Neat Organic Solvents Research Articles

Determination of solubility of sildenafil citrate in propylene glycol + 2-propanol and N-methyl pyrrolidone + water: Comparing solubilization power of aqueous or non-aqueous mixtures

For identifying the solubilization power of aqueous and non-aqueous solvent mixtures for sildenafil citrate (SLC), its solubility was determined in four mono-solvents of propylene glycol, 2-propanol, N-methyl pyrrolidone and water along with the binary solvent mixtures of propylene glycol + 2-propanol and N-methyl pyrrolidone + water at 293.2 to 313.2 K and at pressure of 85 kPa. Among the neat organic solvents and also water, N-methyl pyrrolidone presented a high solubilization power for SLC (8.66 × 10-2 at 313.2 K) and its aqueous binary mixtures had also a more ability to solubilize the drug in compared with the binary (propylene glycol + 2-propanol) mixtures (with the highest value of 4.96 × 10–4 at 313.2 K). Besides, increasing the solubility of SLC with raising temperature illustrated that its dissolution in the aforementioned mixtures was endothermic. The equilibrium solid phase crystal of SLC was also characterized with X-ray powder diffraction analysis to identify no polymorphic transformation, solvate formation or crystal transition during the whole solvent crystallization process. Moreover, the experimental mole fractions were modelled by used commonly cosolvency models and regressed the model parameters. The back-calculated mole fractions of SLC by cosolvency models shown a better agreement with the experimental data (overall mean percentage deviation (OMPD) ≤ 7.6 %) and Jouyban-Acree model as a function of temperature and solvent compositions had the best performance (MPD of 3.2 %). Furthermore, the solubility data sets of SLC in 7 binary solvent mixtures were collected from the literature and correlated with the Jouyban-Acree model and its derivates, the OMPDs for the back-computed solubility indicating the generally trained models, especially Jouyban-Acree-Abraham model (MPD of 24.2 %), had an acceptable ability in the prediction of SLC solubility and can be useful in the pharmaceutical industry. Finally, apparent thermodynamic properties of Gibbs free energy, standard enthalpy and entropy of the dissolution processes were also investigated.

Deducing solute differential heat capacity from experimental solubilities. An exemplified treatment of ascorbic acid to improve solubility prediction

ContextSolubility prediction based on the general solubility equation (GSE) rests on reliable values for the isobaric heat capacity difference ΔCp,1 of the solid solute. Usually, this value is estimated with either zero or the melting entropy ΔS1(Tm,1) or, in few cases, is extrapolated from data of thermally stable melts of the solute. This causes uncertainties in the prediction. ObjectiveTo improve prediction accuracy a simple regression method is proposed that determines ΔCp,1 from measured solubilities. Materials and methodsPublished experimental solubilities in neat organic solvents at 298 K of a model compound (L-(+)-ascorbic acid (LAA)) have been regressed using the GSE together with the Hansen parameter model for the activity coefficient. Results and discussionRegression yielded ΔCp,1 = 238 J∙mol−1∙K−1 which agrees well with cross-validation results and is consistent with estimates from various group contribution methods. It was found that prediction accuracy improved in the order of increasing ΔCp,1, that is, from 0, via 91 (=ΔS1(Tm,1)) to 238 J∙mol−1∙K−1. It could be shown that mole fraction solubility of LAA can be forecast this way with an accuracy within current inter-laboratory variation. ConclusionThe proposed method shows a general way to improve prediction accuracy of activity coefficient based solubility models by determining ΔCp,1 without resorting to common assumptions. The method is universally applicable and easy to implement.

IUPAC-NIST Solubility Data Series. 105. Solubility of Solid Alkanoic Acids, Alkenoic Acids, Alkanedioic Acids, and Alkenedioic Acids Dissolved in Neat Organic Solvents, Organic Solvent Mixtures, and Aqueous–Organic Solvent Mixtures. III. Alkanedioic Acids and Alkenedioic Acids

Solubility data are compiled and reviewed for 19 alkanedioc and alkenedioic acids dissolved in neat organic solvents and well-defined binary organic and aqueous–organic solvent mixtures. The compiled solubility data were retrieved from the published chemical, engineering, and pharmaceutical literature covering the period between 1910 and the beginning of 2021.

