Solvate Formation Research Articles

Formation of a solvate of manganese(III) acetylacetonate with chloroform

Metal acetylacetonates are coordination compounds consisting of the acetylacetonate anion (CH3COCHCOCH3, indicated as acac) and metal ions. Typically, both oxygen atoms of the anion bind with the metal and form a six-membered chelate ring. The simplest complexes have the formulas M(acac)3 and M(acac)2. Many complexes are soluble in organic solvents, and such solutions are used for the synthesis of catalysts. The processes of formation of solvates of acetylacetonates of various metals have not been studied properly. It should be noted that the determination of the composition and properties of solvates is important for understanding the peculiarities of the extraction processes of metal acetylacetonates.Manganese(III) acetylacetonate Mn(acac)3, for example, is also widely used. The recrystallisation of the complex is most commonly conducted from solutions in chloroform, and in this case, the corresponding solvates may be formed, which can affect the structure and properties of Mn(acac)3. There are no data on the synthesis conditions and the composition of the solvates of manganese(III) acetylacetonate with chloroform. Therefore, the purpose of this work is to study the possibilities of its formation and to establish the composition of such solvates. The formation of the solvate in solution was established using Fourier IR spectroscopy by the shift of the absorption band of the C-H chloroform bond. The composition of the Mn(acac)3· 2CHCl3 solvate was determined using gravimetric analysis.

Manipulating Crystallization Kinetics in High-Performance Blade-Coated Perovskite Solar Cells via Cosolvent-Assisted Phase Transition.

Manipulating the perovskite solidification process, including nucleation and crystal growth, plays a critical role in controlling film morphology and thus affects the resultant device performance. In this work, a facile and effective ethyl alcohol (EtOH) cosolvent strategy is demonstrated with the incorporation of EtOH into perovskite ink for high-performance room-temperature blade-coated perovskite solar cells (PSCs) and modules. Systematic real-time perovskite crystallization studies uncover the delicate perovskite structural evolutions and phase-transition pathway. Time-resolved X-ray diffraction and density functional theory calculations both demonstrate that EtOH in the mixed-solvent system significantly promotes the formation of an FA-based precursor solvate (FA2 PbBr4 ·DMSO) during the trace-solvent-assisted transition process, which finely regulates the balance between nucleation and crystal growth to guarantee high-quality perovskite films. This strategy efficiently suppresses nonradiative recombination and improves efficiencies in both 1.54 (23.19%) and 1.60eV (22.51%) perovskite systems, which represents one of the highest records for blade-coated PSCs in both small-area devices and minimodules. An excellent VOC deficit as low as 335mV in the 1.54eV perovskite system, coincident with the measured nonradiative recombination loss of only 77mV, is achieved. More importantly, significantly enhanced device stability is another signature of this approach.

Stable Fatty Acid Solvates of Dasatinib, a Tyrosine Kinase Inhibitor: Prediction, Process, and Physicochemical Properties.

Exploration of alternate solid forms for dasatinib, a potent oncogene tyrosine kinase inhibitor classified under Biopharmaceutics Classification System (BCS) class II drugs with low water solubility and high permeability, has been performed using COSMO-RS excess enthalpy (Hex) to increase dissolution. The theoretical prediction resulted in the potential for the formation of C6–C8 fatty acid solvates with dasatinib. A crystallization process has been identified for the preparation of the predicted solvates and successfully scaled up till the 100 g level. The fatty acid solvates are completely characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, and proton nuclear magnetic resonance (1H NMR) spectroscopy. Unique powder X-ray diffraction patterns and powder indexing of C6–C8 fatty acid solvates indicate the purity of the solid phase. The red shift in the acid carbonyl stretching frequency of C6–C8 fatty acids in FT-IR spectra and the intactness of the fatty acid proton in 1H-NMR spectra provide evidence for solvate formation. The stoichiometry of active pharmaceutical ingredients (APIs) with solvent in solvates is measured using TGA and 1H-NMR spectroscopy. Dasatinib C6–C8 fatty acid solvates were found to retain their solid form under various stress and pharmaceutical processing conditions. In addition, they exhibited improved powder dissolution over dasatinib Form H1-7 by 2.2-fold. They also showed stability at 40 °C and 75% RH for 3 months. C8 fatty acid is a USFDA GRAS listed solvent, and hence may be a viable option for drug product development.

