Equilibrium Aqueous Solubility Research Articles

Solubility, correlation, dissolution thermodynamics and preferential solvation of meloxicam in aqueous mixtures of 2-propanol

Background: Meloxicam is a powerful analgesic and anti-inflammatory drug widely prescribed by physicians in current therapeutics. Because of the very low aqueous equilibrium solubility of meloxicam, this property has been studied in {2-propanol + water} mixtures from (293.15 to 313.15) K to expand the solubility database about pharmaceutical compounds in mixed solvents useful for homogeneous liquid dosage forms design. Methods: Flask shaken method and UV-vis spectrophotometry were used for meloxicam solubility determinations. Jouyban-Acree model was challenged for solubility correlation. The van’t Hoff and Gibbs equations were employed here to calculate the respective apparent standard thermodynamic quantities for the dissolution and mixing processes, namely Gibbs energy, enthalpy, and entropy. In addition, the inverse Kirkwood-Buff integrals were employed to compute the preferential solvation parameters of meloxicam by 2-propanol in the mixtures. Results: Meloxicam solubility increases with temperature arising and maximum solubilities are observed in the mixture of x1 = 0.70 at all temperatures. Jouyban-Acree model correlates the meloxicam solubility very well. Dissolution processes were endothermic in all cases and entropy-driven in the interval 0.20 ≤ x1 ≤ 1.00. Non-linear enthalpy–entropy relationship was observed in the plot of enthalpy vs. Gibbs energy exhibiting negative but variant slopes in the composition region 0.00 < x1 < 0.40 and variant negative and positive slopes in the other mixtures. Meloxicam is preferentially solvated by water in water-rich mixtures, it is apparently solvated by water in 2-propanol-rich mixtures, but it is preferentially solvated by 2-propanol in the composition interval of 0.19 < x1 < 0.78. Conclusion: Solid-liquid equilibrium of meloxicam in {2-propanol + water} mixtures has been studied at several temperatures as a contribution to preformulation studies of homogeneous liquid pharmaceutical dosage forms based on this drug.

Bortezomib Aqueous Solubility in the Presence and Absence of D-Mannitol: A Clarification With Formulation Implications

The solubility of bortezomib, a boronic acid, in water and normal saline is often misquoted in the literature. Here we confirm that bortezomib equilibrium solubility in water and normal saline is 0.59 ± 0.07 and 0.52 ± 0.11 mg/mL, respectively. The aqueous solubility is significantly enhanced, 1.92 ± 0.14 and 3.40 ± 0.21 mg/mL, respectively, in the presence of 55 mM and 137 mM D-mannitol in normal saline, as in the commercial formulation, Velcade®, after reconstitution. This is due to reversible ester formation between bortezomib and D-mannitol. Based on the pH-solubility profile curve for bortezomib in the absence of added D-mannitol, bortezomib's pKa value is estimated to be 8.8 ± 0.2. Boric acid, glycine and a combination of the two, used in an alternative formulation to that of Velcade® do not enhance the equilibrium aqueous solubility of bortezomib.

Further enhanced dissolution and oral bioavailability of docetaxel by coamorphization with a natural P-gp inhibitor myricetin

The current study aims to improve the dissolution and oral bioavailability of a BCS IV drug docetaxel (DOC) by coamorphization with a natural P-gp inhibitor myricetin (MYR). A single-phase coamorphous form of DOC with MYR in a 1:1 molar ratio was prepared by solvent-evaporation method and characterized by differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction. In comparison to crystalline DOC, amorphous DOC showed similar equilibrium aqueous solubility, temporary improvement in the intrinsic dissolution rate (IDR) and supersaturated dissolution; while coamorphous DOC-MYR exhibited a persistent enhanced IDR and prolonged highly supersaturated dissolution. In addition, coamorphous DOC-MYR demonstrated significantly superior physical stability compared to amorphous DOC under the long-term storage condition and accelerated condition. Compared with oral administration of crystalline DOC to rats, amorphous DOC showed a significant increase in Cmax (2.6-fold) and a marginal increase in AUC (1.3-fold) of DOC; but coamorphous DOC-MYR performed a 3.9-fold higher Cmax and 3.1-fold higher AUC. In conclusion, coamorphization of DOC with MYR was a promising approach to enhance both dissolution and oral absorption of poorly soluble and permeable DOC.

