Equilibrium Solubility Measurements Research Articles

Ternary solid dispersions of lacidipine: Enhancing dissolution and supersaturation maintenance through strategic formulation optimization

The study aimed to address the challenges related to insufficient dissolution and maintenance of supersaturation in binary solid dispersions. Lacidipine, categorized as a BCS class II drug, was employed as the model drug. A systematic screening of excipients was conducted to determine the most effective carriers for the formulations of the ternary solid dispersions, utilizing the solvent transfer method and equilibrium solubility measurements. Both binary and ternary solid dispersions were prepared via spray drying, and comprehensive physicochemical characterization confirmed the successful preparation of amorphous solid dispersions. In vitro dissolution tests, the ternary solid dispersion exhibited marked superiority over the binary solid dispersion in dissolution and maintenance of supersaturation. Furthermore, an exploration into the factors influencing the stability of ternary solid dispersions revealed their robust resistance under light-protected, room-temperature, and desiccated conditions. The formation of intermolecular hydrogen bonding within the molecules of the ternary solid dispersions significantly enhanced drug solubility and system stability. Strategic formulation optimization, coupled with judicious selection of suitable carrier types and ratios, may serve as a promising approach for designing supersaturated drug delivery systems.

CO2 absorption kinetics and equilibrium solubility measurements in potassium salts of renewable amino acids from plant‐ and animal‐protein

AbstractAqueous solutions containing alkaline salts of natural amino acids, such as those from protein in plant seeds or high protein animal‐based waste, are green CO2‐separation solvents. In the present work, potassium salts of nine such amino acids were chosen for an in‐depth study: alanine, arginine, aspartic acid, glutamic acid, glycine, leucine, proline, serine, and valine. The kinetics of CO2 absorption in aqueous solutions of these salts was studied using a stirred cell. From the measurements of the absorption rate at different salt concentrations (molarity 0.1 and higher), CO2 partial pressures (5–25 kPa), and temperatures (298–308 K), values of the reaction order, rate constant, and activation energy were determined. Additionally, the liquid‐side mass transfer coefficient (0.005 cm/s) was also found. Potassium salts of proline, glycine, and arginine were most reactive and, hence, were chosen for equilibrium study. The loading capacity of these salts was measured at 308 K in a vapour–liquid equilibrium setup at near‐ambient pressure. On the contrary, the other chosen acids were comparatively less reactive with CO2.

Solubility, solvent effect, preferential solvation and DFT computations of 5-nitrosalicylic acid in several aqueous blends

The purpose of this contribution was to investigate the solubility, computational techniques, solvent effect, and preferential solvation of 5-nitrosalicylic acid in blended solvents of acetonitrile/N,N-dimethylformamide(DMF)/methanol/n-propanol + water. Visualizing regions of weak contact between 5-nitrosalicylic acid and solvent using an independent gradient model based on Hirshfeld partitioning (IGMH), and providing a quantitative study for the molecule’s electrostatic characteristics using a molecular surface research and Hirshfeld surface analysis were carried out. All equilibrium solubility measurements were performed using a shake-flask technique at temperatures from 278.15 to 323.15 K and pressure of 101.2 kPa. For each blends studied, the lowest solubility was observed at 278.15 K in water and the highest at 323.15 K in pure organic solvent. Using linear solvation energy relationships, the effect of molecular interactions on solubility variation was studied, revealing that the solubility parameter and dipolarity-polarizability played a substantial impact in solubility variation. By correlating the derived equilibrium solubilities with the Jouyban-Acree, modified Apelblat-Jouyban-Acree, and van't Hoff–Jouyban–Acree models, a maximum relative average deviation of 4.01 percent was obtained. Quantitative investigation of the solvation behavior of 5-nitrosalicylic acid by solvent species was conducted using the method of inverse Kirkwood–Buff integrals. Positive values of the preferential solvation parameter in acetonitrile/DMF/methanol/n-propanol-middle and -rich blended systems indicated that acetonitrile/DMF/methanol/n-propanol solvated 5-nitrosalicylic acid preferentially. In the above composition ranges, it is hypothesized that 5-nitrosalicylic acid interacts with nearby methanol/DMF/n-propanol molecules as a Lewis acid, whereas solvation by acetonitrile is due to the polarization effect.