Enthalpy-Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem.

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

Structural Insights into the Highly Solvating System of Axitinib via Binary and Ternary Solvates

Axitinib is a well-known model in crystal engineering, exhibiting a high tendency to form various solvates, and more than 70 kinds of solvates have been reported. Therefore, it is a challenge to elucidate the effect of solvents on the crystallization of Axitinib and develop the polymorph or solvate landscape of Axitinib. Here, we illustrate an uncommon and complicated solvation behavior of Axitinib from the structural analysis and theoretical characterization. The structures of two new ternary solvates and five binary solvates are reported for the first time. Experimental and theoretical calculation and studies on phase transition are performed to rationalize and understand the formation of solvates and the transformation of polymorphisms. Crystal structure analysis and molecular properties reveal that shape, size, the hydrogen bond donor of the solvents, and the chance to lower crystal free energy are the main factors to drive solvates. Three sets of isostructural binary solvate are distinguished and calculated quantitatively to prove that the intermolecular interactions, strong hydrogen bond donor, CH−π, and orientation force control the classification results of binary solvates. Stability of solvates is found to be associated with the intermolecular interaction energies of solvent molecules with surrounding molecules. The polymorphic behavior of the desolventized product is attributed to the two-dimensional isostructurality between form IV and solvate.

Steric influence on solvate formation – a comparison of resorcylic acid and two brominated derivatives

Unbalanced steric bulk can lead to increased solvate formation as shown in non-, mono- and dibrominated resorcylic acid.

In-Situ Formation of Hydrophobic Deep Eutectic Solvent for the Enrichment and Quantitative Determination of Triclosan in Personal Care Products from Environmental Samples

In-Situ Formation of Hydrophobic Deep Eutectic Solvent for the Enrichment and Quantitative Determination of Triclosan in Personal Care Products from Environmental Samples

Factors influencing hydrogen peroxide versus water inclusion in molecular crystals.

Hydrate formation is often unavoidable during crystallization, leading to performance degradation of pharmaceuticals and energetics. In some cases, water molecules trapped within crystal lattices can be substituted for hydrogen peroxide, improving the solubility of drugs and detonation performance of explosives. The present work compares hydrates and hydrogen peroxide solvates in two ways: (1) analyzing structural motifs present in crystal structures accessed from the Cambridge Structural Database and (2) developing potential energy surfaces for water and hydrogen peroxide interacting with functional groups of interest at geometries relevant to the solid state. By elucidating fundamental differences in local interactions that can be formed with molecules of hydrogen peroxide and/or water, the analyses presented here provide a foundation for the design and selection of candidate molecules for the formation of hydrogen peroxide solvates.

Comprehensive understanding on solubility and solvation performance of curcumin (form I) in aqueous co-solvent blends

The intermolecular interactions and overall charge distribution of curcumin were respectively investigated by using Hirshfeld surface analysis and molecular electrostatic potential surface. The mole fraction solubility magnitudes of curcumin (I) in aprotic co-solvent blends of DMSO + water, acetone + water and acetonitrile + water ranging from 278.15 to 318.15 (333.15) K under 101.1 kPa was obtained by means of shake-flask method. Under the same conditions, e.g. identical temperature and mass fraction of DMSO (acetone or acetonitrile), the equilibrium solubility of curcumin was greater in DMSO + water blends than in acetone/acetonitrile + water blends. The lowest solubility magnitude was found in neat water at 278.15 K; and the highest one, in acetone/acetonitrile at temperature of T = 318.15 K (aqueous solutions of acetone or acetonitrile) or 333.15 K (aqueous solutions of DMSO). No crystaltransition and solvate formation occurred in experimental processes as documented through X-ray power diffraction analysis. The acquired data were correlated by means of the Jouyban-Acree model, Apelblat model and modified van’t Hoff-Jouyban–Acree model. The preferential solvation at 298.15 K was investigated by the approach of inverse Kirkwood–Buff integrals. The parameters of preferential solvation for DMSO, acetone or acetonitrile were positive in the above three blends with middle and DMSO/acetone/acetonitrile-rich composition ranges, which specified that preferential solvation of curcumin was made by co-solvent. The extended Hildebrand solubility approach was further employed to describe the mole fraction solubility at 298.15 K in DMSO/acetone/acetonitrile + water blends studied in the current work and in ethanol/n-propanol/isopropanol/PG + water blends reported previous by us, obtaining average relative deviations < 5.21%.

