Pilar Bustamante

Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures.

The dissolution profile and solubility of two polymorphic forms of mefenamic acid were studied in solvent mixtures of ethanol-water and ethyl acetate-ethanol. The solubility parameter (delta) was used to study the effect of polarity on the solubility behavior of the two polymorphs. Differential scanning calorimetry and infrared spectroscopy were performed on the original powders and on the solid phases after contact with the solvent systems for the characterization and identification of the polymorphs. The dissolution rates of both polymorphs is greater in the less polar mixtures (ethyl acetate-ethanol) of lower solubility parameter values. Form II showed larger dissolution rates and saturation concentrations than Form I in all the solvent systems studied. The solid phase of Form II converts totally to Form I after equilibration with the solvents. The rate of conversion was faster in the least polar mixtures. The solubility of both polymorphs reaches a single maximum at 80% ethyl acetate in ethanol, delta = 20.09 MPa1/2. The modified extended Hildebrand method was used to predict the solubility profile of each polymorph. A single equation was obtained for both polymorphs which includes the solubility parameter of the mixtures and the logarithm of the solubility mole fraction of each polymorph in water. The Hildebrand solubility parameter of mefenamic acid is independent of the crystalline form and was determined from two methods giving quite similar values, delta 2 = 20-21 MPa1/2.

A MODIFICATION OF THE EXTENDED HILDEBRAND APPROACH TO PREDICT THE SOLUBILITY OF STRUCTURALLY RELATED DRUGS IN SOLVENT MIXTURES

Abstract— A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane‐water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute‐solvent interaction terms consisting of the solubility parameter, δ2, of the solute and the solubility parameter, δ1, and basic partial solubility parameter, δ1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane‐water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p‐hydroxybenzoic acid. This suggests that the intermolecular solute‐solvent interaction of sulphonamides and p‐hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute‐solvent interactions.

The modified extended Hansen method to determine partial solubility parameters of drugs containing a single hydrogen bonding group and their sodium derivatives : benzoic acid/Na and ibuprofen/Na

Sodium salts are often used in drug formulation but their partial solubility parameters are not available. Sodium alters the physical properties of the drug and the knowledge of these parameters would help to predict adhesion properties that cannot be estimated using the solubility parameters of the parent acid. This work tests the applicability of the modified extended Hansen method to determine partial solubility parameters of sodium salts of acidic drugs containing a single hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium benzoate). The method uses a regression analysis of the logarithm of the experimental mole fraction solubility of the drug against the partial solubility parameters of the solvents, using models with three and four parameters. The solubility of the drugs was determined in a set of solvents representative of several chemical classes, ranging from low to high solubility parameter values. The best results were obtained with the four parameter model for the acidic drugs and with the three parameter model for the sodium derivatives. The four parameter model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid properties of the sodium derivatives are blocked by sodium, the three parameter model is recommended for these kind of compounds. Comparison of the parameters obtained shows that sodium greatly changes the polar parameters whereas the dispersion parameter is not much affected. Consequently the total solubility parameters of the salts are larger than for the parent acids in good agreement with the larger hydrophilicity expected from the introduction of sodium. The results indicate that the modified extended Hansen method can be applied to determine the partial solubility parameters of acidic drugs and their sodium salts.

Partial solubility parameters of piroxicam and niflumic acid

The expanded Hansen method is tested with two anti-inflammatory drugs, piroxicam (preferentially Lewis base) and niflumic acid (preferentially Lewis acid). The original dependent variable, ln α2/U, where α is the activity coefficient and U is related to the molar volume of the solute and the volume fraction of the solvent, was compared with the direct use of the logarithm of the mole fraction solubility ln X2 in the three- and four parameter models. The activity coefficient of the drugs was calculated from the heat and temperature of fusion before and after equilibration of each solid phase with the pure solvents used. The dependent variables ln X2 and ln α2/U provided similar partial solubility parameter values for piroxicam with the four parameter model. All the partial parameters of niflumic acid were significant statistically only with the variable ln X2. This indicates that ln X2 is the most suitable variable for the determination of partial solubility parameters. The dispersion solubility parameters are similar for both drugs, the largest differences being observed for the dipolar and hydrogen bonding parameters. The partial solubility parameters give insights into the interaction capability of the drugs and are consistent with their chemical structure. For niflumic acid, a better proton donor, δa>δb whereas for piroxicam, a preferentially Lewis base δb>δa. This result is particularly interesting as it demonstrates for the first time the validity of the method for a mainly proton-acceptor compound.

Proposition of group molar constants for sodium to calculate the partial solubility parameters of sodium salts using the van Krevelen group contribution method

The aim of this study is to propose, for the first time, a set of group molar constants for sodium to calculate the partial solubility parameters of sodium salts. The values were estimated using the few experimental partial solubility parameters of acid/sodium salt series available either from the literature (benzoic acid/Na, ibuprofen acid/Na, diclofenac Na) or determined in this work (salicylic acid/Na, p-aminobenzoic acid/Na, diclofenac), the group contribution method of van Krevelen to calculate the partial parameters of the acids, and three reasonable hypothesis. The experimental method used is a modification of the extended Hansen approach based on a regression analysis of the solubility mole fraction of the drug lnX(2) against models including three- or four-partial solubility parameters of a series of pure solvents ranging from non-polar (heptane) to highly polar (water). The modified method combined with the four-parameter model provided the best results for both acids and sodium derivatives. The replacement of the acidic proton by sodium increased the dipolar and basic partial solubility parameters, whereas the dispersion parameter remained unaltered, thus increasing the overall total solubility parameter of the salt. The proposed group molar constants of sodium are consistent with the experimental results as sodium has a relatively low London dispersion molar constant (identical to that of -OH), a very high Keesom dipolar molar constant (identical to that of -NO(2), two times larger than that of -OH), and a very high hydrogen bonding molar constant (identical to that of -OH). The proposed values are: F((Na)d)=270 (J cm(3))(1/2) mol(-1); F((Na)p)=1030 (J cm(3))(1/2) mol(-1); U((Na)h)=17000 J mol(-1). Like the constants for the other groups, the group molar constants proposed for sodium are certainly not the exact values. However, they are believed to be a fair approximation of the impact of sodium on the partial solubility parameters and, therefore, can be used as such in the group contribution method of van Krevelen.