Equilibrium solubility, solvation and dissolution thermodynamics, and DFT study of 18β-glycyrrhetinic acid in solutions of 1,4-dioxane/N,N-dimethylformamide/ethanol/isopropanol + water

This study investigated the solubility, solvation behavior, dissolution thermodynamics, and intermolecular interactions of 18β-glycyrrhetinic acid (GA) in binary aqueous blends of 1,4-dioxane, N,N-dimethylformamide (DMF), ethanol and isopropanol. The solubility experiments were performed using the shake-flask technique at 101.0 kPa and temperatures ranging from 278.15 to 323.15 K. The lowest and highest GA solubility was observed in water and neat organic solvent, respectively. Experiments based on XRD analysis revealed no crystal transition or solvation. Modified van't Hoff–Jouyban–Acree and Jouyban–Acree models connected the solubility with relative average deviations (RAD) not exceeding 3.63 %. The extended Hildebrand solubility parameter method was utilized here to examine the equilibrium solubility at 298.15 K, yielding a RAD of 3.95 %. According to the linear solvation energy relationship examination, the dipolarity-polarizability and solubility parameter of solutions significantly influence the solubility variation. Using the inverse Kirkwood–Buff integrals, the preferential solvation of GA by organic solvents and water was investigated quantitatively. Positive preferential solvation parameter for organic solvents in rich and moderate organic solvent blends indicated that GA was preferentially solvated by the organic solvents. GA is a Lewis acid with respect to the cosolvent molecules. Thermodynamic investigation of dissolution characteristics and enthalpy–entropy compensation revealed an endothermic process and enthalpy-driven mechanism for dissolving GA in various blends. Finally, microscopic quantitative examination of molecular surface was used to highlight the electrostatic properties of acidity/basicity of GA. The –C = O, OH, and > COOH groups are the main targets of electrophilic and nucleophilic attack. The weak interactions between GA and solvent were visually examined using an independent gradient model based on Hirshfeld partition analysis.

Protease-catalyzed synthesis of α-poly-L-Lysine and amphiphilic poly(L-lysine-co-L-phenylalanine) in a neat non-toxic organic solvent.

Subtilisin Carlsberg (alkaline protease from Bacillus licheniformis) catalyzes the syntheses of high molecular weights (ca. 20 KDa) cationic α-poly-L-lysine and amphiphilic poly(α-L-lysine-co-L-phenylalanine) in neat organic solvent. The synthesis is conducted in liquid 1,1,1,2-tetrafluoroethane solvent, which is a hydrophobic non-toxic gas that does not deplete the ozone layer and approved for pharmaceutical applications. Solubility of substrates and adequate protease activity in this system with low water environment limits the reaction of hydrolysis of the growing peptide chains. The pressurization of this organic compressed fluid to liquid has low-pressure requirements (25bar, 40 ºC), and its complete evaporation at atmospheric pressure after completing the reaction ensures solvent-free residues in products. The resulting polypeptides present null cytotoxicity according to MTT and NR analyses, as well as Calcein/EthD-1 assay in human cells.

Chemoenzymatic Synthesis of Optically Active Alcohols Possessing 1,2,3,4-Tetrahydroquinoline Moiety Employing Lipases or Variants of the Acyltransferase from Mycobacterium smegmatis

The enzymatic kinetic resolution (EKR) of racemic alcohols or esters is a broadly recognized methodology for the preparation of these compounds in optically active form. Although EKR approaches have been developed for the enantioselective transesterification of a vast number of secondary alcohols or hydrolysis of their respective esters, to date, there is no report of bio- or chemo-catalytic asymmetric synthesis of non-racemic alcohols possessing 1,2,3,4-tetrahydroquinoline moiety, which are valuable building blocks for the pharmaceutical industry. In this work, the kinetic resolution of a set of racemic 1,2,3,4-tetrahydroquinoline-propan-2-ols was successfully carried out in neat organic solvents (in the case of CAL-B and BCL) or in water (in the case of MsAcT single variants) using immobilized lipases from Candida antarctica type B (CAL-B) and Burkholderia cepacia (BCL) or engineered acyltransferase variants from Mycobacterium smegmatis (MsAcT) as the biocatalysts and vinyl acetate as irreversible acyl donor, yielding enantiomerically enriched (S)-alcohols and the corresponding (R)-acetates with E-values up to 328 and excellent optical purities (>99% ee). In general, higher ee-values were observed in the reactions catalyzed by lipases; however, the rates of the reactions were significantly better in the case of MsAcT-catalyzed enantioselective transesterifications. Interestingly, we have experimentally proved that enantiomerically enriched 1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-2-ol undergoes spontaneous amplification of optical purity under achiral chromatographic conditions.