Highly Productive Oxidative Biocatalysis in Continuous Flow by Enhancing the Aqueous Equilibrium Solubility of Oxygen

AbstractWe report a simple, mild, and synthetically clean approach to accelerate the rate of enzymatic oxidation reactions by a factor of up to 100 when compared to conventional batch gas/liquid systems. Biocatalytic decomposition of H2O2 is used to produce a soluble source of O2 directly in reaction media, thereby enabling the concentration of aqueous O2 to be increased beyond equilibrium solubility under safe and practical conditions. To best exploit this method, a novel flow reactor was developed to maximize productivity (g product L−1 h−1). This scalable benchtop method provides a distinct advantage over conventional bio‐oxidation in that no pressurized gas or specialist equipment is employed. The method is general across different oxidase enzymes and compatible with a variety of functional groups. These results culminate in record space‐time yields for bio‐oxidation.

Highly Productive Oxidative Biocatalysis in Continuous Flow by Enhancing the Aqueous Equilibrium Solubility of Oxygen

We report a simple, mild, and synthetically clean approach to accelerate the rate of enzymatic oxidation reactions by a factor of up to 100 when compared to conventional batch gas/liquid systems. Biocatalytic decomposition of H2 O2 is used to produce a soluble source of O2 directly in reaction media, thereby enabling the concentration of aqueous O2 to be increased beyond equilibrium solubility under safe and practical conditions. To best exploit this method, a novel flow reactor was developed to maximize productivity (g product L-1 h-1 ). This scalable benchtop method provides a distinct advantage over conventional bio-oxidation in that no pressurized gas or specialist equipment is employed. The method is general across different oxidase enzymes and compatible with a variety of functional groups. These results culminate in record space-time yields for bio-oxidation.

Effect of β-cyclodextrin and different surfactants on solubility, stability, and permeability of hydrochlorothiazide

Physicochemical properties play a pivotal role in the absorption mechanism of orally administered drugs. Hydrochlorothiazide (HZT), a class IV drug inherently lacks the required solubility and permeability. In addition, the drug tends to degrade rapidly in an aqueous media. In order to eliminate these issues, different excipients were selected including β-cyclodextrin (β-CD), sodium lauryl sulfate (SLS), and Tween 20 which were physically mixed with HZT in order to enhance its solubility, stability, and permeability. The equilibrium aqueous solubility for HZT was successfully achieved with the selected method. β-CD was superior to other surfactants in the extent of equilibrium solubility at 25°C across the selected concentration range of (0.25–2% w/v). β-CD was also able to increase the degradation half-life (247.5h for 2.0% w/v β-CD) about 28 folds compared to 3 folds for Tween 20 (32.7h for 2.0% w/v Tween 20). Non-everted intestinal sac model showed significantly higher permeation rate for HZT as an inclusion complex (>80.0%) compared to HZT alone (47%). This study suggested that β-CD was alone able to not only increase the solubility and permeability of HZT, but also prevent the degradation for at least 60days at ambient temperature.

Solubility Enhancement of Ezetimibe by a Cocrystal Engineering Technique

The present study illustrates the formation and characterization of three different cocrystals of ezetimibe using methyl paraben as a coformer, employing three different processes, namely, solution crystallization, liquid assisted grinding, and reaction crystallization. Thermal analysis by differential scanning calorimetry (DSC) and thermogravimetric analysis were used as a primary analytical tool, followed by spectroscopic and crystallographic study as a confirmatory analytical tool. Equilibrium aqueous solubility studies were performed for all cocrystals taking ezetimibe as the control. The ideal solubility of drug and cocrystals was also calculated using data obtained from DSC (heat of fusion, ΔH, and transition melting temperature, Tm). The equilibrium aqueous solubility of ezetimibe was enhanced by about 2-fold in the case of cocrystal prepared by solution crystallization. Cocrystals prepared via reaction crystallization showed solubility that was almost the same as that of pure ezetimibe. The dissol...