The extraction mechanism research for the separation of indole through the formation of deep eutectic solvents with quaternary ammonium salts

Indole is an important industrial substance that can be derived from coal tar. However, traditional acid-base separation method causes serious environmental problems. In this research, the indole separation abilities of different quaternary ammonium salts (QASs) from nitrogen-containing compounds and azeotrope systems were explored. Series of QASs with different substituent groups were investigated through examining the extraction efficiency, including tetraethylammonium chloride (TEAC), betaine hydrochloride (BHC), tetramethylammonium chloride (TMAC), tetraethylammonium bromide (TEAB), and benzyl trimethylammonium chloride (BTMAC). Among them, TEAC was found to be able to form deep eutectic solvents (DES) with indole. The effects of different experimental conditions such as extraction time, extraction temperature, and mole ratio were studied and optimum extraction conditions were obtained. Quantum calculation was employed to explore the extraction mechanism. σ-profiles and σ-surfaces of QASs ions and related compounds were derived from COSMO database and analyzed to explore their interaction forces. The interaction energies between QASs ions and related compounds composed by misfit, van der Waals (VDW) and hydrogen bond (HB) were calculated based on COSMO-RS theory. Using these methods, the separation possibilities of indole through DES formation by QASs can be speculated. Ultimately, the bond lengths and interaction energies between QASs and indole were calculated concretely using Material Studio. The above quantum calculation proved the existence of hydrogen bonds between indole and QASs and the deductions obtained from quantum calculation were consistent with the experimental results. According to the above analysis, the separation method through DES formation was proved to have a relatively high requirement for extractant. The mechanism research in this article provided essential reference for the selection of applicable extractant, and the prediction of the separation efficiency.

Enantiomeric separation of racemic amlodipine by sequential fractional crystallization through formation of diastereomeric salt solvates and co-crystals of solvate-like compounds with specific structure - A tandem resolution.

A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25-mol equivalent of (R,R)-tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half-equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)-tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re-resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co-crystals in the structure of the diastereomeric salts. The used solvate-former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA-EGA-MS, and -FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key-intermediate crystalline diastereomeric salts-as solvates and co-crystals-inherit a kind of structural similarity from their related additives-solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively.

Recent Advances in Pharmaceutical Cocrystals: From Bench to Market.

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products.

Behavior of quaternary ammonium salts and terpenoids-based deep eutectic solvents in aqueous phase

Numerous articles have been presented on efficient liquid–liquid extraction procedures from aqueous samples using deep eutectic solvents based on quaternary ammonium salts or natural terpenoids as hydrogen bond acceptors and fatty acids as hydrogen bond donors. However, precursors of these solvents are soluble in the aqueous phase and the composition of the solvents can be changed in the presence of water. In this research the stability and composition of deep eutectic solvents based on quaternary ammonium salts (tetrabutylammonium bromide and tetraoctylammonium bromide), terpenoids (menthol and thymol) and fatty acids (hexanoic, heptanoic, octanoic, nonanoic and decanoic acids) in aqueous phase were systematically investigated. It was shown that all studied two-component solvents are transformed into three-component solvents in the presence of water. Effects of hydrogen bond acceptors and donors type on formation of three-component solvents were investigated and discussed. It was established that, the ratio of aqueous and organic phases plays a key-role for stability of the solvents based on tetrabutylammonium bromide. The solvents based on terpenoids and tetraoctylammonium bromide remain stable in the wide range of phases ratios. In addition to the study of stability, changes in the physicochemical and extraction properties of ternary eutectic solvents in comparison with two-component solvents have been shown.

