Daniel R. Delgado

Preferential solvation of methocarbamol in aqueous binary co-solvent mixtures at 298.15 K

The preferential solvation parameters of methocarbamol in dioxane + water, ethanol + water, methanol + water and propylene glycol + water mixtures are derived from their thermodynamic properties by using the inverse Kirkwood–Buff integrals (IKBI) method. This drug is sensitive to solvation effects, being the preferential solvation parameter δx1,3, negative in water-rich and co-solvent-rich mixtures, but positive in mixtures with similar proportions of solvents, except in methanol + water mixtures, where positive values are found in all the methanol-rich mixtures. It is conjecturable that the hydrophobic hydration around the non-polar groups in water-rich mixtures plays a relevant role. Otherwise, in mixtures of similar solvent compositions, the drug is mainly solvated by co-solvent, probably due to the basic behaviour of the co-solvents; whereas, in co-solvent-rich mixtures, the preferential solvation by water could be due to the acidic behaviour of water. Nevertheless, the specific solute–solvent interactions present in the different binary systems remain unclear.

Preferential solvation of some structurally related sulfonamides in 1-propanol + water co-solvent mixtures

The preferential solvation parameters by 1-propanol of sulfadiazine, sulfamerazine and sulfamethazine in 1-propanol + water mixtures were derived from their solution thermodynamic properties by means of the inverse Kirkwood–Buff integrals method. These sulfonamides are sensitive to solvation effects, so the preferential solvation parameter δx1,3 is negative in water-rich and 1-propanol-rich mixtures but positive in intermediate compositions. It is possible that the hydrophobic hydration around aromatic rings and/or other non-polar groups plays a relevant role in the solvation in water-rich mixtures. The more solvation by 1-propanol in mixtures of similar composition could be due mainly to polarity effects and acidic behaviour of the sulfonamides in front to the more basic solvent 1-propanol. Otherwise, the more solvation by water in 1-propanol-rich mixtures could be due to basic behaviour of the sulfonamides in front to water, which is the more acidic solvent.

Volumetric properties of the glycerol formal + water cosolvent system and correlation with the Jouyban–Acree model

Excess molar volumes and partial molar volumes were investigated from density measurements for glycerol formal + water mixtures at temperatures from 278.15 to 313.15 K. Excess molar volumes are fitted using Redlich–Kister equation and compared with literature values for other systems. The system exhibits negative excess volumes, probably due to increased interactions like hydrogen bonding or large differences in molar volumes of components. The effect of temperature on different volumetric properties studied is also analysed. Besides, the volume thermal expansion coefficients are also calculated as 2.51 × 10−4 K−1 for water and 7.24 × 10−4 K−1 for glycerol formal at 298.15 K. Finally, the Jouyban–Acree model was used for density and molar volume correlations of the studied mixtures at different temperatures. The mean relative deviations between experimental and calculated data were 0.24 ± 0.14% and 0.71 ± 0.62%, respectively, for density and molar volume data.

Further Numerical Analyses on the Solubility of Sulfapyridine in Ethanol + Water Mixtures

Background: Dissolution thermodynamic quantities of sulfapyridine (SP) have been reported in the literature for aqueous alcoholic mixtures. Nevertheless, no attempts to evaluate the preferential solvation of this drug in this binary system, have been reported. In this way, the inverse Kirkwood-Buff integrals (IKBI) were used to evaluate this behavior in solution. Methods: Solubility data for SP dissolved in binary ethanol (EtOH) + water mixtures at various temperatures were mathematically represented using the Jouyban-Acree (J-A) model. The preferential solvation parameters of SP by EtOH (δx1,3) in EtOH + water mixtures were obtained from some thermodynamic properties of the mixtures by means of the IKBI method. Results: Solubility of SP in EtOH + water mixtures is adequately described by the J-A model in second order. Moreover, SP is sensitive to specific solvation effects, so the δx1,3 values are negative in water-rich and EtOH-rich mixtures indicating preferential solvation by water in these mixtures. By contrary, δx1,3 values are positive in the range 0.24 < x1 < 0.53 indicating preferential solvation by EtOH in these mixtures. Conclusion: It can be assumed that in water-rich mixtures the hydrophobic hydration around the aromatic rings plays a relevant role in the solvation. The higher drug solvation by EtOH in mixtures of similar solvent proportions could be due to polarity effects. Moreover, in EtOH + water mixtures SP could be acting as a Lewis acid with the EtOH molecules and in EtOH-rich mixtures the drug could be acting as a Lewis base with water molecules.