Relationship between dissolution and bioavailability for nimodipine colloidal dispersions: The critical size in improving bioavailability

To compare the dissolution and bioavailability for nimodipine microcrystals and nanocrystals, and to determine the critical size range in improving the oral absorption of nimodipine. Nimodipine microcrystals and nanocrystals were prepared using a microprecipitation method. The particle size was determined with a laser diffraction method. X-ray powder diffraction was applied to inspect the potential crystal form transition. The aqueous solubility was determined by shaking flasks, and the dissolution behavior was evaluated using the paddle method. The pharmacokinetics was performed in beagle dogs in a crossover experimental design. Three nimodipine colloidal dispersions (16296.7, 4060.0 and 833.3nm) were prepared, respectively. Nimodipine had undergone crystal form transition during microprecipitation process, but experienced no conversion under the high-pressure homogenization. The colloidal dispersions did not show any difference in aqueous equilibrium solubility. Additionally, the three formulations also displayed similar dissolution curves in purified water and 0.05% SDS. The AUC for dispersions of 4060.0 and 833.3nm sizes was 1.69 and 2.59-fold higher than that for 16296.7nm system in dogs. To sum up, the critical particle size was found to be within the range of 833.3–4060.0nm (average volume-weighted particle size) in improving the bioavailability of nimodipine, and dissolution performance was not an effective index in evaluating the bioavailability for nimodipine colloidal dispersions.

A Highly Automated Assay for Determining the Aqueous Equilibrium Solubility of Drug Discovery Compounds

Aqueous solubility is an important physicochemical parameter for any potential drug candidate, and high-throughput kinetic assays are frequently used in drug discovery to give an estimate of a compound's aqueous solubility. However, the aqueous solubility data from an equilibrium (thermodynamic) shake-flask technique is considered more relevant, but is slower and more labor intensive to generate. A highly automated aqueous equilibrium solubility shake-flask technique is described and validated on a set of 15 marketed drugs, whose aqueous solubilities cover four orders of magnitude. The assay uses a Tecan Freedom Evo 200 liquid handling robot (Tecan Group Ltd., Männerdorf, Switzerland) with integrated appliances for the transportation, decapping and recapping, and centrifugation of sample tubes. These bespoke automation solutions help overcome the labor intensive steps associated with performing conventional, gold standard, aqueous equilibrium solubility shake-flask measurements, enabling the assay to be used as a primary-wave drug discovery screen.

Dissolution Study of Salt of Long Chain Fatty Acids (Soap Scum) in Surfactant Solutions. Part I: Equilibrium Dissolution

AbstractDissolution of calcium salt of a long chain fatty acid or soap scum is a major challenge for hard surface cleaners since soap scum forms when soap is exposed to hard water and has very low water solubility. In this paper, the aqueous equilibrium solubility of calcium octadecanoate (or calcium stearate) was measured as a function of pH as well as chelating agent (ethylenediaminetetraacetate disodium salt) and surfactant concentrations. Anionic, nonionic, and amphoteric surfactants were studied. The highest soap scum solubility was observed at high pH with an amphoteric surfactant. Under this condition, the chelant effectively binds calcium, and the stearate anion forms mixed micelles well with the amphoteric surfactant, which is in zwitterionic form at high pH.