A novel molecular structure-based model for prediction of CO2 equilibrium absorption in blended imidazolium-based ionic liquids

• A comprehensive dataset including 4397 data points of CO 2 equilibrium solubility in imidazolium-based ionic liquids was acquired. • Various blended of imidazolium-based ILs were characterized based on their molecular frameworks. • Three machine learning predictive models were proposed to predict CO 2 solubility. • The simple but effective FFNN model gives reliable predictions, as compared with RBFNN and SVM algorithms. The present study highlights a comprehensive database including 4397 data points of CO 2 equilibrium solubility measurements in the 43 different imidazolium-based ionic liquids (ILs) over a broad range of pressures and absorption temperatures. The relation between the equilibrium CO 2 solubility and the molecular structure of the imidazolium-based ILs mixed with different kinds of solvents, including Diethanolamine (DEA), Methyl diethanolamine (MDEA), Diisopropylamine (DIPA), Amionomethyl propanol (AMP), and the equilibrium absorption pressure and the temperature has been accurately correlated. According to this database, a novel chemoinformatics-based descriptor model with a large number of 26 input data of structural information of all involved cation and anions and experimental conditions has been extracted. Three different machine learning methods, namely feed-forward neural network (FFNN), radial-based function neural network (RBFNN), and support vector machine (SVM), are employed to develop the derived descriptor-based model. The results of the three machine learning methods demonstrate that the prediction performance of the suggested models is quite reliable. Comparing the results indicate that the FFNN with corresponding values of RMSE = 0.071, R 2 = 0.952, and MAPE = 0.544 is the best paradigm to predict the CO 2 equilibrium solubility in imidazolium-based ILs.

Synthesis, crystal structure, and solubility study of a supramolecular assembly cocrystal formed by levofloxacin and nicotinic acid

A novel chemical structure named pharmaceutical cocrystal was synthesized with the purpose to enhance the solubility of levofloxacin (LVFX). Nicotinic acid (NA) was selected as cocrystal coformer (CCF). The cocrystal was successfully obtained by solvent evaporation method combined with ultrasonic technology. The crystal structure of LVFX-NA is triclinic with a P1 space group, unit cell parameters a = 7.1392 Å, b = 10.0188 Å, c = 17.5394 Å, α=86.109 (7), β=86.082 (6), γ=73.809 (7), z = 2, R1=0.0518, ωR2=0.1425. The supramolecular structure of LVFX-NA is mainly controlled by OH···N and CH···O intermolecular hydrogen bond. Moreover, intramolecular hydrogen bonds CH···F have also been found in the cocrystal structural units. The obtained cocrystal exhibits unique properties of thermoanalysis, Fourier transform infrared (FT-IR) spectrum and X-ray powder diffraction (PXRD) spectrum, demonstrated the new formed crystal material. Equilibrium solubility measurement revealed that LVFX-NA exhibited improved aqueous solubility, that is 5.02 times higher than the original LVFX.

Equilibrium Solubility and Solvent Effect Study of 3-Nitrosalicylic Acid in Different Monosolvents Covering Temperatures from 278.15 to 323.15 K

