Thermochemical investigations of associated solutions: 5. Calculation of solute-solvent equilibrium constants from solubility in mixtures containing two complexing solvents

Solubilities are reported for carbazole in binary dibutyl ether plus 1-chlorohexane mixtures at 25 degrees C. Results of these measurements are compared with solution models developed for solubility in systems containing specific solute-solvent interactions. A simple stoichiometric complexation model based on a 1:1 carbazole:dibutyl ether complex could describe the measured solubility to within an average absolute deviation of 1.7%. The calculated equilibrium constant, though, was about one-half of values previously determined from carbazole solubilities in several binary dibutyl ether plus alkane mixtures. A more sophisticated solution model, derived by assuming both 1:1 carbazole: dibutyl ether and carbazole:chlorohexane complexes, could describe the solubilities to within 2.4%. This latter model enables the carbazole-chlorohexane association constant to be calculated from experimental carbazole solubilities and a priori knowledge of the carbazole-dibutyl ether equilibrium constant.     

Thermochemical investigations of associated solutions: 4. Calculation of carbazole-dibutyl ether association constants from measured solubility in binary solvent mixtures

Experimental solubilities are reported for anthracene and carbazole in binary dibutyl ether plus n-hexadecane and dibutyl ether plus squalane solvent mixtures at 25 degrees C. Results of these measurements, used in conjunction with the extended nearly ideal binary solvent (NIBS) model, enabled calculation of the carbazole-dibutyl ether association constant. The numerical value obtained was independent of the hydrocarbon cosolvent, and compared favorably with previously reported values based on carbazole solubilities in solvent mixtures containing much smaller alkane cosolvents.     

General method for determining macrodissociation constants of polyprotic, amphoteric compounds from solubility measurements.

Equilibrium solubility and pH measurements can be used to determine macrodissociation constants of weak acids and bases of some highly insoluble substances. Equations are derived extending solubility, pH, and pKa (macroscopic) relationships to polyprotic, amphoteric substances. A general method for estimating pKa values, given a set of solubility and pH measurements, is presented. Included in the estimation procedure is a subroutine for approximating thermodynamic pKa values. The method was tested on two data sets (tyrosine and 2,3-dihydroxyadenine) and rendered pKa (thermodynamic) estimates in close agreement with those using other methods.     

Mat-pKa calculation tool development for evaluation of acidity constants from solubility profiles-Large study of 41 compounds

In the context of the Quantitative Structure-Activity Relationship (QSAR) for new drugs, knowledge and understanding of the behavior of the molecules in solution and simulated media are key points to provide the best formulated compounds. Current analytical determinations can give solubility data and dedicated techniques can provide other physico-chemical constants, such as pKa(s), logP and logD. All of these data represent the capability of the compound to enter into solutions, but correlations between solubility measurements and these constants are not frequently established, to confirm that the compound observed in solution is the expected one. The study presented here, shows how a dedicated software was elaborated and used in a large study of 41 compounds, to retrieve the dissociation constants, starting with the solubility and pH couples of data acquired.     

Thermochemical investigations of nearly ideal binary solvents. VII: Monomer and dimer models for solubility of benzoic acid in simple binary and ternary solvents

Solubilities are reported for benzoic acid at 25.0 degrees in binary mixtures of carbon tetrachloride with cyclohexane, n-hexane, or n-heptane and of cyclohexane with n-hexane or n-heptane and in ternary mixtures of carbon tetrachloride-cyclohexane-n-hexane and carbon tetrachloride-cyclohexane-n-heptane. Solubilities also are reported for benzoic acid in some binary solvents at 30.0 degrees and for m-toluic acid in binary mixtures of cyclohexane and n-hexane at 25.0 degrees. The results are compared to the predictions of equations developed previously for solubility in systems of purely nonspecific interactions, with the benzoic acids considered as either monomeric or dimeric molecules in solution. The dimer model gave more accurate predictions, with a maximum deviation of 4.4% between observed and predicted solubilities in all systems studied. Solubility maxima were predicted and observed for benzoic and m-toluic acids in cyclohexane-n-hexane and for benzoic acid in cyclohexane-n-heptane. The application of these solubility relationships to liquid-liquid partition coefficients is discussed.     

Coulter Counter measurements of solubility and dissolution rate of sparingly soluble compounds using micellar solutions

A Coulter Counter, Model TAII, was used to determine both solubility and surface specific dissolution rate of two sparingly soluble materials suspended in micellar solutions. The equilibrium solubility increased linearly with surfactant concentration, thereby making it possible by extrapolation to characterize materials with an aqueous solubility down to 1 ppm or less. At high concentrations (greater than 0.1% w/v) the effect of surfactant concentration on the surface specific dissolution rate was less than that predicted from the increased bulk solubility.     

