Excess free energy approach to the estimation of solubility in mixed solvent systems III: Ethanol-propylene glycol-water mixtures

The reduced three-suffix solubility equation derived from the Wohl excess free energy expression is used to describe the solubility of phenobarbital in propylene glycol-water, ethanol-propylene glycol, and ethanol-water-propylene glycol mixtures and the solubility of hydrocortisone in propylene glycol-water mixtures. Solvent-solvent interaction constants were obtained by fitting total vapor pressure versus composition data, obtained at 25 +/- 0.1 degrees C, to the Wohl excess free energy model for the solvents. The equation describes solubility in these systems satisfactorily except for phenobarbital in ethanol-propylene glycol, where the solubility is fairly high and assumptions involved in the derivation of the equation do not hold.     

The effects of pH and mixed solvent systems on the solubility of oxytetracycline

The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pKa') of OTC were determined by a solubility method. The pKa' values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pKa' values in each solvent system. pKa' values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.     

Effects of solvent medium on solubility. A linear free energy relationship treatment

Linear relationships exist between the logarithms of the solubility equilibria of structurally closely related compounds, as they vary with changes in solvent or solvent composition in water and water-like solvents, trie slope P_y of these linear free energy relationships quantitatively accounts for the direction and intensity of the relative solubility variations due to medium effects. Results obtained by applying the concept to series of both p-hydroxy- and p-aminobenzoic esters, and α-aminoacids, are presented. These results are explained by a simple model in terms of solute-solvent interactions.     

Models for calculating solubility in binary solvent systems

Two empirical models which express the relationship between the solute solubility and the concentration of one of the solvents in a binary solvent system are presented. The proposed models have been compared with previous similar models similar either in their original or modified forms from accuracy and predictability points of view using many experimental data taken from the literature. Both models were in some respects superior to the original and modified forms of the previous models. The modification of some of the previous models has improved the accuracy of the original models.     

A model to represent solvent effects on the chemical stability of solutes in mixed solvent systems

The applicability of the combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K) equation for quantification of solvent effects on the stability of a solute is shown employing the experimental data of three solutes in different aqueous binary solvents. The proposed model provides a simple computational method to correlate/predict the instability rate constant of a drug in mixed solvent systems. The accuracy of the model is compared with that of a model proposed by Connors and co-workers employing various methods including mean percentage deviation (MPD) as comparison criteria. The obtained overall MPD values for the proposed model to correlate and predict the instability rate constants are 2.05 +/- 1.44 and 4.41 +/- 3.21%, respectively, where the corresponding values for Connors' model are 4.34 +/- 3.28 and 10.74 +/- 9.86%. The results suggest that by using only five experimental instability rate constants at different concentrations of the cosolvent in a binary mixture, it is possible to predict unmeasured values falling between data points within an acceptable error range.     

Electrophoretic behavior of alprenolol in mixed solvent electrolyte systems

The electrophoretic mobilities of alprenolol have been determined in a mixed solvent background electrolyte system containing sodium acetate (40 mM)+acetic acid (40 mM) as buffering agent and different volume fractions of water, methanol and ethanol using capillary electrophoresis. The mobility of alprenolol has been used to test the prediction capability of a model trained by previously reported mobility data of five beta-blocker drugs at the same electrophoretic conditions. The average percentage mean deviations (APMD) between experimental and predicted values were used as an accuracy criterion. The APMD (+/-SD) obtained for alprenolol data in binary/ternary solvent electrolyte system employing the mobility values in mono-solvent buffers was 4.37 (+/-3.50)% and the corresponding value for an ab initio prediction method was 7.65 (+/-4.30)%.     

Effects of solvent medium on solubility. V: Enthalpic and entropic contributions to the free energy changes of di-substituted benzene derivatives in ethanol:water and ethanol:cyclohexane mixtures

The solubility at four different temperatures in water, cyclohexane, and mixtures of water and ethanol and ethanol and cyclohexane of nine derivatives of the structure pX1-C6H4-X2, together with their heats of fusion are reported. The enthalpy and entropy of mixing (delta HM and delta SM, respectively), and also the excess free energy (delta GE) for pure solvents and several compositions of solvent mixtures were calculated. The enthalpic and entropic contribution to the free energy of transfer for water:solvent mixtures was also calculated for each compound. Solvent systems may be classified by means of the enthalpic-entropic relationships exhibited by the series in each case.     