In-situ formation/decomposition of deep eutectic solvent during solidification of floating organic droplet-liquid-liquid microextraction method for the extraction of some antibiotics from honey prior to high performance liquid chromatography-tandem mass spectrometry

A new liquid-liquid microextraction approach by applying a deep eutectic solvent was adopted for the extraction of four antibiotics (penicillin G, dihydrostreptomycin, enrofloxacin, and ciprofloxacin) from honey samples. The enriched analytes were analyzed by HPLC-MS/MS. The procedure was carried out by synthesis of tetrabutylammonium chloride: p-cresol deep eutectic solvent in the sample solution and then its decomposition in the presence of an acid. In-solution formation of deep eutectic solvent provided wide contact areas among the extractant and sample solution, and accelerated sample preparation. Also, its decomposition enabled collection of the final extraction phase without centrifugation. Low LODs (0.55–0.79 ng/g) and LOQs (1.9–2.6 ng/g), high ERs (70–92%), and suitable RSDs (≤ 6.9%) were obtained. After performing the method on real samples, dihydrostreptomycin was found in several honey samples.

Conformational Change in Molecular Crystals: Impact of Solvate Formation and Importance of Conformational Free Energies

Changes in molecular conformation and its relationship with crystal polymorphism have been well documented in previous work. To the best of our knowledge, however, the effect of solvate formation on molecular conformation has never been explored. Using the Cambridge Structural Database in combination with molecular modeling, we provide insights into the impact of solvate formation on the conformation adopted by a compound and whether such conformation is different to that found in its neat form(s). Typically, the more flexible a molecule is, the higher the chances that conformational change occurs upon solvate formation. There are no trends as to the relative stability of conformers and their likelihood to be observed in either the solvates or the neat forms. Typically, conformer energy differences in solvate-neat form pairs are small (<5 kJ/mol) and when larger energy differences are observed (>15 kJ/mol), these can be reduced significantly when both solvent and thermal effects are considered in the simulations. This highlights of the importance of computing thermal contributions in conformer energies as well as accounting for environmental effects. Overall, we find that conformational change in solvate-neat form pairs mirrors the behavior of conformational change in polymorphism.

Hydrolysis of triglycerides in milk to provide fatty acids as precursors in the formation of deep eutectic solvent for extraction of polycyclic aromatic hydrocarbons

A microextraction pretreatment for powdered milk analysis, relying on the formation of a natural deep eutectic solvent is proposed. It relies on the in situ hydrolysis of milk fats (triglycerides) which yields fatty acids as precursors in the formation of the natural deep eutectic solvent. As a proof-of-concept, the innovation was applied to the determination of thirteen polycyclic aromatic hydrocarbons in powdered milk samples by HPLC with fluorometric detection. The alkaline hydrolysis of milk triglycerides minimized sample matrices interference through removal of proteins and fats, and led to formation of natural deep eutectic solvent precursors (fatty acids) directly from the sample components. Addition of only one precursor (terpenoid) was then required. Menthol and thymol (natural terpenoids) were investigated as deep eutectic solvent precursors for microextraction of polycyclic aromatic hydrocarbons. Under the selected experimental conditions, limits of detection were estimated within the 0.002–0.09 μg kg−1 range. The innovation provided satisfactory (70–91%) extraction of hydrophobic analytes from complex powdered milk matrices containing hydrophobic components (triglycerides) without the need for hazardous organic solvents. The RSD values were <5.2%.

Structure and dynamics of thymol - fatty acids based deep eutectic solvent investigated by molecular dynamics simulation