Volumetric Properties of Glycerol Formal + Propylene Glycol Mixtures at Several Temperatures and Correlation with the Jouyban–Acree Model

Molar volumes, excess molar volumes, and partial molar volumes were investigated for glycerol formal + propylene glycol mixtures from density measurements at temperatures from (278.15 to 313.15) K. Mixture compositions were varied in 0.05 in mass fraction of both components. Excess molar volumes were fitted to the Redlich–Kister equation and compared with literature values for other systems. The system exhibits positive excess volumes probably due to increased non-specific interactions. The effect of temperature on the different volumetric properties studied was also analyzed. In addition, the volumetric thermal expansion coefficients were calculated. The Jouyban–Acree model was used for density and molar volume correlations of the mixtures at the different experimental temperatures. The mean relative deviations between experimental and calculated data are 0.04±0.03 and 0.04 ±0.05, respectively, for the density and molar volumes, using the minimum number of data points, the Jouyban–Acree model can predict density and molar volume with acceptable accuracies (0.06±0.04 and 0.08±0.05, respectively).

The Importance of Dielectric Constant for Drug Solubility Prediction in Binary Solvent Mixtures: Electrolytes and Zwitterions in Water + Ethanol

In drug discovery and formulation, drug solubility in water and organic solvent plays an important role and affects many pharmaceutical processes including design, synthesis, extraction, purification, formulation, absorption, and distribution in body fluids (1). In most cases, aqueous solubility of a chemical compound as a medicine is not enough to be applicable in pharmaceutical formulations and clinical administration. Hence, different kinds of solubilization techniques including cosolvency, complexation, micellization, and salt formation have been applied to increase the solubility (1,2). However, in some cases, it is required to reduce solubility in the medium, for example, in crystallization process (3). These methods not only influence the solubility of a compound, but can also alter its stability in the liquid medium (1). Cosolvency is the most feasible method for this purpose, and the most common pharmaceutical cosolvent is ethanol. Another useful and more employed method is salt formation, and an accountable proportion of the available medicinal compounds is in salt form. For developing liquid formulations of these compounds or crystallization process design, the use of cosolvents might be necessary to influence their solubility/stability. To speed up the development processes in the pharmaceutical industry, calculative models for solubility prediction in mixture of solvents have been proposed in recent decades (1,2). Almost all of the proposed models were designed for solubility correlation/prediction of the non-electrolytes in the solvent mixtures (1,2). The main pattern of solubility behavior in water + ethanol mixture has a maximum of solubility in ethanol-rich area for most of the non-electrolyte solutes (1,2). This pattern is not the same for ionizable compounds in water such as sodium salts of medicines and amino acids where the solubility value in water is more than solubility value in neat ethanol (4). Maybe changes in dielectric constant of the medium have a dominant effect on the solubility of the ionizable solute in which higher dielectric constant can cause more ionization of the solute and results in more solubilization (5). As an example, water (DW,298 = 78.5) has higher dissociation strength on ions in comparison with ethanol (DE,298 = 24.2) which is resulted in more solubilization power of ions in water. Born has proposed a theoretical model for solubility correlation in two different phases as following equation (6): 1 where S1 and S2 are the solubilities of the solute in media 1 and 2; e is the charge of an electron; r is the effective radius of the ion in the medium; k is the Boltzmann constant; T is the absolute temperature; and D1 and D2 are the dielectric constants of the media 1 and 2, respectively. Unfortunately, by using this equation, the predicted solubility values (when r values are known) or predicted r values (when solubility values are known) based on experimental data do not seem to be meaningful (7). However, one can consider the constant value of as AT for a specific solute and obtain: 2 where AT is a slope which can be calculated using two experimental solubility data points (e.g., solubility values in water and ethanol).

