed the two-step mechanism of dehydration process, which proceeds through a formation of the distinct intermediate crystalline products.
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125793, 2024
In this study, we have analyzed the thermodynamic formation functions for four multi-component cr... more In this study, we have analyzed the thermodynamic formation functions for four multi-component crystals based on the solubility data in the range of 293.15-313.15 K. The investigation was performed for the cocrystals of fluconazole (FLZ) with 4-hydroxybenzoic (4OHBA) and vanillic (VA) acids, and salts of fenbendazole (FNB) with maleic (Mal) and oxalic (Ox) acids. A database on the thermodynamic parameters of the multi-component molecular crystals (Gibbs free energy, enthalpy, and entropy) obtained in this study and borrowed from the literature was created. These parameters were determined using the experimental data on the solubility of the individual components and the product of the solubilities of the multi-component crystals at 298.15 K. A regression model was proposed to estimate the solubility product of the two-component crystals using the intrinsic solubility of the individual components as an independent variable. A detailed analysis of the database disclosed the relationship between the entropy term and the molecular volume of the multi-component crystal formation.
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Olaparib (OLA) is an insoluble targeting antitumor drug for the treatment of ovarian cancer. Here... more Olaparib (OLA) is an insoluble targeting antitumor drug for the treatment of ovarian cancer. Herein, polyamorphism of OLA was systematically studied aiming to improve its solubility and dissolution properties. Three amorphous forms of OLA were prepared by ball milling (form I), rotary evaporation (form II), and melting (form III) methods, and the effects of polyamorphism on the morphology, thermodynamic properties, dissolution and gelation phenomenon, and the stability of OLA were studied for the first time. The results indicate that morphology has an impact on the gelation process of amorphous forms and thereby affects the dissolution of the drug. Among them, form II shows the best solubility and dissolution rate due to its slightest gelation, as well as relatively good stability and tabletability, which exhibits good application prospects in the amorphous solid formulation development of OLA.
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Two new multicomponent crystalline phases of fenbendazole (FNB), a benzimidazole anthelmintic age... more Two new multicomponent crystalline phases of fenbendazole (FNB), a benzimidazole anthelmintic agent, with maleic and oxalic acids have been prepared, and their structural and physicochemical properties carefully investigated. The crystal structures of the solid forms have been determined from powder X-ray diffraction data. The positions of dynamic hydrogen atoms have been further refined via dispersioncorrected density functional theory calculations, which validated the salt nature of the resulting solid forms by demonstrating proton transport from the corresponding acids to the FNB molecule. The in vitro dissolution performance of the solid forms in aqueous media at different pH values, as well as the in vivo anthelmintic efficacy of fenbendazole on the laboratory model of Trichinella spiralis infection in mice have been evaluated and compared to that of the previously reported salt of FNB with p-toluenesulfonic acid. A relationship between the in vitro dissolution characteristics and the in vivo therapeutic action has been revealed and discussed.
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Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole, 2023
In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the... more In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the formation of two novel solid forms of FluBZ with l-phenylalanine (Phe) and l-tryptophan (Trp). A variety of physicochemical techniques have been used to describe new systems, including powder X-ray diffraction, thermal methods, infrared spectroscopy, and scanning electron microscopy. Co-amorphization has been shown to suppress crystallization tendency and considerably increase the shelf-life storage of amorphous flubendazole solid across a wide range of relative humidities. The dissolution behavior of the amorphous forms in biorelevant media at pH = 1.6, pH = 6.5, and 37 °C has been studied in terms of Cmax (maximum FluBZ concentration), Tmax (time to attain peak drug concentration), and AUC (concentration area under the curve during dissolution). At pH = 6.5, a continuous supersaturation and the highest AUC value of all examined systems were observed for the FluBZ-Phe (1:1) system. The phase solubility diagrams revealed that the reason for the better dissolution performance of FluBZ-Phe (1:1) at pH = 6.5 is a complexation between the components in a solution. This work highlights the applicability of co-amorphous systems in improving the physical stability and dissolution performance of drug compounds with poor biopharmaceutical characteristics.