The measurement of equilibrium solubility for 3-nitrosalicylic acid in 13 monosolvents such as methanol, N,N-dimethylformamide (DMF), isobutanol, ethanol, ethylene glycol (EG), N-methyl-2-pyrrolidinone (NMP), n-propanol, ethyl acetate, isopropanol, water, n-butanol, acetonitrile, and 1,4-dioxane was made by the saturation shake-flask technique covering temperatures from 278.15 to 323.15 K under p = 101.2 kPa. As the studied temperature increased, the mole fraction solubility of 3-nitrosalicylic acid increased and had a decreasing tendency in the following order: NMP > DMF > ethyl acetate > methanol > ethanol > n-propanol > acetonitrile > isopropanol > n-butanol > EG > isobutanol > 1,4-dioxane > water. The solvent effects, such as solvent–solute and solvent–solvent molecular interactions, were further examined by the linear solvation energy relationships. Then, the equilibrium solubility magnitudes were correlated with thermodynamic models and semiempirical equations, namely, Wilson, Apelblat, λh, and NRTL. The calculated maximum value of root-mean-square deviation was 182.0 × 10–4, and the maximum value of relative average deviation was 7.24 × 10–2. In general, the obtained relative average deviation values with the Apelblat equation were smaller than those with the other equation/models for a fixed monosolvent. Finally, the mixing solution properties, activity coefficient, and partial molar excess enthalpy at infinite dilution were determined with the help of the Wilson equation.

Equilibrium solubility measurement of carbon dioxide in hybrid solvents of aqueous N-methyldiethanolamine blended with 1-Methyl-3-octyl-imidazolium tetrafluoroborate ionic liquid at high pressures

Solubility of CO2 in the hybrid solvents composed of aqueous N-methyldiethanolamine (MDEA) blended with 1-methyl-3-octyl-imidazolium tetrafluoroborate ([Omim][BF4]) ionic liquid (IL) was measured at temperatures from (298.15–343.15 K) and pressures of (0.2–4 MPa). The experimental trials were performed in a static high pressure equilibrium cell to determine the CO2 absorption capacity of novel absorbent solutions based on the isochoric saturation technique. The experimental data showed that, by rising the concentration of IL in the absorbent solutions’, the mole fraction of dissolved CO2 gas enhances gradually. Absorption capacity of these aqueous solutions was assessed and compared with pure ILs and alkanolamine solvents, which indicates the solutions studied in this research as better hybrid solvents in terms of CO2 loading. Furthermore, a semi empirical model is used to correlate the solubility data of this work, which presents a good agreement with an absolute average deviation (AAD %) of below 1%.

Intermolecular interactions and solubility behavior of multicomponent crystal forms of 2,4-D: design, structure analysis, and solid-state characterization

Five new multicomponent solid forms of 2,4-D were successfully synthesized. The equilibrium solubility measurement confirmed the improvements in water solubility of new multicomponent crystals.

Solid-liquid equilibrium solubility measurement, model evaluation and Hansen solubility parameter of thiamethoxam in three binary solvents

This work determined the mole fraction solubility of thiamethoxam in three binary solvent mixtures ((DMSO, DMA and acetic acid) + methanol) under the conditions of “T = 278.15 K to 323.15 K” and “p = 0.1 MPa”. The results demonstrated that with the increase of temperature and co-solvent mass fraction, the measured solubility of thiamethoxam increases in all the solvent mixtures studied. The results of using Hansen solubility parameters to investigate the affinity between thiamethoxam and the three mixed solvents studied indicate that this affinity may be caused by a combination of factors. Five thermodynamic models including modified Apelblat model, λh model, Wilson model, NRTL model and UNIQUAC model were used to regress the experimental solubility data of thiamethoxam in the three binary solvent mixtures. It was found that the UNIQUAC model and the modified Apelblat model correlated the experimental solubility more accurately than the other three models. In addition, the mixed thermodynamic properties for mixing process of thiamethoxam in different mixed solvents were estimated and discussed in term of Wilson model and experimental solubility data of thiamethoxam. Moreover, Wilson model was used to calculate the mixing thermodynamic parameters (ΔmixG, ΔmixH, ΔmixS) of the mixing process of thiamethoxam. All ΔmixG and ΔmixH values are negative and ΔmixS values are positive, which indicate that the mixture process of thiamethoxam in all the binary solvent mixtures studied is an entropy driven and spontaneous endothermic process.