Measurement and correlation of 4,4′-dihydroxydiphenylsulfone solubility in ten neat organic solvents at temperatures from 278.15 to 313.15 K

The equilibrium solubility of 4,4′-dihydroxydiphenylsulfone (BPS) in ten neat organic solvents, including methanol, 2-butanol, acetonitrile, 2-butanone, cyclohexanone, formamide, N, N-dimethylformamide, ethyl formate, isopropyl acetate, and dimethyl carbonate at temperatures from 278.15 to 313.15 K under atmospheric pressure (101.3×103Pa) was studied using an isothermal saturation method. In all studied solvents, the solubility of BPS increased with the increase in temperature. Three solubility fitting models, including the van’t Hoff equation, modified Apelblat equation, and λh equation, were used to correlate the experimental solubility data. The maximum magnitudes of the relative average deviation (RAD%) and root mean square deviation (RMSD) were 5.27 % and 9.45 × 10-3. Generally, the magnitudes of the RAD% generated by the modified Apelblat equation were the smallest among the selected solubility fitting models.The thermodynamic properties of BPS, such as the apparent standard dissolution enthalpy (ΔHsolo), standard dissolution Gibbs energy (ΔGsolo), and standard dissolution entropy change (ΔSsolo), were calculated. The ΔHsolo is positive in all studied cases, indicating that the dissolution process of BPS is endothermic. The obtained solubility data and relevant thermodynamic studies have an important guiding significance for optimizing the crystallization and purification process of BPS.

Solubility, MD simulation, thermodynamic properties and solvent effect of perphenazine (Form I) in eleven neat organic solvents ranged from 278.15 K to 318.15 K

Perphenazine has rather effective in the treatment of mental illness. In this work, the solid-liquid equilibrium data of perphenazine in eleven organic neat solvents were determined by laser dynamic method under the atmospheric pressure and temperature range of 278.15 K ∼ 318.15 K. The selected solvents were n-propanol, n-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, n-amyl acetate, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), acetone, 2-methoxyethanol, glycol ether, respectively. From the results, the solubility of perphenazine is all positively correlated with temperature. Separately, we have adopted the KAT-LSER model and molecular dynamics simulation to investigate the influence of solvent effects and solute-solvent interaction on solute solubility. Meanwhile, there were four activity coefficient models being used to correlate the solubility data and Average relative deviation of models are 4.13% (Margules model), 3.94% (NRTL model), 4.49% (NRTL-SAC model) and 3.06% (UNIQUAC model), respectively, all of which do not exceed 5%. It manifests that the four activity coefficient models can fit the experimental values well, in which the UNIQUAC model gives the best regression effect. Moreover, the apparent thermodynamic properties(△solG°, △solH° and △solS°) of perphenazine in various solvents were calculated by Van’t Hoff equation. In accordance with the analysis and calculation of dissolution, the dissolution process is an endothermic entropy-driven process. This research can provide basic data for the crystallization process of perphenazine.

Application of immobilized glycosidase in the synthesis of glycoside compounds

Glycoside compounds are widely used in medicine, food, surfactant, and cosmetics. The glycosidase-catalyzed synthesis of glycoside can be operated at mild reaction conditions with low material cost. The glycosidase-catalyzed processes include reverse hydrolysis and transglycosylation, appropriately reducing the water activity in both processes may effectively improve the catalytic efficiency of glucosidase. However, glucosidase is prone to be deactivated at low water activity. Thus, glucosidase was immobilized to maintain its activity in the low water activity environment, and even in neat organic solvent system. This article summarizes the advances in glycosidase immobilization in the past 30 years, including single or comprehensive immobilization techniques, and immobilization techniques combined with genetic engineering, with the aim to provide a reference for the synthesis of glycosides using immobilized glycosidases.