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In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with... more In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with isonicotinamide, picolinamide, 2-hydroxybenzamide, and 2-aminobenzamide have been obtained and thoroughly characterized by various analytical techniques. The crystal structures of the solid forms have been elucidated by single-crystal X-ray diffraction, and the energy distribution of intermolecular interactions has been further quantified on the basis of QTAIMC analysis. Eight distinct supramolecular heterosynthons of hydrogen bonding have been identified in the studied crystals, and their relative stability has been ranked in terms of total interaction energies. The thermodynamics of the cocrystallization reactions has been systematically investigated using two independent experimental techniques, namely solution calorimetry and phase solubility diagram, which allowed us to assess both the enthalpic and the entropic contributions to the cocrystal formation driving force. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components. Although all of the cocrystals reported here were found to be more soluble than the parent drug, their advantage in thermodynamic solubility did not translate into enhanced dissolution performance due to a rapid solution-mediated phase transformation in aqueous media. In addition, the effect of cocrystallization on other pharmaceutically relevant properties of nitrofurantoin, including photostability and membrane permeability, has been considered and analyzed.
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Isavuconazole (ISV) is a systemic antifungal agent and is used to treat invasive aspergillosis, m... more Isavuconazole (ISV) is a systemic antifungal agent and is used to treat invasive aspergillosis, mucormycosis 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 the initial crystalline ISV and newly obtained forms (ISV monohydrate, two amorphous forms obtained by different means and two pharmaceutical salts with p-toluenesulfonic acid and phosphoric acid) were described for the first time. The structures of all crystalline forms were solved based on 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 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.
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In this work, three new pharmaceutical salts of fenbendazole (FNB), a benzimidazole-based anthelm... more In this work, three new pharmaceutical salts of fenbendazole (FNB), a benzimidazole-based anthelmintic drug, with sulfonic acids have been obtained and thoroughly investigated by different analytical techniques, including thermal methods, infrared/Raman spectroscopy, and theoretical methods (periodic DFT computations and Bader analyses of the crystalline electronic density). Single-crystal and high-resolution synchrotron powder X-ray diffraction data for the first time made it possible to determine the crystal structures of mesylate and tosylate salts of the drug, which were further validated by dispersion-corrected density functional theory calculations. All the solid forms were stabilized by a robust R 2 2 (8) supramolecular motif formed by relatively strong N−H•••O hydrogen bonds. In the monohydrate of FNB tosylate, a considerable gain in the stabilization energy was due to the intermolecular interactions generated by the water molecules. A careful examination of the solubility−pH profile of the FNB salts revealed that, despite being thermodynamically unstable within the physiologically relevant pH range, the new solid forms demonstrated superior dissolution performance in terms of both the apparent solubility and the release rate in comparison to the parent drug. Since FNB has also been reported to possess anticancer activity, improving the drug's poor physicochemical properties through salt formation with the selected sulfonic acids is expected to promote further investigations toward repurposing of this potent compound.
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International Journal of Pharmaceutics, 599, 120441, 2021
In this work, the cocrystallization approach was applied to itraconazole (ITR), a very slightly s... more 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. Powder X-Ray diffraction analysis confirmed the formation of two different polymorphic forms of the [ITR + 4OHBZA] (1:2) cocrystal obtained either through solution or melt crystallization. Cocrystal formation and polymorphic transition processes were 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. It was found that the cocrystallization of itraconazole with 4OHBZA and 4AmBA can potentially increase the drug solubility at pH1.2 and 37 • C by 225 and 64 times, respectively. The cocrystal dissolution behavior in biorelevant media was analyzed in terms of C max , σ max parameters (the maximum ITR concentration and supersaturation), and AUC (the concentration area under the curve during the dissolution-supersaturation-precipitation process). The cocrystals had similar σ max values during the dissolution and sustained supersaturation for up to 6 h, which gave them an advantage in the AUC values (13-37 times higher) over the drug. The differences in the dissolution profiles of the cocrystals were rationalized in terms of their dissolution rate values.
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Symmetry. 13(3):425, 2021
Two new hydrated multicomponent crystals of zwitterionic 2-aminonicotinic acid with maleic and fu... more Two new hydrated multicomponent crystals of zwitterionic 2-aminonicotinic acid with maleic and fumaric acids have been obtained and thoroughly characterized by a variety of experimental (X-ray analysis and terahertz Raman spectroscopy) and theoretical periodic density functional theory calculations, followed by Bader analysis of the crystalline electron density) techniques. It has been found that the Raman-active band in the region of 300 cm−1 is due to the vibrations of the intramolecular O-H...O bond in the maleate anion. The energy/enthalpy of the intermolecular hydrogen bonds was estimated by several empirical approaches. An analysis of the interaction networks
reflects the structure-directing role of the water molecule in the examined multicomponent crystals. A general scheme has been proposed to explain the proton transfer between the components during the formation of multicomponent crystals in water. Water molecules were found to play the key role in this process, forming a “water wire” between the COOH group of the dicarboxylic acid and the COO–
group of the zwitterion and the rendering crystal lattice of the considered multicomponent crystals.