Measurement and Modeling of the Solubility of Dodecylcyclohexane in Supercritical Carbon Dioxide

In developing the application of using supercritical carbon dioxide (sc-CO2) to extract fresh base oil from waste lubricant oil, the equilibrium solubility data is very valuable. In this study, the equilibrium solubilities for one of the single lubricant oil component, dodecylcyclohexane, were determined in the temperature T = 313.2 K, 328.2 K, 343.2 K, 358.2 K, 373 K and at pressures up to 17.76 MPa. Phase equilibrium solubility measurements were made in a high-pressure visual cell with variable volume, based on the static-analytic method. Oil solubility is strongly dependent on the density of carbon dioxide (CO2), which increased with pressure at constant temperature while decreased with temperature at same pressure. The solubility data were correlated using three density-based models: Mendez-Santiago and Teja (MST) equation, del Valle and Aguilera equation, Adachi and Lu equation, the results showed that all of these models can represent the experimental data well. Since the Adachi and Lu model provided the best regression analysis (R2) and the lowest average absolute relative deviation (AARD) than the other two models in the examined experimental range, indicating the nonlinear equation of Adachi and Lu model best agreement with the experimental data.

Harmonizing solubility measurement to lower inter-laboratory variance - progress of consortium of biopharmaceutical tools (CoBiTo) in Japan.

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The “mandatory” and “recommended” procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP.

Crystalline adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved residence time in the lungs

A crystalline adduct of the anti-tubercular drug, moxifloxacin and trans-cinnamic acid (1:1 molar ratio (MCA1:1)) was prepared to prolong the residence time of the drug in the lungs by reducing its solubility and dissolution rate. Whether the adduct is a salt or cocrystal has not been unequivocally determined. Equilibrium solubility and intrinsic dissolution rate measurements for the adduct (MCA1:1) in phosphate buffered saline (PBS, pH 7.4) revealed a significant decrease in the solubility of moxifloxacin (from 17.68 ± 0.85 mg mL−1 to 6.10 ± 0.05 mg mL−1) and intrinsic dissolution rate (from 0.47 ± 0.04 mg cm−2 min−1 to 0.14 ± 0.03 mg cm−2 min−1) compared to the supplied moxifloxacin. The aerosolization behaviour of the adduct from an inhaler device, Aerolizer®, using a Next Generation Impactor showed a fine particle fraction of 30.4 ± 1.2%. The dissolution behaviour of the fine particle dose of respirable particles collected was assessed in a small volume of stationary mucus fluid using a custom-made dissolution apparatus. The respirable adduct particles showed a lower dissolution (microscopic observation) and permeation compared to the supplied moxifloxacin. The crystalline adduct MCA1:1 has a lower solubility and dissolution rate than moxifloxacin and could improve the local residence time and therapeutic action of moxifloxacin in the lungs.

The role of higher coformer stoichiometry ratio in pharmaceutical cocrystals for improving their solid-state properties: The cocrystals of progesterone and 4-hydroxybenzoic acid

Progesterone (PROG) is a naturally occurring and poorly water soluble steroid hormone that belongs to the broad category of progestins. In this study, the poor aqueous solubility of PROG had been addressed through its cocrystallization with suitable coformer, 4-hydroxybenzoic acid (4-HBA). Investigation of the role of higher coformer concentration in cocrystals to enhance the aqueous solubility of PROG was the main objective of this study. For this purpose, cocrystals of PROG and 4-HBA were prepared in different stoichimetry ratios such as 1:1_A, 2:1 and 1:2 of PROG to 4-HBA,. All cocrystals were systematically characterized through X-ray powder diffraction, DSC, 1H NMR, IR and optical microscopy techniques. The crystal structure for 2:1 and 1:2 cocrystals was obtained from single crystal X-ray diffraction and analysed. A mixture of kinetic forms (named as 1:1_B) was obtained with grinding of equimolar mixture of PROG and 4-HBA, which produced thermodynamically stable 1:1_A cocrystal upon recrystallization. Cocrystals were characterized with single crystal X-ray diffraction, XRPD, DSC and FTIR. The equilibrium solubility measurements for the cocrystals were carried out in water and ethanol where the cocrystal forms exhibited enhanced solubility profiles than PROG.