Preferential solvation of some n-alkyl p-substituted benzoates in propylene glycol + water cosolvent mixtures

The preferential solvation parameters by propylene glycol (PG) of the homologous series of the n-alkyl esters of p-hydroxybenzoic and p-aminobenzoic acids, namely, methyl, ethyl, propyl and butyl derivatives, were derived from their thermodynamic properties of solution by means of the inverse Kirkwood–Buff integrals (IKBI) method. The preferential solvation parameters by the cosolvent, δx1,3, are negative in water-rich mixtures, but positive in PG-rich mixtures, and the relative magnitudes of δx1,3 are proportional to the alkyl chain length despite of the solvent involved in the preferential solvation, i.e. PG or water. It is possible that the hydrophobic hydration around aromatic ring and/or methylene groups plays a relevant role in the drugs solvation in water-rich mixtures. The more solvation by PG in PG-rich mixtures could be due mainly to polarity effects and acidic behaviour of the hydroxyl or amine groups of the compounds in front to the more basic solvent present in the mixtures, i.e. PG.

Preferential solvation of indomethacin and naproxen in ethyl acetate + ethanol mixtures according to the IKBI method

The preferential solvation parameters of indomethacin and naproxen in ethyl acetate + ethanol mixtures are derived from their thermodynamic properties by using the inverse Kirkwood–Buff integrals method. It is found that both drugs are sensitive to solvation effects, so the preferential solvation parameter, δxEA,D, is negative in ethanol-rich and ethyl acetate-rich mixtures but positive in compositions from 0.36 to 0.71 in mole fraction of ethyl acetate. It is conjecturable that in ethanol-rich mixtures, the acidic interaction of ethanol on basic sites of the analgesics plays a relevant role in the solvation. The more solvation by ethyl acetate in mixtures of similar co-solvent compositions could be due to polarity effects. Finally, the slight preference of these compounds for ethanol in ethyl acetate-rich mixtures could be explained as the common participation of basic sites in both solvents and the acidic site of ethanol. Nevertheless, the specific solute–solvent interactions remain unclear.

Preferential Solvation of Indomethacin in Some Aqueous Co-Solvent Mixtures

The preferential solvation parameters for indomethacin (IMC) in ethanol (EtOH) + water and propylene glycol (PG) + water binary mixtures were obtained from their thermodynamic properties by means of the inverse Kirkwood–Buff integrals (IKBI) and the quasi-lattice quasi-chemical (QLQC) methods. According to IKBI method, the preferential solvation parameter by co-solvents, (δx1,3), is negative in the water-rich mixtures of both binary systems but positive in the other compositions at temperatures of 293.15, 303.15, and 313.15 K. It is conjecturable that in water-rich mixtures the hydrophobic hydration around the aromatic rings and methyl groups of the drug plays a relevant role in the solvation. The higher drug solvation by co-solvent in mixtures of similar solvent proportion and in co-solvent-rich mixtures could be due mainly to polarity effects. Here IMC would be acting as a Lewis acid with the EtOH or PG molecules because these co-solvents are more basic than water.

Solution thermodynamics of methocarbamol in some ethanol + water mixtures

Apparent thermodynamic functions, Gibbs energy, enthalpy and entropy of solution and mixing, for methocarbamol in ethanol + water mixtures, were evaluated from solubility data determined at temperatures from 293.15 K to 313.15 K and from calorimetric values of drug fusion. The drug solubility was greatest in the mixtures with 0.70 or 0.80 mass fraction of ethanol and lowest in neat water across all temperatures studied. Non-linear enthalpy-entropy compensation was found for the dissolution processes. Accordingly, solution enthalpy drives the respective processes in almost all the solvent systems analyzed.