Predicting the solubility of drugs in solvent mixtures: multiple solubility maxima and the chameleonic effect.

Abstract— An approach to reproduce the solubility profile of a drug in several solvent mixtures showing two solubility maxima is proposed in this work. The solubility of sulphamethoxypyridazine was determined at 25°C in several mixtures of varying polarity (hexane: ethyl acetate, ethyl acetate:ethanol and ethanol: water). Sulphamethoxypyridazine was chosen as a model drug because of its proton‐donor and proton‐acceptor properties. A plot of the mole fraction of the drug vs the solubility parameter of the solvent mixtures shows two solubility peaks. The two peaks found for sulphamethoxypyridazine demonstrate the chameleonic effect as described by Hoy and suggest that the solute‐solvent interaction does not vary uniformly from one mixture to another. The different behaviour of the drug in mixtures of two proton‐donor and proton‐acceptor solvents (alcohol and water), and in mixtures of one proton acceptor (ethyl acetate) and one proton donor‐proton acceptor (ethanol) is rationalized in terms of differences in the proton donor‐acceptor ability of the solvent mixtures. An approach based on the acidic and basic partial solubility parameters together with the Hildebrand solubility parameter of the solvent mixtures is developed to reproduce the experimental results quantitatively. The equation predicts the two solubility maxima as found experimentally, and the calculated values closely correspond to the experimental values through the range composition of the solvent mixtures. These results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid‐base interactions; this approach can assist the product formulator to choose the proper solvent mixture for a new drug. A good solvent blend should result in a solubility parameter close to that of the drug; the acidic and basic partial solubility parameter values should provide maximum acid‐base interaction of the mixed solvent with the drug. The failure in one of these conditions results in decreased solubility. Solubility parameters as well as the acidic and basic parameters are tabulated or they can be obtained from group contribution methods, making easier the evaluation of the best solvent mixture for a drug.

Partial-solubility Parameters of Naproxen and Sodium Diclofenac

The expanded Hansen method was tested for determination of the solubility parameters of two non‐steroidal anti‐inflammatory drugs, naproxen and sodium diclofenac. This work describes for the first time the application of the method to the sodium salt of a drug. The original dependent variable of the expanded Hansen method, involving the activity coefficient of the drug, was compared with the direct use of the logarithm of the mole fraction solubility lnX2 in the solubility models.

The expanded Hansen approach to solubility parameters. Paracetamol and citric acid in individual solvents

In this study two solubility‐parameter models have been compared using as dependent variables the logarithm of the mole fraction solubility, lnX2e, and ln(α)/U (originally used in the extended Hansen method), where α is the activity coefficient and U is a function of the molar volume of the solute and the volume fraction of the solvent.

Exothermic-endothermic heat of solution shift of cyclosporin a related to poloxamer 188 behavior in aqueous solutions

The solubility of cyclosporin A was determined in water and aqueous solutions of a surface active poly (oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymer (poloxamer 188 or pluronicR F68 (PF68)) at concentrations and temperatures ranging from 4 to 22 g/1 and from 10 to 50°C, respectively. The solubility behaviour was different between PF68 solutions and water. Solubility values indicated an exothermic heat of solution in each case except for PF68 solutions above 10 g/l at 37–50°C, where a change to endothermic heat of solution was detected. The slopes corresponding to water samples or 4g/l PF68 solutions at temperatures above 37°C do not statistically differ from zero. Aqueous solutions of the poloxamer 188 were also studied using frequency spectrum analysis (dynamic light scattering) and size exclusion chromatography. Below 40°C and 16 g/1 essentially invariant values for the hydrodynamic radius were found with broad polydispersities associated. Increasing temperature and poloxamer concentration, the hydrodynamic radius also increased and the systems showed a narrower size distribution, possibly due to micelle formation according to the closed association model.

Influence of temperature on the solubilization of thiabendazole by combined action of solid dispersions and co-solvents

Co-solvents and solid dispersions with polyvinyl pyrrolidone were tested to increase solubility of thiabendazole. Solid dispersions were prepared by the solvent method and analyzed by differential scanning calorimetry. The solubility was measured at 15-35 degrees C in aqueous (ethanol-water) and non-aqueous (ethanol-ethyl acetate) mixtures. Combination of solid dispersions with cosolvents increased the water solubility of thiabendazole in a larger extent that each method separately. The effect of the solid dispersions is greatest in water and it decreases nonlinearly as the volume fraction of ethanol-in water increases. The solubility enhancement is smaller in ethanol-ethyl acetate and is uncorrelated with co-solvent concentration. Solubility parameters delta were used to predict drug/carrier compatibility and related to solubility profiles. Thiabendazole shows an intermediate behaviour between solubility curves with two peaks (more polar drugs with larger delta values) and a single peak (less polar drugs with lower delta values). The solid dispersions increase the solubility parameter of thiabendazole from delta=24 to delta=25.7 MPa(1/2). The model of Bustamante et al. allowed solubility prediction including jointly both mixtures whereas the equation of Jouyban et al. was able to predict the solubility at several temperatures in each binary mixture separately, using a few experiments.