IUPAC–NIST Solubility Data Series. 105. Solubility of Solid Alkanoic Acids, Alkenoic Acids, Alkanedioic Acids, and Alkenedioic Acids Dissolved in Neat Organic Solvents, Organic Solvent Mixtures, and Aqueous–Organic Solvent Mixtures. II. Alkenoic and Alkynoic Acids

Solubility data are compiled and reviewed for ten alkenoic acids and one alkynoic acid dissolved in neat organic mono-solvents. The compiled solubility data were retrieved from the published chemical, engineering, and pharmaceutical literature covering the period from 1910 to the beginning of 2021.

Antioxidant Activity of Different Extracts from Black Alder (Alnus glutinosa) Bark with Greener Extraction Alternative.

Phenolic compounds isolated from plant biomass consist of bioactive components showing a wide range of benefits for humans, including antioxidant, antimicrobial or anti-inflammatory effects. This paper presents the potential value of black alder (Alnus glutinosa (L.) Gaertn. (Betulaceae)) bark for the production of biologically active substances, despite its current use as a low value fuel source. Most of the extraction methods employ neat organic solvents to obtain extracts with a high antioxidant potential from biomass. The aim of this work is to show the advantages and disadvantages of the extraction process by taking into account the principles of ‘green chemistry’ and replacing the organic solvents with ‘green’ solvent water. Using the advantages of accelerated solvent extraction (ASE), it has been shown that the use of deionized water has the prospect of replacing organic solvents. In the case of the one-step water extraction, the total polyphenol content (TPC) varies from 0.55 to 0.62 Gallic acid equivalent (GAE) g/g in the extracts, depending on the temperature, whereas with the result of the sequential extraction with the organic solvents, the TPC content of the 40% (v:v) ethanol extracts ranges from 0.39 to 0.61 GAE g/g, depending on the temperature. The influence of the total polyphenol content and the total proanthocyanidin content on the antioxidant activity is shown. The antioxidant activity (IC50, mg/L) of the extracts obtained with the organic solvents in the (2,2-diphenyl-1-picrylhydrazyl) DPPH• test varies from 4.05 to 9.58, depending on the temperature in the range of 70–150 °C, respectively, while the results obtained with the deionized water showed promising results in the range of 6.33–7.36 in the temperature range of 70–150 °C, respectively. The extraction with the deionized water showed that approximately 90% of the substances in the extracts obtained with the organic solvents by sequential extraction are possible to obtain as deionized water extracts.

Solubility, solvent effect, enthalpy–entropy compensation and solvation thermodynamics of 4-(bromomethyl)-2(1H)-quinolinone in several aqueous blends

The current study was mainly devoted to solubility for the systems formed by 4-(bromomethyl)-2(1H)-quinolinone (BMQ) and blended solvents of isopropanol, N-methyl-2-pyrrolidinone (NMP), ethanol and n-propanol with water. Experiments for solubility determination were conducted by employing the shake-flask equilibration method from 278.15 to 318.15 K under 101.2 kPa. For each aqueous cosolvent mixture, the minimum solubility was recorded in water at 278.15 K; and the maximum value, in neat organic solvents at 318.15 K. The solubility performance was illustrated by Hansen solubility parameters of water, BMQ and co-solvents. No occurrence of polymorphic transformation or solvation was observed after experiments based on the XRD spectra of raw BMQ and excess solids analyzed. The satisfactory correlation results for solubility data was obtained by modified Wilson model, mixture response surface model, modified van’t Hoff-Jouyban–Acree model and Jouyban–Acree model. The relative average deviations were calculated to be no more than 8.72 %. Investigation on the relative contributions from inter- and intra-molecular interactions to the solubility variation of BMQ at temperature of 298.15 K was quantitatively performed via the linear solvation energy relationships (LSER). The descriptors of solvent blends including solubility parameter, dipolarity-polarizability and hydrogen-bond basicity were primarily responsible for the solubility variation. As well, the preferential solvation of BMQ was researched quantitatively via the inverse Kirkwood–Buff integrals method on the basis of some obtainable properties of solvent blends. The positive preferential solvation parameters for BMQ in middle and cosolvent-rich blends strongly suggest that the crystalline solute of BMQ is preferentially solvated by cosolvents of isopropanol, NMP, ethanol and n-propanol. The transfer and apparent dissolution properties including apparent Gibbs energy change (298.15 K), dissolution enthalpy and dissolution entropy (298.15 K) were derived and discussed. Analysis of enthalpy–entropy compensation indicates the entropy-driven mechanism of BMQ dissolved in all blend solvents.