Nutraceutical cocrystals: utilizing pterostilbene as a cocrystal former

The nutraceutical compound pterostilbene is investigated for its propensity to form cocrystalline materials with active pharmaceutical ingredients. Three cocrystals of a 1 : 1 stoichiometric molar ratio of pterostilbene with caffeine (two polymorphs, Form I and Form II) and carbamazepine were prepared and characterized by crystallographic (XRPD, single-crystal) and thermoanalytical (TGA, DSC) techniques. Physical stability of the cocrystals with respect to relative humidity (RH) was examined and found to be dramatically improved in relationship to caffeine or carbamazepine. The carbamazepine : pterostilbene cocrystal was stable upon slurrying in water for 3 days; therefore, aqueous equilibrium solubility measurements were carried out, revealing that the cocrystal solubility was 7× lower than carbamazepine dihydrate and 2.5× lower than pterostilbene. Slurrying the caffeine : pterostilbene cocrystal (Form I) in water led to a solution that was supersaturated with respect to pterostilbene, resulting in the precipitation of pterostilbene after three days; therefore concentrations at specific time points were measured as opposed to equilibrium solubility. At five hours the concentration of the caffeine cocrystal was 33× lower than the caffeine hydrate solubility, but was 27× higher than the pterostilbene solubility.

Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution

Aqueous colloidal dispersions of amorphous cyclosporin A (CsA) nanoparticles, intended for pulmonary delivery, were formed by antisolvent precipitation and stabilized with 10% polysorbate 80. Dissolution of the dispersion of CsA nanoparticles produced supersaturation values 18 times the aqueous equilibrium solubility. Nebulization of the dispersion to mice produced therapeutic lung levels and systemic concentrations below toxic limits. The sizes of the aerosolized aqueous droplets are optimal for deep lung deposition, whereas the amorphous drug nanoparticles facilitate rapid dissolution. A dissolution/permeation model was developed to characterize the effects of particle size, solubility, and drug dose on the absorption half-lives of poorly water soluble drugs in the alveolar epithelium. For crystalline 3µm particles with a solubility of 1µg/mL, the half-life for absorption was estimated to be 500 min. The half-life may be reduced to less than 1 min by increasing the solubility by a factor of 100 with an amorphous form as well as by decreasing the particle size 10-fold. The in vitro and in vivo data, as well as the dissolution/permeation model, indicate that nebulization of amorphous nanoparticle suspensions has the potential to enhance lung epithelial absorption markedly for poorly water soluble drugs, relative to respiratory delivery of crystalline, micron-sized particles.

Investigation of equilibrium solubility of a carob galactomannan

The equilibrium aqueous solubility of a commercial carob flour was investigated by determining the percentage of soluble and insoluble components as a function of dissolution temperature. The cumulative polysaccharide yield was ca. 50% at 5 °C, increasing approximately as a linear function of temperature to ca. 90% at 85 °C. Overall molecular weight and intrinsic viscosity of the soluble polysaccharide were determined by size-exclusion chromatography. With increasing dissolution temperature, there was weak trend towards higher overall molecular weight and intrinsic viscosity: M w from 1060 to 1150 kg/mol, and [ η] from 11.8 to 12.5 dl/g, between 5 and 65 °C, respectively. Broad, amorphous peaks were evident in the wide-angle X-ray scattering profiles, indicating no role for polysaccharide melting. The continuous increase of molecular weight and decrease of DS gal with dissolution temperature is interpreted as the result of thermodynamic partitioning based on a classical polymer-solvent fractionation, a mechanism that applies only for polysaccharide components with DS gal<0.35 within the accessible temperature range.

Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution—a validation study

A novel potentiometric procedure has recently been described for rapid measurement of equilibrium aqueous solubility values of organic acids, bases, and ampholytes that form supersaturated solutions. In this procedure, the equilibrium solubility is actively sought by changing the concentration of the neutral form by adding HCl or KOH titrants and monitoring the rate of change of pH due to precipitation or dissolution in a process called Chasing Equilibrium. In this article, we seek to validate the procedure against a shake-flask protocol for solubility determination. A set of 16 small organic compounds, covering a wide range of solubilities was chosen for the study. Interestingly, while 10 compounds in the study were found to chase equilibrium, the others did not. Kinetic solubility data was also collected. It was noted that kinetic solubility was consistently higher than equilibrium solubility for chasers, but correlated well with equilibrium solubility for nonchasers. The ratio of kinetic to equilibrium solubility indicated a compound's ability to form supersaturated solutions.

