A Computational and Spectroscopic Analysis of Solvate Ionic Liquids Containing Anions with Long and Short Perfluorinated Alkyl Chains.

Anion-driven, nanoscale polar-apolar structural organization is investigated in a solvate ionic liquid (SIL) setting by comparing sulfonate-based anions with long and short perfluorinated alkyl chains. Representative SILs are created from 1,2-bis(2-methoxyethoxy)ethane ("triglyme" or "G3"), lithium nonafluoro-1-butanesulfonate, and lithium trifluoromethanesulfonate. Molecular dynamics simulations, density functional theory computations, and vibrational spectroscopy provide insight into the overall liquid structure, cation-solvent interactions, and cation-anion association. Significant competition between G3 and anions for cation-binding sites characterizes the G3-LiC4F9SO3 mixtures. Only 50% of coordinating G3 molecules form tetradentate complexes with Li+ in [(G3)1Li][C4F9SO3]. Moreover, the SIL is characterized by extensive amounts of ion pairing. Based on these observations, [(G3)1Li][C4F9SO3] is classified as a "poor" SIL, similar to the analogous [(G3)1Li][CF3SO3] system. Even though the comparable basicity of the CF3SO3- and C4F9SO3- anions leads to similar SIL classifications, the hydrophobic fluorobutyl groups support extensive apolar domain formation. These apolar moieties permeate throughout [(G3)1Li][C4F9SO3] and persist even at relatively low dilution ratios of [(G3)10Li][C4F9SO3]. By way of comparison, the CF3 group is far too short to sustain polar-apolar segregation. This demonstrates how chemically modifying the anions to include hydrophobic groups can impart unique nanoscale organization to a SIL. Moreover, tuning these nano-segregated fluorinated domains could, in principle, control the presence of dimensionally ordered states in these mixtures without changing the coordination of the lithium ions.

Desolvation Processes in Channel Solvates of Niclosamide.

The antiparasitic drug niclosamide (NCL) is notable for its ability to crystallize in multiple 1:1 channel solvate forms, none of which are isostructural. Here, using a combination of time-resolved synchrotron powder X-ray diffraction and thermogravimetry, the process-induced desolvation mechanisms of methanol and acetonitrile solvates are investigated. Structural changes in both solvates follow a complicated molecular-level trajectory characterized by a sudden shift in lattice parameters several degrees below the temperature where the desolvated phase first appears. Model fitting of kinetic data obtained under isothermal heating conditions suggests that the desolvation is rate-limited by the nucleation of the solvent-free product. The desolvation pathways identified in these systems stand in contrast to previous investigations of the NCL channel hydrate, where water loss by diffusion initially yields an anhydrous isomorph that converts to the thermodynamic polymorph at significantly higher temperatures. Taking the view that each solvate lattice is a unique "pre-organized" precursor, a comparison of the pathways from different starting topologies to the same final product provides the opportunity to reevaluate assumptions of how various factors (e.g., solvent binding strength, density) influence solid-state desolvation processes.

Toward New Ion Conductive Liquids via Ionic Liquids.

In the current era that it is strongly expected the SDGs would be achieved, electrolyte solutions in electrochemical devices and processes are being studied from dilute and concentrated solutions, through inorganic molten salts, deep eutectic solvents, and ionic liquids, to super-concentrated solutions. Although concepts based on empirical laws such as the Walden rule and hydrodynamics such as the Stokes rule are still useful for ionic conduction in solution, it is expected that superionic conduction-like mechanisms that are scarcely found in conventional electrolytes. Here, the authors' recent results are described based on the local structure and speciation of ionic species in solution, focusing on protons and lithium ions.

Ion Transport in Glyme- and Sulfolane-Based Highly Concentrated Electrolytes.

Highly concentrated electrolytes (HCEs) have a similarity to ionic liquids (ILs) in high ionic nature, and indeed some of HECs are found to behave like an IL. HCEs have attracted considerable attention as prospective candidates for electrolyte materials in future lithium secondary batteries owing to their favorable properties both in the bulk and at the electrochemical interface. In this study, we highlight the effects of the solvent, counter anion, and diluent of HCEs on the Li+ ion coordination structure and transport properties (e. g., ionic conductivity and apparent Li+ ion transference number measured under anion-blocking conditions, t L i a b c ${{t}_{{\rm L}{\rm i}}^{{\rm a}{\rm b}{\rm c}}}$ ). Our studies on dynamic ion correlations unveiled the difference in the ion conduction mechanisms in HCEs and their intimate relevance to t L i a b c ${{t}_{{\rm L}{\rm i}}^{{\rm a}{\rm b}{\rm c}}}$ values. Our systematic analysis of the transport properties of HCEs also suggests the need for a compromise to simultaneously achieve high ionic conductivity and high t L i a b c ${{t}_{{\rm L}{\rm i}}^{{\rm a}{\rm b}{\rm c}}}$ values.