IUPAC–NIST Solubility Data Series. 105. Solubility of Solid Alkanoic Acids, Alkenoic Acids, Alkanedioic Acids, and Alkenedioic Acids Dissolved in Neat Organic Solvents, Organic Solvent Mixtures, and Aqueous–Organic Solvent Mixtures. I. Alkanoic Acids

Solubility data are compiled and reviewed for 15 alkanoic acids dissolved in neat organic solvents and well-defined binary organic and aqueous–organic solvent mixtures. The compiled solubility data were retrieved from the published chemical, engineering, and pharmaceutical literature covering the period between 1910 and the beginning of 2021.

Experimental and Theoretical Screening for Green Solvents Improving Sulfamethizole Solubility.

Solubility enhancement of poorly soluble active pharmaceutical ingredients is of crucial importance for drug development and processing. Extensive experimental screening is limited due to the vast number of potential solvent combinations. Hence, theoretical models can offer valuable hints for guiding experiments aimed at providing solubility data. In this paper, we explore the possibility of applying quantum-chemistry-derived molecular descriptors, adequate for development of an ensemble of neural networks model (ENNM), for solubility computations of sulfamethizole (SMT) in neat and aqueous binary solvent mixtures. The machine learning procedure utilized information encoded in σ-potential profiles computed using the COSMO-RS approach. The resulting nonlinear model is accurate in backcomputing SMT solubility and allowed for extensive screening of green solvents. Since the experimental characteristics of SMT solubility are limited, the data pool was extended by new solubility measurements in water, five neat organic solvents (acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, and methanol), and their aqueous binary mixtures at 298.15, 303.15, 308.15, and 313.15 K. Experimentally determined order of decreasing SMT solubility in neat solvents is the following: N,N-dimethylformamide > dimethyl sulfoxide > methanol > acetonitrile > 1,4dioxane >> water, in all studied temperatures. Similar trends are observed for aqueous binary mixtures. Since N,N-dimethylformamide is not considered as a green solvent, the more acceptable replacers were searched for using the developed model. This step led to the conclusion that 4-formylmorpholine is a real alternative to N,N-dimethylformamide, fulfilling all requirements of both high dissolution potential and environmental friendliness.

Solubility, solvation thermodynamics and solvent effect of thiabendazole in several cosolvent blends

Equilibrium solubility determination and model correlation were performed in the present research for the systems formed by solid solute of thiabendazole and binary aqueous blends of acetonitrile, methanol, n-propanol and isopropanol. Experiments at temperatures ranging from 283.15 to 323.15 K were conducted by the use of the shake-flask saturation technique at 101.2 kPa. For the given binary solvent blends, the minimum mole fraction solubility was recorded in water at 283.15 K; and the maximum one, in neat organic solvent at 323.15 K. The generated equilibrium solubility was satisfactorily described by two models, modified van’t Hoff-Jouyban–Acree and Jouyban–Acree, with the relative average deviations (%) of no more than 6.08. Good prediction results of extend Hildebrand solubility approach (relative average deviations < 4.10%) were observed in terms of quartic polynomial for the four solution systems to correlate the interaction parameter (W) and solubility parameters of the solvents’ blends in the absence of thiabendazole (δ1+2). Analysis of the relative contributions from intra- and inter-molecular interactions to solubility variation of solid solute of thiabendazole (298.15 K) was quantitatively carried out via the linear solvation energy relationships (LSER). The descriptors of blended solvents comprising solubility parameter and hydrogen-bond basicity were principally responsible for the variation of determined solubility. Besides, the preferential solvation of thiabendazole was quantitatively researched via the inverse Kirkwood–Buff integrals method on the basis of some accessible properties for blended solvent systems. The positive preferential solvation parameters for thiabendazole in the middle and cosolvent-rich blends powerfully suggested that thiabendazole was preferentially solvated by cosolvents of isopropanol, acetonitrile, n-propanol, ethanol and methanol. The conjecture was reasonable that in above compositions, thiabendazole mainly served as Lewis acidic in terms of its interactions with alcohol molecules; while for the acetonitrile mixtures, this behavior was contributed by polarization effect. Besides, thiabendazole was preferentially solvated by ethanol (2) in ethyl acetate (1) + ethanol (2) solutions with ethyl acetate-rich compositions, and by water (2) solvent in aqueous blends with rich water compositions.