Estimation of the aqueous solubility I: application to organic nonelectrolytes

The estimation of aqueous solubilities of organic nonelectrolytes by the General Solubility Equation (GSE) as proposed by Valvani and Yalkowsky (1980) is used in this study. The data and assumptions on which the GSE are based are reevaluated, and the equation is revised. The revised GSE is validated on a set of 580 pharmaceutically, environmentally, and industrially relevant nonelectrolytes. The revised equation has a stronger theoretical background and provides a more accurate estimation of aqueous solubility.     

Investigation of the solubility relationships of polar,semi-polar and non-polar drugs in mixed co-solvent systems

The solubility relationships of a non-polar (tioconazole), polar (oxfenieine) and semi-polar (caffeine) drug have been investigated in aqueous ethanol, propylene glycol and polyethylene glycol 400 (PEG 400) binary co-solvent systems. A semi-empirical equation was deduced to describe the relationship between the amount of drug dissolved and the volume fraction of co-solvent employed. The data for tioconazole and oxfenicine followed the expected semi-logarithmic relationship between solubility and fraction co-solvent. However, the semi-polar drug, caffeine followed this relationship only with PEG 400; the other two co-solvents yielded parabolic relationships.Using the binary solubility data, multiple linear regression was used to deduce an equation for the solubility of tioconazole in ternary ethanol, propylene glycol and PEG 400 co-solvent systems. The derived relationship gave excellent prediction of the drug solubility throughout the complete volume fraction range. This allowed a graphical representation of the drug solubility-co-solvent fraction relationship to be established. This visualization of are drug solubility relationship was then used to demonstrate its utility to optimize drug solubility within the competing constraints of the pharmaceutical system.     

Predicting the solubility of sulfamethoxypyridazine in individual solvents. I: Calculating partial solubility parameters

Sulfamethoxypyridazine, a representative model of a drug molecule, is used to test the extended Hansen method for estimating partial solubility parameters of solid compounds. Solubilities are determined in polar and nonpolar solvents. The method provides reasonable partial parameters for the sulfonamide, and it may be useful in obtaining partial parameters for other drug molecules. A four-parameter extended Hansen approach involving proton donor and acceptor parameters is used in fitting the data to a theoretical model. A term, Wh, is introduced as an empirical measure of solute-solvent interactions due to hydrogen bonding. The use of the empirical term Wh allows the researcher to fit experimental solubilities and thus design regression models and equations which provide a reasonable prediction of solubilities of a polar drug in a number of very different solvents. A Flory-Huggins size correction term improves the prediction of sulfamethoxypyridazine solubilities in these irregular solutions.     

Native-state solubility and transfer free energy as predictive tools for selecting excipients to include in protein formulation development studies

In the present report, two formulation strategies, based on different aggregation models, were compared for their ability to quickly predict which excipients (cosolutes) would minimize the aggregation rate of an immunoglobulin G1 monoclonal antibody (mAb-1) stored for long term at refrigerated and room temperatures. The first formulation strategy assumed that a conformational change to an aggregation-prone intermediate state was necessary to initiate the association process and the second formulation strategy assumed that protein self-association was instead controlled by the solubility of the native state. The results of these studies indicate that the stabilizing effect of excipients formulated at isotonic concentrations is derived from their ability to solubilize the native state, not by the increase of protein conformational stability induced by their presence. The degree the excipients solvate the native state was determined from the apparent transfer free energy of the native state from water into each of the excipients. These values for mAb-1 and two additional therapeutic antibodies correlated well to their long-term 4°C and room temperature aggregation data and were calculated using only the literature values for the apparent transfer free energies of the amino acids into the various excipients and the three-dimensional models of the antibodies.     