Thermodynamic modeling of activity coefficient and prediction of solubility: Part 2. Semipredictive or semiempirical models

The solubility of stearic acid, ranitidine hydrochloride, and stavudine were predicted in selected organic solvents. The experimental solubility data of stearic acid and ranitidine hydrochloride were reported in previous work of the authors and stavudine's solubility was measured in this work. Equilibrium aqueous solubility of crystalline stauvudine was determined at controlled temperatures by stirring and filtration, with spectrophotometric quantification. The new model developed in Part 11 of this communication was modified as a semipredictive model with two adjustable parameters. Predicting the solubility data with the NRTL model using just one experimental point resulted in a big error while the modified new model and the UNIQUAC model showed much smaller errors. A new method was proposed in this work for predicting the solubility data of all polymorphs of a given compound using the experimental solubility data of one of the polymorphs of the same chemical compound. Although in general, the UNIQUAC model predictions were marginally superior, the new model is simpler and does not require the molecular parameters such as Van der Waals area and volume. The solubility prediction in a mixture of solvents using the NRTL and UNIQUAC models was also discussed.

An Automated Screening Assay for Determination of Aqueous Equilibrium Solubility Enabling SPR Study During Drug Lead Optimization

Aqueous solubility is one of the most critical physicochemical properties to be determined in the process of drug lead optimization. Particularly, an equilibrium solubility method is highly valuable to the study of structure property relationship (SPR), while meeting the needs of analytical sensitivity, reproducibility, and throughput. In this report, an automated solubility assay in a 96-well library format was designed and developed by means of robotic liquid handling, centrifugal separation, and HPLC-UV quantification. Requiring 1 mg of solid compound, this assay was used to determine the equilibrium solubility in three user-selected media, that is, 0.01 N HCl, phosphate buffer saline (PBS), and fasted state simulated intestinal fluid (SIF), with a throughput of up to 192 compounds a week. The assay parameters, including the equilibration time and the separation technique, were optimized to ensure that the thermodynamic solubility was measured at the presence of excess solid compound. A fast gradient HPLC method was developed with single-point on-plate calibration for each compound, followed by a customized 96-well chromatographic data analysis. The reporting solubility range was 1–200 μg/mL, appropriate for oral drug candidate selection at the stage of discovery lead optimization. Based on the test results obtained on the commercially available drugs and Amgen research compounds, this assay was considered to be equivalent to the conventional shake-flask methods. Examples were given to demonstrate that the thermodynamic solubility determined by this assay enabled the SPR study to support drug lead optimization.

Acoustically enhanced multicomponent NAPL ganglia dissolution in water saturated packed columns.

The impact of acoustic pressure waves on multicomponent nonaqueous phase liquid (NAPL) ganglia dissolution in water saturated columns packed with glass beads was investigated. Laboratory data from dissolution experiments with two and three component NAPL mixtures suggested that acoustic waves significantly enhance ganglia dissolution due to the imposed oscillatory interstitial water velocity. The dissolution enhancement was shown to be directly proportional to the acoustic wave frequency. Furthermore, it was demonstrated that the greatest dissolution enhancement in the presence of acoustic waves is associated with the component of the NAPL mixture having the smallest equilibrium aqueous solubility. Finally, square shaped acoustic waves were shown to lead to greater NAPL dissolution enhancement compared to sinusoidal and triangular acoustic waves. The results of this study suggested that aquifer remediation using acoustic waves is a promising method particularly for aquifers contaminated with NAPLs containing components with very low equilibrium aqueous solubilities.