Crystallization Selectivity of Ribavirin Solution and Amorphous Phase.

Crystallization selectivity is an important principle in polymorph control. Ribavirin Form I, Form II, DMSO solvate, and amorphous ribavirin are prepared, and the short-range order similarities between these solid forms and ribavirin aqueous solution and DMSO solution are compared via mid-frequency Raman difference spectra (MFRDS). The crystallization process from amorphous ribavirin to Form I and from solution to amorphous phase is explained. Reasons for the difficulty in preparing the DMSO solvate are proposed. The rationale provided for the crystallization selectivity provides a foundation for the synthesis of metastable phases with a robust and convenient method.

The Effect of Fluorinated Solvents on the Physicochemical Properties, Ionic Association, and Free Volume of a Prototypical Solvate Ionic Liquid.

Solvate ionic liquid (SIL) synthesis and properties depend on a delicate balancing of cation-solvent and cation-anion interactions to produce materials containing only cation-solvent complexes and solvent-separated anions. Most SILs meeting these characteristics fall within the paradigm of oligomeric ethylene oxides (e.g. glymes and glycols) and lithium salts. Targeted functionalization of solvent molecules to achieve desired properties is a relatively unexplored avenue of research. Fluorinated solvents have significantly different electric charge distributions compared to their nonfluorinated analogs. We test the impact of solvent fluorination for a SIL created from equimolar mixtures of lithium bis(trifluoromethylsulfonyl)imide (LiNTf2 ) and triethylene glycol (TEG), hereafter [(TEG)1 Li]NTf2 . In the first experiment, TEG is partially substituted with 2,2,4,4,5,5,7,7-octafluoro-3,6-dioxaoctane-1,8-diol (FTEG). This leads to a precipitous decrease in ionic conductivity and larger quantities of ionically-associated Li(NTf2 )2 - species, as detected with vibrational spectroscopy. These observations suggest FTEG does not readily coordinate Li+ ions in a manner analogous to TEG. Computational studies reinforce this conclusion. Relative complex cation stabilities are ranked as [(FTEG)1 Li]+ >[(TEG)1 Li]+ . A second experiment adds FTEG as a diluent to [(TEG)1 Li]NTf2 . This places FTEG and TEG in competition to coordinate a limited number of Li+ ions. The resulting mixtures exhibit conductivity enhancement over the parent SIL and minimal changes in ion speciation due to the poor Li+ binding by FTEG compared to TEG. Positron annihilation lifetime spectroscopic studies point to increased amounts of free volume upon dilution of FTEG. This likely explains the origin of the conductivity and viscosity enhancements.

Correlation of Solubility Thermodynamics of Glibenclamide with Recrystallization and In Vitro Release Profile.

The solubility of glibenclamide was evaluated in DMSO, NMP, 1,4-dioxane, PEG 400, Transcutol® HP, water, and aqueous mixtures (T = 293.15~323.15 K). It was then recrystallized to solvate and compressed into tablets, of which 30-day stability and dissolution was studied. It had a higher solubility in 1,4-dioxane, DMSO, NMP (Xexp = 2.30 × 103, 3.08 × 104, 2.90 × 104) at 323.15 K, its mixture (Xexp = 1.93 × 103, 1.89 × 104, 1.58 × 104) at 298.15 K, and 1,4-dioxane (w) + water (1-w) mixture ratio of w = 0.8 (Xexp = 3.74 × 103) at 323.15 K. Modified Apelblat (RMSD ≤ 0.519) and CNIBS/R-K model (RMSD ≤ 0.358) suggested good comparability with the experimental solubility. The minimum value of ΔG° vs ΔH° at 0.70 < x2 < 0.80 suggested higher solubility at that molar concentration. Based on the solubility, it was recrystallized into the solvate, which was granulated and compressed into tablets. Among the studied solvates, the tablets of glibenclamide dioxane solvate had a higher initial (95.51%) and 30-day (93.74%) dissolution compared to glibenclamide reference (28.93%). There was no stability issue even after granulation, drying, or at pH 7.4. Thus, glibenclamide dioxane solvate could be an alternative form to improve the molecule's properties.

High-resolution 13 C and 43 Ca solid-state NMR and computational studies of the ethylene glycol solvate of atorvastatin calcium.