The interaction between oxytetracycline and divalent metal ions in aqueous and mixed solvent systems

The effects of pH, mixed solvent systems, and divalent metal ions on oxytetracycline (OTC) solubility and the interactions between OTC and metal ions in aqueous and mixed solvent systems were investigated. OTC solubility profiles were obtained for pH 4-9. The cosolvents studied were glycerin, propylene glycol, PEG 400, and 2-pyrrolidone with the following metal ions: magnesium, calcium, and zinc. OTC and its interactions with these metal ions were evaluated by solubility, NMR, circular dichroism (CD), and electron diffraction (ED) methods. At pH 5.6, no complexation occurred with these metal ions, but OTC zwitterion formed aggregates in aqueous solutions as shown by NMR spectra. The hydration of the metal ions was observed to affect OTC aggregation, with Mg+2 causing the greatest OTC aggregation. At pH 7.5, OTC aggregation and metal-OTC complexation were observed in solutions with Ca+2 and Mg+2. Zinc ion was found to decrease OTC solubility because of zincate formation, which caused anionic OTC to precipitate. Electron diffraction revealed a relationship between OTC and metal-OTC complex crystallinity and solubility behavior. The zinc-OTC complex exhibited the highest crystallinity and lowest solubility at pH 8.0. Various cosolvents generally enhanced OTC solubility, with 2-pyrrolidone having the best solubility power. In OTC-metal-2-pyrrolidone and OTC-Zn(+2)-PEG 400 systems, circular dichroism provided evidence for the formation of soluble ternary complexes.     

Solubility in binary solvent systems. V. Monomer and dimer models for the solubility of p-tolylacetic acid in systems of non-specific interactions

Solubilities are reported for p-tolylacetic acid in binary mixtures of cyclohexane with n-hexane, n-heptane, n-octane and isooctane at 25 °C. The results are compared to the predictions of equations developed previously for solubility in systems of purely non-specific interactions, with the carboxylic acid considered as either monomeric or dimeric molecules in solution. The dimer model provided the more accurate predictions, with a maximum deviation of 5.6% between observed and predicted solubility in all systems studied.     

Determination of poly(ɛ-caprolactone) solubility parameters: Application to solvent substitution in a microencapsulation process

The evolution of regulation on chemical substances (i.e. REACH regulation) calls for the progressive substitution of toxic chemicals in formulations when suitable alternatives have been identified. In this context, the method of Hansen solubility parameters was applied to identify an alternative solvent less toxic than methylene chloride used in a microencapsulation process. During the process based on a multiple emulsion (W/O/W) with solvent evaporation/extraction method, the solvent has to dissolve a polymer, poly(?-caprolactone) (PCL), which forms a polymeric matrix encapsulating or entrapping a therapeutic protein as the solvent is extracted. Therefore the three partial solubility parameters of PCL have been determined by a group contribution method, swelling experiments and turbidimetric titration. The results obtained allowed us to find a solvent, anisole, able to solubilize PCL and to form a multiple emulsion with aqueous solutions. A feasibility test was conducted under standard operating conditions and allowed the production of PCL microspheres.     

High throughput UV method for the estimation of thermodynamic solubility and the determination of the solubility in biorelevant media

The growing interest for high quality solubility data in the early stages of drug discovery suggested a detailed optimization of experimental conditions for a 96-well HTS UV method in order to obtain solubility values close to thermodynamic solubility measured by shake-flask method. Results have shown that solubility data obtained by the HTS approach were highly dependent on shaking intensity and incubation times due to the formation of supersaturated solutions resulting from the dilution of DMSO stock solutions in aqueous buffer. Thus, careful experimental set-up was developed to improve the quality and the reproducibility of the HTS method. Moreover, the early qualitative prediction of bioavailability and absorption of orally administered drugs require more and more biorelevant solubility values in drug discovery programs. Thus, the optimized HTS method was also adapted to measure solubility directly in FaSSIF and FeSSIF media. The versatile HTS UV approach presented in this paper provides a unique and reliable way to determine solubility in various experimental conditions.