Right filter-selection for phase separation in equilibrium solubility measurement

The phase separation is a crucial step in equilibrium solubility measurements. In the standardized protocol of saturation shake-flask method, sedimentation is proposed as the safest technique. However filtration is widely used in pharma practice. In this paper the effect of the filtration on the measured equilibrium solubility results is presented. The equilibrium solubility values of four model compounds, namely diclofenac sodium, hydrochlorothiazide, papaverine hydrochloride and progesterone were determined at various pH values using the saturation shake-flask method. Two phase separation techniques (sedimentation and filtration) were applied for the separation of the solid from the saturated solution. Four membrane filters, polyvinylidene fluoride (PVDF), polyether sulfone (PES), polytetrafluoroethylene (PTFE) and nylon, as well as an analytical filter paper were investigated. The results obtained by filtration were compared with those measured by sedimentation and the distortion effect of the filter (DEF) on solubility results was expressed in %. The results showed that the filter material type is able to remarkably influence the results in solubility measurements. In several cases, the significant adsorption to the filter caused high inaccuracy in the measured concentration value, more over in some cases failed to work at all. As a main conclusion of this work, if the step of filtration is inevitable, the adsorption to the filter can be mitigated with the appropriate filter type selection what needs some experiences and knowledge about the acid-base chemistry and polar/apolar nature of the sample.

Two- and three-phase equilibrium experimental measurements for the ternary CH4 + CO2 + H2O mixture

Experimental measurements are reported for the ternary methane + carbon dioxide + water mixture under three-phase hydrate equilibrium conditions utilizing a recently-introduced experimental apparatus. In addition to measuring the three-phase equilibrium pressure and temperature conditions, vapor and liquid phase analysis measurements are also reported. In particular, we performed gas chromatographic analysis of the vapor phase and the solubility of each gas in the aqueous phase was measured under three-phase equilibrium conditions. Additionally, two-phase equilibrium solubility measurements are also reported at pressure and temperature conditions that are in the close neighborhood of hydrate-formation conditions.

Equilibrium solubility measurement of compounds with low dissolution rate by Higuchi's Facilitated Dissolution Method. A validation study

Incubation time plays a critical role in the accurate measurement of equilibrium solubility of compounds. Substances which dissolve very slowly generally need long incubation times (days or weeks) to reach equilibrium. However, long times may pose several problems, such as decomposition of solute, molding of buffer, and drifting of pH. Higuchi in 1979 proposed the Facilitated Dissolution Method (FDM) to dramatically reduce incubation time. It employs a small volume of water-immiscible organic solvent to partly solubilize the sample and thereby increase the surface area available for dissolution. The method has been used only rarely. In this study we performed a systematic validation of FDM using progesterone as model compound. The reference solubility value, 7.95±0.21μg/mL (p<0.05, n=5), was determined in Britton-Robinson buffer solution (pH7.4) at 25.0°C by the standardized protocol of Saturation Shake-Flask (SSF) method. Also, the solubility was measured by the FDM approach under varied experimental conditions (e.g., type and volume of organic solvent, time of agitation, and amount of solid excess), and compared to the reference value. It was demonstrated that the small amount of organic solvent used in the FDM does not impact the measured solubility, compared to the reference value. Additionally, four compounds of low dissolution rate (dexamethasone, digoxin, haloperidol and cosalane) were used to demonstrate that FDM can reduce the long equilibration time to the standardized 24h (6h stirring and 18h sedimentation). The time dependence of solubility equilibrium was measured by SSF, and the results were compared with those obtained by FDM. Our study, based on >200 solubility experiments, supports the validity of Higuchi's method. In this study we propose a standardized protocol for the FDM, where 1% v/v of organic solvent is used. Octane (or isooctane) was found to be suitable for highly hydrophobic compounds. Alternatively, octanol or 1,2-dichloroethane can be used for less lipophilic compounds.