We report 43 Ca and 13 C solid-state nuclear magnetic resonance (NMR) spectroscopic studies of the ethylene glycol solvate of atorvastatin calcium. The 13 C and 43 Ca chemical shift and 43 Ca quadrupolar coupling tensor parameters are reported. The results are interpreted in terms of the reported X-ray diffraction crystal structure of the solvate and are compared with the NMR parameters of atorvastatin calcium trihydrate, the active pharmaceutical ingredient in Lipitor®. Hartree-Fock and density functional theory calculations of the NMR parameters based on a cluster model derived from the optimized X-ray diffraction crystal structure of the ethylene glycol solvate of atorvastatin calcium are in reasonable agreement with the experimental 43 Ca and 13 C NMR measurables.

Thiabendazole and Thiabendazole-Formic Acid Solvate: A Computational, Crystallographic, Spectroscopic and Thermal Study.

Thiabendazole (TBZ) is a substance which has been receiving multiple important applications in several domains, from medicine and pharmaceutical sciences, to agriculture and food industry. Here, a comprehensive multi-technique investigation on the molecular and crystal properties of TBZ is reported. In addition, a new solvate of the compound is described and characterized structurally, vibrationally and thermochemically for the first time. Density functional theory (DFT) calculations were used to investigate the conformational space of thiabendazole (TBZ), revealing the existence of two conformers, the most stable planar trans form and a double-degenerated-by-symmetry gauche form, which is ~30 kJ mol-1 higher in energy than the trans conformer. The intramolecular interactions playing the major roles in determining the structure of the TBZ molecule and its conformational preferences were characterized. The UV-visible and infrared spectra of the isolated molecule (most stable trans conformer) were also calculated, and their assignment undertaken. The information obtained for the isolated molecule provided a strong basis for the understanding of the intermolecular interactions and properties of the crystalline compound. In particular, the infrared spectrum for the isolated molecule was compared with that of crystalline TBZ and the differences between the two spectra were interpreted in terms of the major intermolecular interactions existing in the solid state. The analysis of the infrared spectral data was complemented with vibrational results of up-to-date fully-periodic DFT calculations and Raman spectroscopic studies. The thermal behavior of TBZ was also investigated using differential scanning calorimetry (DSC) and thermogravimetry. Furthermore, a new TBZ-formic acid solvate [2-(1,3-thiazol-4-yl)benzimidazolium formate formic acid solvate] was synthesized and its crystal structure determined by X-ray diffraction. The Hirshfeld method was used to explore the intermolecular interactions in the crystal of the new TBZ solvate, comparing them with those present in the neat TBZ crystal. Raman spectroscopy and DSC studies were also carried out on the solvate to further characterize this species and investigate its temperature-induced desolvation.

Enabling High-Voltage Lithium Metal Batteries by Manipulating Solvation Structure in Ester Electrolyte.

Lithium metal is an ideal electrode material for future rechargeable lithium metal batteries. However, the widespread deployment of metallic lithium anode is significantly hindered by its dendritic growth and low Coulombic efficiency, especially in ester solvents. Herein, by rationally manipulating the electrolyte solvation structure with a high donor number solvent, enhancement of the solubility of lithium nitrate in an ester-based electrolyte is successfully demonstrated, which enables high-voltage lithium metal batteries. Remarkably, the electrolyte with a high concentration of LiNO3 additive presents an excellent Coulombic efficiency up to 98.8 % during stable galvanostatic lithium plating/stripping cycles. A full-cell lithium metal battery with a lithium nickel manganese cobalt oxide cathode exhibits a stable cycling performance showing limited capacity decay. This approach provides an effective electrolyte manipulation strategy to develop high-voltage lithium metal batteries.

Remarkable Effect of [Li(G4)]TFSI Solvate Ionic Liquid (SIL) on the Regio- and Stereoselective Ring Opening of α-Gluco Carbasugar 1,2-Epoxides.

Carba analogues of biologically relevant natural carbohydrates are promising structures for the development of future drugs endowed with enhanced hydrolytic stability. An open synthetic challenge in this field is the optimization of new methodologies for the stereo- and regioselective opening of α-gluco carbasugar 1,2-epoxides that allow for the preparation of pseudo mono- and disaccharides of great interest. Therefore, we investigated the effect of Lewis acids and solvate ionic liquids (SILs) on the epoxide ring opening of a model substrate. Of particular interest was the complete stereo- and regioselectivity, albeit limited to simple nucleophiles, toward the desired C(1) isomer that was observed using LiClO4. The results obtained with SILs were also remarkable. In particular, Li[NTf2]/tetraglyme ([Li(G4)]TFSI) was able to function as a Lewis acid and to direct the attack of the nucleophile preferentially at the pseudo anomeric position, even with a more complex and synthetically interesting nucleophile. The regioselectivity observed for LiClO4 and [Li(G4)]TFSI was tentatively ascribed to the formation of a bidentate chelating system, which changed the conformational equilibrium and ultimately permitted a trans-diaxial attack on C(1). To the best of our knowledge, we report here the first case in which SILs were successfully employed in a ring-opening process of epoxides.