NAPL Pool Dissolution in Stratified and Anisotropic Porous Formations

A two-dimensional numerical model is developed to study contaminant transport resulting from the dissolution of single- and multicomponent dense nonaqueous-phase liquid (DNAPL) pools in heterogeneous porous media. The aqueous-phase concentration of each dissolved component is assumed to undergo first-order decay as well as sorb under local equilibrium conditions. Pool shrinkage is accounted for by modeling the progressive reduction of the DNAPL pool surface area as a time-dependent boundary. Multicomponent pool dissolution is modeled using an effective solubility (or equilibrium aqueous solubility) relationship, where the nonaqueous-phase activity coefficient for each constituent is evaluated at each and every time step. Subsurface heterogeneities are depicted by an ideally stratified porous formation and by a statistically anisotropic aquifer. In the stratified formation, a multicomponent DNAPL pool is assumed to be formed at the interface between a sand layer and a clay layer, where DNAPL dissolution occurs simultaneously in both strata. The ground-water velocity inside the sand stratum is uniform in the longitudinal direction whereas the interstitial liquid in the aquitard is stagnant. In the statistically anisotropic aquifer, a single-component DNAPL pool is assumed to be formed on top of an impermeable bedrock, where DNAPL dissolution occurs in the aquifer only. Results from several model simulations indicate that dissolved contaminant concentrations in aquifers are reduced significantly in the presence of aquitards, and most importantly, the transfer of dissolved contaminants along the pool-water interface is slower within statistically anisotropic than within homogeneous aquifers.

Physical characterization of nedocromil sodium hydrates

Nedocromil sodium, which is used in the treatment of reversible obstructive airway diseases, such as asthma, is found to exist in the following hydrate phases: the heptahemihydrate, the trihydrate, a monohydrate, and an amorphous phase which contains variable amounts of water (1.5−3.0 mol). An anhydrate phase is formed from the trihydrate at zero humidity at ≥ 150°C, but is rapidly hydrated under ambient conditions. The physical and thermodynamic properties of the four hydrate phases were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X‐ray diffraction (PXRD) at ambient and elevated temperatures, hot‐stage microscopy (HSM), solid phase interconversion at various relative humidities (RH), intrinsic dissolution rate (IDR), equilibrium solubility measurements, and critical RH measurements. Below 100°C in open pan TGA, the heptahemihydrate and the amorphous forms lose virtually all their water, the monohydrate loses negligible amounts of water, whereas the trihydrate loses the first two moles of water. From 130°C to 200°C in open pan TGA the trihydrate and the monohydrate lose their last mole of water to form the anhydrate. In crimped pan DSC, the thermal events observed are analogous to those observed in open pan TGA, but the temperatures are increased by about 75°C for all except the heptahemihydrate, for which the thermal events are more complex. When the heptahemihydrate is heated in a crimped pan, a melting endotherm is observed at about 75°C followed by three dehydration endotherms. For the crystalline hydrate phases at 22°C, the ranges of stability are as follows: the monohydrate from 0 to 6.4% RH; the trihydrate from 6.4 to 79.5% RH; the heptahemihydrate above 80% RH. A microbalance study showed that the heptahemihydrate is kinetically stable over the range 11 to 79.5% RH. The IDR in water at 25°C under constant hydrodynamic conditions decreases in the rank order: monohydrate > trihydrate > heptahemihydrate, corresponding to the rank order of free energy with respect to the aqueous solution. The equilibrium aqueous solubility of the heptahemihydrate at 25.0 ±0.2°C is 0.956 ±0.010 M.

Determination of Aqueous Solubility and Surface Adsorption of Polycyclic Aromatic Hydrocarbons by Laser Multiphoton Ionization

Polycyclic aromatic hydrocarbons (PAHs) are of considerable analytical interest due to their environmental effects. On-line monitoring of these compounds based on microdroplet sampling requires accurate characterization of their solubilities and surface adsorption. A new method to determine aqueous solubility and surface adsorption of PAHs is suggested, using a combination of microdroplet sampling and multiphoton ionization-based fast-conductivity (MPI-FC) techniques. Controlled droplet contamination by PAHs was performed by external deposition upon direct contact with renewable water droplets (≅10 μL). Our approach relies on the finding that, at the onset of aqueous equilibrium solubility, X(E), a sharp increase in the detected photocharges is recorded. We show that this is directly related to enhanced surface adsorption of a particular PAH material. This behavior manifests itself in slope variation of the respective calibration curves. The PAH materials used, which have provided about four decades variation in X(E) figures, were anthracene, perylene, pyrene, and phenanthrene. Applicability of the method for studying the surface excess and adsorption is specified. The MPI-FC technique provides an easy analytical tool for measuring low aqueous solubility of organic compounds and characterization of their adsorption, with no need for laborious sample preparation routines.