Equilibrium solubility measurement and Kent‐Eisenberg modeling of CO2 absorption in aqueous mixture of N‐methyldiethanolamine and hexamethylenediamine

AbstractVapor‐liquid equilibrium of CO2 in aqueous mixture of hexamethylenediamine (HMDA) and N‐methyldiethanolamine (MDEA) has been investigated using a stirred equilibrium cell set‐up in the temperature and pressure range of 303–333K and 1–100kPa, respectively. Composition of the mixed amine solvents used are (5mass% HMDA+25mass% MDEA), (10 mass% HMDA+20 mass% MDEA), (15mass% HMDA+15mass% MDEA), and (20 mass% HMDA+10 mass% MDEA). Equilibrium solubility data is fitted using the Kent‐Eisenberg thermodynamic model. To fit experimental solubility data with model predicted data, bicarbamate formation and zwitterion deprotonation reaction equilibrium constants of HMDA are regressed as a function of CO2 loading and temperature. Average absolute deviation between experimental and model predicted data is found to be 7.16%. © 2016 Society of Chemical Industry and John Wiley &amp; Sons, Ltd.

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

&lt;p class="ADMETabstracttext"&gt;This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation), use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method), solubility type (water, buffer, intrinsic), temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pK&lt;sub&gt;a&lt;/sub&gt;, equilibration time (stirring and sedimentation), separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.&lt;/p&gt;

Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated β-cyclodextrins: models for cyclodextrin-steroid interaction.

The interaction between the potent anticancer agent 2-methoxyestradiol (2ME) and a series of cyclodextrins (CDs) was investigated in the solid state using thermal analysis and X-ray diffraction, while the possibility of enhancing its poor aqueous solubility with CDs was probed by means of equilibrium solubility and dissolution rate measurements. Single crystal X-ray diffraction studies of the inclusion complexes between 2ME and the derivatised cyclodextrins heptakis(2,6-di-O-methyl)-β-CD (DIMEB) and heptakis(2,3,6-tri-O-methyl)-β-CD (TRIMEB) revealed for the first time the nature of the encapsulation of a bioactive steroid by representative CD host molecules. Inclusion complexation invariably involves insertion of the D-ring of 2ME from the secondary side of each CD molecule, with the 17-OH group generally hydrogen bonding to a host glycosidic oxygen atom within the CD cavity, while the A-ring and part of the B-ring of 2ME protrude from the secondary side. In the case of the TRIMEB·2ME complex, there is evidence that complexation proceeds with mutual conformational adaptation of host and guest molecules. The aqueous solubility of 2ME was significantly enhanced by CDs, with DIMEB, TRIMEB, randomly methylated β-CD and hydroxypropyl-β-CD being the most effective hosts. The 2:1 host–guest β-CD inclusion complex, prepared by two methods, yielded very rapid dissolution in water at 37 °C relative to untreated 2ME, attaining complete dissolution within 15 minutes (co-precipitated complex) and 45 minutes (complex from kneading).

Thermodynamic equilibrium solubility measurements in simulated fluids by 96-well plate method in early drug discovery.

An early prediction of solubility in physiological media (PBS, SGF and SIF) is useful to predict qualitatively bioavailability and absorption of lead candidates. Despite of the availability of multiple solubility estimation methods, none of the reported method involves simplified fixed protocol for diverse set of compounds. Therefore, a simple and medium-throughput solubility estimation protocol is highly desirable during lead optimization stage. The present work introduces a rapid method for assessment of thermodynamic equilibrium solubility of compounds in aqueous media using 96-well microplate. The developed protocol is straightforward to set up and takes advantage of the sensitivity of UV spectroscopy. The compound, in stock solution in methanol, is introduced in microgram quantities into microplate wells followed by drying at an ambient temperature. Microplates were shaken upon addition of test media and the supernatant was analyzed by UV method. A plot of absorbance versus concentration of a sample provides saturation point, which is thermodynamic equilibrium solubility of a sample. The established protocol was validated using a large panel of commercially available drugs and with conventional miniaturized shake flask method (r(2)>0.84). Additionally, the statistically significant QSPR models were established using experimental solubility values of 52 compounds.