Pharmaceutical Salts of Carvedilol: Polymorphism and Physicochemical Properties.

We report novel pharmaceutical salts of an anti-hypertensive drug carvedilol (CVD) with pharmaceutically acceptable salt formers, including oxalic acid (OXA), fumaric acid (FUMA), benzoic acid (BZA), and mandelic acid (MDA) via conventional solvent evaporation technique. The pKa difference between CVD and selected acids was greater than 3, thus suggesting salt formation. Two polymorphic forms of CVD/MDA salts and one p-Dioxane solvate of CVD/FUMA salt were also reported in this paper. The salts were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Stability of the salts was assessed by storage at 40°C/75% RH for 1 month. All CVD salts exhibited higher solubility in phosphate buffer solution pH 6.8 compared to the parent drug CVD and showed good stability in accelerated ICH conditions at 40°C/75% RH for 1 month. CVD/FUMA salt showed the highest solubility (1.78 times). Based on thermal analysis and slurry experiment, it was found that CVD/MDA polymorphs were related monotropically with Form 1 as the stable form. The results suggested that salt formation could be an alternative method to improve CVD solubility.

Kamlet-Taft Solvation Parameters of Solvate Ionic Liquids.

The Kamlet-Taft solvent parameters of solvate ionic liquids (SILs) prepared from lithium salts with glyme and glycol ligands are determined. The dipolarity/polarisibilities (π*) are high, similar to those found in conventional ionic liquids. The H-bond basicities (ß) depend strongly on the anion. The H-bond acidities (α) are high in both glyme and glycol SILs, indicating that the lithium is acting as a H-bond donor site. "Poor" SILs have glyme-rich and salt-rich regions. In these liquids the π* and ß values are almost identical to the parent glyme or glycol, and the α values are determined by the salt alone.

Computational Screening of Drug Solvates.

PURPOSE: Solvates are mainly undesired by-products during the pharmaceutical development of new drugs. In addition, solvate formation may also distort solubility measurements. The presented study introduces a simple computational approach that allows for the identification of drug solvent pairs which most likely form crystalline solid phases. METHODS: The mixing enthalpy as a measure for drug-solvent complementarity is obtained by computational liquid phase thermodynamics (COSMO-RS theory). In addition a few other simple descriptors were taking into account describing the shape and topology of the drug and the solvent. Using an extensive dataset of drug solvent pairs a simple and statistically robust model is developed which allows for a rough assessment of a solvent's ability to form a solvate. RESULTS: Similar to the related issue of cocrystal screening, the mixing (or excess) enthalpy of the subcooled liquid mixture of the drug-solvent pair proves to be an important quantity controlling solvate formation. Due to the fact that many solvates form inclusion compounds, the solvent shape is another important factor influencing solvate formation. Solvates forming channel-like voids in the solid state are predicted less well. CONCLUSION: The approach ranks any drug-solvent pair that forms a solvate before any non-solvate by a probability of about 81% (AUC = 0.81), giving a significant advantage over any trial and error approach. Hence it can help to identify suitable solvent candidates early in the drug development process.

Assessment of the Stoichiometry of Multicomponent Crystals Using Only X-ray Powder Diffraction Data.

Knowledge of the unit cell volume of a crystalline form and the expected space filling requirements of an API molecule can be used to determine if a crystalline material is likely to be multicomponent, such as a solvate, hydrate, salt, or a co-crystal. The unit cell information can be readily accessed from powder diffraction data alone utilizing powder indexing methodology. If the unit cell has additional space not likely attributable to the API entity, then there is either a void or another component within the crystal lattice. This "leftover" space can be used to determine the likely stoichiometry of the additional component. A simple approach for calculating the expected required volume for a given molecule within a crystal using an atom based additive approach will be discussed. Coupling this estimation with the actual unit cell volumes and space group information obtained from powder indexing allows for the rapid evaluation of the likely stoichiometry of multicomponent crystals using diffraction data alone. This approach is particularly useful for the early assessment of new phases during salt, co-crystal, and polymorph screening, and also for the characterization of stable and unstable solvates.