Experimental and Theoretical Study on Theobromine Solubility Enhancement in Binary Aqueous Solutions and Ternary Designed Solvents.

The solubility of theobromine was studied both experimentally and theoretically. The solubility was determined spectrophotometrically at 25 °C in neat organic solvents, aqueous binary mixtures, Natural Deep Eutectic Solvents (NADES) and ternary NADES mixtures with water. It was found that addition of water in unimolar proportions with some organic solvents increases theobromine solubility compared to neat solvents. Additionally, using NADES results in a solubility increase of the studied compound not only in relation to water but also DMSO. The addition of water (0.2 molar fraction) to NADES is responsible for an even larger increase of solubility. The measured solubilities were interpreted in terms of three theoretical frameworks. The first one—belonging to the set of data reduction techniques—proved to be very efficient in quantitative back-computations of excess solubility of theobromine in all studied systems. The default approach utilizing the well-recognized COSMO-RS (Conductor-like Screening Model for Real Solvents) framework offered at most a qualitative solubility description. The extended search for possible contacts provided evidence for the existence of many intermolecular complexes that alter the electron density of the solute molecule, thus influencing solubility computations. Taking into account such intermolecular contacts by using the COSMO-RS-DARE (Conductor-like Screening Model for Realistic Solvation-Dimerization, Aggregation, and Reaction Extension) framework seriously increased the accuracy of solubility computations.

Comments on “Assessment of solubility and Hansen solubility parameters of rifampicin in various permeation enhancers: Experimental and computational approach”

A polemic is given regarding the published curve-fit equation coefficients for both the van’t Hoff and Modified Apelblat equations, as well as for the published apparent thermodynamic properties of dissolution of rifampicin in several neat permeation enhancers and in several neat organic solvents.

Measurement of relative static permittivity and solvatochromic parameters of binary and ternary CO2-expanded green solvents

CO2-expanded liquids (CXLs) is a class of solvent systems giving relatively low viscosity in comparison to neat organic solvents. The challenge is to achieve a high overall polarity of the CXL, despite the presence of compressed liquid CO2. In this study, the relative static permittivity (εr) was measured for binary and ternary one-phase mixtures of CO2 + green solvent using an in-line microfluidic device. In addition, Kamlet-Taft solvatochromic parameters were experimentally determined, allowing the characterization of the polarizability, acidity, and basicity. Novel data is shown for binary and ternary systems of CO2 expanded ethanol and ethyl lactate, with or without glycerol or water added, at moderate conditions of pressure and temperature (8 MPa and 35 °C). One-phase CXLs systems of a wide relative permittivity range (7.7–75.3) at lowered viscosity were enabled, by mixing different green solvents with CO2.

Research on the 2-Chloro-4-amino-6,7-dimethoxyquinazoline Solubility in 12 Monosolvents at Various Temperatures: Experimental Measurement and Thermodynamic Correlation

The present study investigating the experimental equilibrium solubility of 2-chloro-4-amino-6,7-dimethoxyquinazoline (CADQ) dissolved in 12 kinds of neat organic solvents, including methanol, ethan...

Saturated Solubility of 2-Acrylamide-2-methylpropanesulfonic Acid in 14 Neat Organic Solvents from 283.15 to 328.15 K

This investigation was devoted to the saturated solubility of 2-acrylamide-2-methylpropanesulfonic acid in 14 pure organic solvents, namely, ethyl acetate, methanol, 1,4-dioxane, ethanol, isopropan...