Good laboratory practice of equilibrium solubility measurement

The biggest part of my PhD work was the standardization of the classical saturation shake-flask solubility method. During the experiments we examined systematically which parameters have significant influence on the solubility value and how large experimental error (standard deviation) is caused by them in the solubility method. Hydrochlorothiazide was used as model compound. Modification in temperature, sedimentation time, composition of aqueous buffer and the technique of separation of solid and liquid phases were found to influence the equilibrium solubility results strongly. However, variations in the amount of solid excess and stirring time were found to have less influence. Based on this standardization study, we developed a new shorter (36 hours) protocol for measurements of equilibrium solubility of drug molecules. The new protocol was validated with the aid of 6 structurally different compounds. The equilibrium solubility was measured by both (standard and new) protocols. The results were in good agreement, so the shorter protocol can be applied to measure the equilibrium solubility of drug compounds.     

Lorazepam solubility in and sorption from intravenous admixture solutions

The solubility of lorazepam in aqueous i.v. solutions and the potential for lorazepam sorption from i.v. admixtures in flexible polyvinyl chloride (PVC) bags and tubing were determined. The solubility of triplicate samples containing 15 mg of lorazepam and 20 ml of deionized water, 5% dextrose, lactated Ringer's, or 0.9% sodium chloride injections was determined. The decrease in lorazepam concentration from a 40-micrograms/ml admixture solution in 5% dextrose injection stored in PVC bags was calculated. Duplicate samples of (1) 50 ml in 50-ml PVC bags, (2) 100 ml in 50-ml PVC bags, and (3) 100 ml in 250-ml PVC bags were laid flat to approximate surface areas of 80, 160, and 270 sq cm, respectively, to determine sorptive loss. The continuous flow sorption of lorazepam from duplicate admixtures was tested at three rates through 180- and 350-cm PVC tubing. The solubility of lorazepam in deionized water, 5% dextrose, lactated Ringer's, and 0.9% sodium chloride injections was 0.054, 0.062, 0.055, and 0.027 mg/ml, respectively. Lorazepam solubility was pH dependent. The decrease in lorazepam concentration from the admixture solution stored in PVC bags for up to 121 hours followed biexponential kinetics that account for both the sorptive loss of the drug and the increasing ratio of bag surface area to solution volume. At least 90% of the initial concentration was maintained for five and two hours when the ratio was less than 2.0 and 2.7-2.8 sq cm/ml, respectively. The admixture solution retained a minimum of 95% of initial concentration when 50-ml aliquots were delivered at 600, 200, and 100 ml/hr through both sizes of PVC tubing. Because of its adequate aqueous solubility and slow sorption by PVC delivery components, lorazepam is suited for dilution in i.v. admixtures for treating conditions with intermittent or continuous infusions.     

Evaluation of acidity constants for sparingly soluble compounds from fluorescence measurements

A method to evaluate acidity constants in the ground state of sparingly soluble compounds based on fluorescence measurements is proposed. Mathematical relationships are obtained and presented in a form suitable for easy calculations. Depending on the availability of experimental points at the limiting zones of the fluorescence intensity vs pH graph, three possible cases are considered.     

Rate constants for drug release from micellar solutions of non-ionic surfactants

The release of weak acid from micellar solutions containing different concentrations of two structurally related non-ionic surfactants was estimated using a dynamic dialysis apparatus. In all cases the effect of the surfactant was to reduce the amount of weak acid transferred. The data have been subjected to compartmental analysis using non-linear regression analysis. Rate constants for exchange cross the dialysis membrane were independent of surfactant concentration. As surfactant concentration increased the rate constants for transfer from the non-micellar region did not show a marked change.     

Rate constants for drug release from micellar solutions of non-ionic surfactants

The release of a weak acid from micellar solutions containing different concentrations of two structurally related non-ionic surfactants was estimated using a dynamic dialysis apparatus. In all cases the effect of the surfactant was to reduce the amount of weak acid transferred. The data have been subjected to compartmental analysis using non-linear regression analysis. Rate constants for exchange across the dialysis membrane were independent of surfactant concentration. As surfactant concentration increased the rate constants for transfer from the non-micellar region did not show a marked change.     

Good laboratory practice of equilibrium solubility measurement II. Study of pH-dependent solubility of ionizable compounds

In this paper the pH-equilibrium solubility profiles of ionizable drugs are presented. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. In the case of monoprotic bases, namely papaverine, promethazine and propafenone the experimental equilibrium solubility data precisely follow the theoretical HH curve until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. It is critical that the pKa value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.     

Ligand dissociation constants from competition binding assays: errors associated with ligand depletion

The dissociation constant of a ligand at a binding site (e.g., receptor, antibody) is often determined indirectly by competitive displacement of a radioligand. It is well known that such a determination may be seriously in error unless the free concentrations of both the radioligand and the unlabeled ligand can be measured. By means of computer simulations we have explored the conditions under which this error may occur and its magnitude. We offer guidelines for recognizing a probably inaccurate dissociation constant, and we show how, in some cases, a correction can be made. The problem addressed here is not only a theoretical one; it can arise in the ordinary performance of competition binding assays.