Crystal structure of chlorido-penta-kis(dimethyl sulfoxide-κO)chromium(III) dichloride.

In the complex cation of the title salt, [CrCl(C2H6OS)5]Cl2, the Cr(III) ion is coordinated by one chloride ligand and five O atoms from dimethyl sulfoxide (DMSO) ligands, leading to a slightly distorted octa-hedral coordination environment [O-Cr-O angles range from 86.69 (16) to 92.87 (16)°]. In the crystal, complex cations are arranged in hexa-gonally packed rows parallel to [010], with the chloride counter-anions situated in between. The inter-actions between cations and anions are mainly ionic in nature.

Crystal structure of 2,5-bis-(4-methyl-pyridin-2-yl)pyrazine chloro-form disolvate.

The heterocyclic molecule in the title solvate, C16H14N4·2CHCl3, possesses inversion symmetry, with the inversion centre situated at the centre of the pyrazine ring. The outer pyridine rings are inclined to the central pyrazine ring by 4.89 (9)°. The compound crystallized as a chloro-form disolvate with the solvent mol-ecules linked to the title mol-ecule by C-H⋯N hydrogen bonds. In the crystal, mol-ecules are further linked by π-π inter-actions involving the pyrazine and pyridine rings of neighbouring mol-ecules [inter-centroid distance = 3.5629 (12) Å; symmetry code: x, y + 1, z + 1].

About the polymorphism of [Li(C4H8O)3]I: crystal structures of trigonal and tetra-gonal polymorphs.

Two new trigonal and tetra-gonal polymorphs of the title compound, iodido-tris-(tetra-hydro-furan-κO)lithium, are presented, which both include the isolated ion pair Li(THF)3 (+)·I(-). One Li-I ion contact and three tetra-hydro-furan (THF) mol-ecules complete the tetra-hedral coordination of the lithium cation. The three-dimensional arrangement in the two polymorphs differs notably. In the trigonal structure, the ion pair is located on a threefold rotation axis of space group P-3 and only one THF mol-ecule is present in the asymmetric unit. In the crystal, strands of ion pairs parallel to [001] are observed with an eclipsed conformation of the THF mol-ecules relative to the Li⋯I axis of two adjacent ion pairs. In contrast, the tetra-gonal polymorph shows a much larger unit cell in which all atoms are located on general positions of the space group I41 cd. The resulting three-dimensional arrangement shows helical chains of ion pairs parallel to [001]. Apart from van der Waals contacts, no remarkable inter-molecular forces are present between the isolated ion pairs in both structures.

Crystal structure of 2,4-di-amino-5-(4-hy-droxy-3-meth-oxy-phen-yl)-8,8-dimethyl-6-oxo-6,7,8,9-tetra-hydro-5H-chromeno[2,3-b]pyridine-3-carbo-nitrile-di-methyl-formamide-water (1/1/1).

In the structure of the title compound, C22H22N4O4·C3H7NO·H2O, the entire tricyclic system is approximately planar except for the carbon atom bearing the two methyl groups; the meth-oxy-phenyl ring is approximately perpendicular to the tricycle. All seven potential hydrogen-bond donors take part in classical hydrogen bonds. The main mol-ecule and the DMF combine to form broad ribbons parallel to the a axis and roughly parallel to the ab plane; the water mol-ecules connect the residues in the third dimension.

Molecular spectroscopy, solvent effect, and DFT studies of azithromycin solvate.

Azithromycin ethanol solvate monohydrate [C38H72N2O120.5(C2H6O)H2O], abbreviated by AZM-MH-EtOH, was synthesized by slow evaporation method and investigated by powder X-ray diffraction, Raman and infrared (IR) spectroscopy combined with density functional theory (DFT) studies. Electronic and vibrational properties were properly investigated based on a theoretical study of solvation effects, using implicit solvation and solute electron density models. The electronic and vibrational studies were evaluated under aqueous, ethanolic, and vacuum conditions. The electronic structure calculations indicated that the AZM-MH-EtOH is chemically more stable in solvents compared to vacuum condition. Ultraviolet-visible (UV-vis) measurements confirmed the stability of the material in ethanolic medium, due to higher absorbance values compared to the aqueous medium. Vibrational changes were observed in the Raman and IR bands, which have connection with hydrogen bonds. The experimental vibration modes showed better accordance with the predicted modes' values under solvation effects, but a slight divergence is noticed when we compared to vibration modes obtained in vacuum. Furthermore, the results have revealed a greater affinity profile of AZM-MH-EtOH for water and ethanol solvents compared to theoretical data under vacuum condition.