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Five new multicomponent solid forms of the biologically active 1,2,4-thiadiazole derivative (TDZH... more Five new multicomponent solid forms of the biologically active 1,2,4-thiadiazole derivative (TDZH) with dicarboxylic and hydroxybenzoic acids have been discovered by combined virtual/experimental cocrystal screening. The interplay between the intrinsic hierarchy of the donor/acceptor groups in the TDZH/coformer molecules and the hydrogen bond pattern in the multicomponent crystals was rationalized using quantitative analysis of molecular electrostatic potential (MEP) surfaces along with periodic DFT computations. All the TDZH cocrystals are based on a carboxy-aminothiadiazole heterosynthon which is stabilized by a combination of enthalpic factors and the “supramolecular chelating effect”. According to the analysis of the non-covalent interaction energies, the mean energy value of this heterosynthon equals ~77 kJ·mol-1, which is comparable to the well-known carboxyl-amide and carboxyl-pyridine synthons in terms of the dissociation energy. The thermal stability of the multicomponent crystals was investigated by the DSC and TG methods. The pH-solubility behavior of the cocrystals was investigated at different pH values using eutectic concentrations of the components. Three out of five co-crystals were found to be more soluble than the parent TDZH at low pH values (≈ 2.0). However, cocrystallization significantly alters the solubility-pH dependence of TDZH, increasing the compound solubility at neutral pH values.
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In this work, three new pharmaceutical hydrated salts of ciprofloxacin with selected derivatives ... more In this work, three new pharmaceutical hydrated salts of ciprofloxacin with selected derivatives of benzoic acid, namely 4-hydroxybenzoic acid, 4-aminobenzoic acid and gallic acid, were obtained and systematically investigated by several solid-state analytical techniques. In situ Raman spectroscopy was applied to elucidate the alternative pathways of the solid forms' formation under mechanochemical conditions. Crystal structure analysis and a CSD survey allowed us to establish a distinct supramolecular motif formed by infinite columnar stacks of ciprofloxacin dimers arranged in the "head-to-tail" manner. An alternative "head-to-head" packing arrangement was only observed in the crystal of the hydrated ciprofloxacin salt with 4-aminobenzoic acid. In addition, the pH-solubility behavior of the solid forms was thoroughly investigated. Furthermore, a distinct structure-property relationship between the specific features of the supramolecular organization of the hydrated salts and their solubility was observed and discussed.
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Through cocrystallization of the broad-spectrum antifungal agent fluconazole (FLZ) with a number ... more 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) and 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), thermogravi-metric analysis (TG), scanning electron microscopy (SEM), and 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 noncovalent 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·H 2 O) is highly sensitive to particle size and morphology of crystals. The pH-solubility behavior of the cocrystals has been investigated at different pH values 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.
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The crystallization of ciprofloxacinan antibacterial fluoroquinolone compoundwith salicylic aci... more The crystallization of ciprofloxacinan antibacterial fluoroquinolone compoundwith salicylic acid resulted in the isolation of five distinct solid forms of the drug, namely, an anhydrous salt, two polymorphic forms of the salt monohydrate, methanol and acetonitrile solvates, and the salt-cocrystal hydrate. The salicylate salts were investigated by different analytical techniques ranging from powder and single crystal X-ray diffractometry, differential scanning calorimetry, thermogravimetric analysis, variable temperature powder X-ray diffraction, dynamic vapor sorption analysis, dissolution, and solubility investigations. Real-time in situ Raman spectroscopy was used to investigate the mechanochemical formation pathways of the different solid polymorphs of ciprofloxacin salicylate. The mechanism of the phase transformation between the crystalline forms was evaluated under mechanochemical conditions. It was found that the formation pathway and kinetics of the grinding process depend on the form of the starting material and reaction conditions. The analysis of the solid-state thermal evolution of the hydrated salts revealed the two-step mechanism of dehydration process, which proceeds through a formation of the distinct intermediate crystalline products.
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