The current work focuses on the design of hydrophobic eutectic solvents (HDESs) based on Thymol and fatty acids and the investigation of their dynamical and structural properties. Binary mixtures of Thymol and fatty acids such as Caprylic acid (C8), Decanoic acid (C10), Lauric acid (C12), and Myristic acid (C14) were prepared at different ratios. Molecular dynamics simulations were carried out to evaluate the change in the percentage composition of the designed DESs on the bulk properties at the temperature of 323 K. The percentage composition of the binary mixtures that have the most intermolecular interaction between the donor and the acceptor of the hydrogen bond was selected, and their thermos-physical properties were investigated at different temperatures. The analysis of atom-atom radial distribution functions (RDFs), spatial distribution functions (SDFs), the energy of non-bonded interactions, and the Hydrogen bonding network between Thymol molecules and fatty acids were obtained to understand effective interactions in binary mixture formation. The evidence was found for the hydrogen bonds with the more significant percent occupancies between Thy and FAs in the angular/distance probability region at around 150°−180°/2 Å. The results of MD simulations showed that the intermolecular interactions were impacted in the pure state by interactions between the hydroxyl group of Thymol and fatty acids, and the main interactions interrupt. Dynamical properties of the eutectic mixtures were investigated by the mean-square displacement (MSD) and the self-diffusion. The strong Hydrogen bonding network of binary mixture led to changes in the molecule migration. The intermolecular interaction understanding will aid in determining suitable ratios for the design of eutectic solvents. Finally, we proposed possible explanations for the composition of the appropriate percentage for the formation of the eutectic solvent.

Guest-Mediated Hierarchical Self-Assembly of Dissymmetric Organic Cages to Form Supramolecular Ferroelectrics

Guest-Mediated Hierarchical Self-Assembly of Dissymmetric Organic Cages to Form Supramolecular Ferroelectrics

Rationalizing the Formation of Belinostat Solvates with Experimental Screening and Computational Predictions

Belinostat is a histone deacetylase inhibitor for the treatment of refractory T-cell lymphoma. Our study found that the tendency to form solvates of belinostat with hydrogen-bond acceptor type solvents was obvious based on the COSMO-RS model. Motivated by the prediction results, we investigated eight novel solvates, with 1,4-dioxane, tetrahydrofuran, furan, 3-picoline, cyclopentanone, 1-methyl-2-pyrrolidinone, and dimethyl sulfoxide/water as guest molecules, obtained by different crystallization methods. The obtained solid forms were thoroughly characterized with various analytical techniques, namely, powder X-ray diffraction, Fourier transform infrared spectroscopy, and thermal analysis. The thermal stability order of solvates was S3PC > S′Diox > SNMP > SCP > SFuran > STHF > SDiox > SDMSO/H2O, and a strong correlation between the boiling points of solvents and the crystal lattice energy with the thermal stability of solvates was observed. Additionally, six crystal structures of five solvates and the reported Form I were successfully determined from single-crystal X-ray diffraction data. The results revealed that the belinostat molecule adopted flexible conformations in different crystal structures; meanwhile, the formation of belinostat solvate was mainly driven by the belinostat–solvent intermolecular interactions and the improved packing efficiency due to the introduction of solvent molecules.

In-situ formation of a hydrophobic deep eutectic solvent based on alpha terpineol and its application in liquid-liquid microextraction of three β-blockers from plasma samples

A new microextraction procedure based on liquid-liquid microextraction using a deep eutectic solvent has been used for the extraction of three β-blockers (atenolol, propranolol, and metoprolol) from plasma samples. The enriched analytes were analyzed by gas chromatography-mass spectrometry. In this study, both of the microextraction and synthesis processes were accelerated by using microwave radiations. In this procedure, 5 mL diluted plasma sample was transferred into a glass test tube and it was mixed with 0.20 g tetramethylammonium chloride. Then 0.5 mL of dimethylformamide (as a co-disperser) was mixed with 610 µL alpha terpineol and the mixture was dispersed into the solution to form a homogenous solution. The tube was placed under microwave radiations for 1 min. By doing so, tetramethylammonium chloride-alpha terpineol deep eutectic solvent was formed in sample solution as tiny droplets and the analytes were extracted into them. Then the tube was cooled with tap water and centrifuged for 5 min at 5000 rpm. Finally 1 µL of the deep eutectic solvent was injected into the determination system. Low limits of detection (0.130–0.205 ng mL−1) and quantification (0.435–0.692 ng mL−1), high extraction recovery (72–86%), and good precision (relative standard deviation ≤ 5.3%) were obtained. The introduced method was effectively applied for determination of the β-blockers’ concentrations in plasma samples.