Solubility parameters from maxima in solubility/solvent plots

Solubility data of a substance in solvents with known solubility parameters have been used graphically in the past to determine the solubility parameter of the solute. A multiple regression method of handling this is presented. It gives rise to self-consistent solubility parameters, but the solvent molar volumes calculated are anomalous, pointing to the presence of factors not accounted for in the traditional approach to solubility parameter determination through solubility determination.     

Effects of solvent polarity on the acid dissociation constants of benzoic acids

The pKa values of benzoic acid, p-methylbenzoic, and p-aminobenzoic acid (PABA) were determined by potentiometric titration in mixtures of 0-0.5 volume fractions of various cosolvents and water. The differences between the aqueous and semiaqueous pKa values were similar for the three solutes at a particular cosolvent-water mixture for most of the cosolvents studied. The largest differences occurred in the dimethyl sulfoxide (Me2SO)-water system, where the pKa changes were larger for PABA than the other two solutes. The data are analyzed by a consideration of both electrostatic and nonelectrostatic medium effects. The electrostatic medium effect was calculated from the Born Equation while any residual pKa change was attributed to nonelectrostatic medium effects. The residual effects were found to correlate well with indexes of solvent hydrogen bond acceptor ability such as HBA and beta-values. These results provide a rationale for the use of two solvent polarity indexes for more accurate estimates of pKa values of weak electrolytes in semiaqueous solvent systems. Analysis of solubility data of the salt and acid forms of PABA and benzoic acid in ethanol-water and Me2SO-water mixtures suggests that the higher activity of the anionic form of PABA in Me2SO-water mixtures is primarily responsible for the large pKa changes observed for that solute.     

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.     

The effect of proton-acceptor sites of the solute on its solubility in proton-donor solvents

The solubilities of five solid ketones and two esters are predicted in common organic nonelectrolyte solvents using the solubility equation derived from the mobile order theory. In the framework of this theory, the formation of solute-solvent hydrogen bonds is treated on the basis of standard stability constants. Two different values characterizing the ketone-alcohol and the ester-alcohol hydrogen bonds, respectively 170 and 110 cm³/mol, have been determined. The formation of specific molecular interactions brings about a net increasing of the solubility without modifying the values of the other contributions relevant to the solution process. Using the predetermined values of the stability constants, the solubility equation is then successfully applied to predict the solubility of testosterone propionate in 28 solvents including alcohols and water from the sole knowledge of its solubility in hexane.     

The effect of solvent polarity upon rotational barriers in nikethamide

In summary, dynamic nuclear magnetic resonance techniques were used to study the hindered internal rotation of the amide bond of the analeptic nikethamide. The rotatory motion of this bond was studied in a series in a series of solvents of increasing polarity: CDCl₃, CH₃(CH₂)₃OD, CH₃CH₂OD, CH₃OD and D₂O. Motion about the amide bond was increasingly hindered in direct proportion to solvent polarity, correlating with enhanced hydrogen bond formation between nikethamide and the more polar solvent molecules. Diethylamide group motion would be expected to affect binding to the carbonyl oxygen to cholinergic receptor sites. The degree to which association to a receptor site can be affected by this rotatory motion may vary from 0 to 4 kcal/mole, the variability being entirely dependent upon the polarity of the binding site. An increase in rotamer lifetime, corresponding to a more polar environment, would be expected to enhance the kinetics of nikethamide association to the receptor site.     

Dependence of pharmacokinetic parameters on the body weight

By employing the theory of biological similarity, equations concerning the dependence of the clearance on the body weight are being presented for different elimination processes. Changes in the biological half-life depending on the body weight are demonstrated by way of the one and two compartment model. The discussion of the results based on our own data as well as those derived from literature shows that it is very ofter possible to estimate the weight-depending differences between half-lives of various species by simple empirical formulas.     

Comparison of various cosolvency models for calculating solute solubility in water-cosolvent mixtures

Previously published cosolvency models are critically evaluated in terms of their ability to mathematically correlate solute solubility in binary solvent mixtures as a function of solvent composition. Computational results show that the accuracy of the models is improved by increasing the number of curve-fit parameters. However, the curve-fit parameters of several models are limited. The combined nearly ideal binary solvent/Redlich-Kister, CNIBS/R-K, was found to be the best solution model in terms of its ability to describe the experimental solubility in mixed solvents. Also resented is an extension of the mixture response surface model. The extension was found to improve the correlational ability of the original model.     

Corticosteroid solubility and lipid polarity control release from solid lipid nanoparticles

Solid lipid nanoparticles (SLN) show promise as a drug delivery system for skin administration. The solid state of the lipid particle enables efficient drug encapsulation and controlled drug release. The present study addresses the influence of lipid composition and drug substance lipid solubility on the in vitro release profile of corticosteroids from SLN for topical administration. Firstly, the effect of lipid composition on the lipid solubility and in vitro release of betamethasone-17-valerate (BMV) was determined by varying the lipid monoglyceride content and the chain length of the fatty acid moiety. Secondly, the effect of drug substance physicochemical properties was determined by studying five different corticosteroid derivatives with different lipophilicity. A high concentration of monoglyceride in SLN increased the amount of BMV released. The corticosteroid release rate depended on the drug substance lipophilicity and it was clear that the release profiles depended on drug partitioning to the aqueous phase as indicated by zero order kinetics. The results emphasize that the corticosteroid solubility in the lipid phase greatly influence drug distribution in the lipid particles and release properties. Thus knowledge of drug substance solubility and lipid polarity contributes to optimize SLN release properties.     

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.     

An improved empirical model to calculate solute solubility in supercritical carbon dioxide

To provide more accurate solubility predictions in supercritical carbon dioxide (SC-CO2) using an empirical model employing density as an independent variable, the density of SC-CO2 at different temperatures and pressures has been calculated and compared with experimental densities. The average percentage deviation (APD) has been determined as an accuracy criterion and the obtained APD for the equations studied were between 1.3 (+/-1.4)-11.6 (+/-8.9)%. To show the effects of density values on solubility prediction, the solubility of 18 drug compounds in SC-CO2 has been calculated using an empirical equation with respect to temperature, pressure and density. The APD values for correlative analysis was 8.5 (+/-5.8)% for the most accurate density values calculated by BACK equation of state. A minimum number of experimental data (i.e. 6 points) has been used to train the model then the solubility at other temperatures and pressures has been predicted and the APD value for the most accurate densities obtained was 14.2 (+/-9.4)%. This prediction error could be considered as acceptable when it is compared with RSD values for repeated measurements (approximately 10%) and the proposed predictive method could be employed in industry to calculate the solubility of a drug using a limited number of experimental data.     

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.     

Measurement and correlation of solute solubility in HFA-134a/ethanol systems

The goals of this study were to determine the solubility values of solid organic solutes in pure HFA-134a and in HFA-134a/ethanol cosolvent systems (0-20%, w/w), and to investigate the relationship between these solubilities and a solute's physico-chemical properties. A direct inject on-line HPLC method was used to determine the solubility of 21 solutes in HFA-134a/ethanol. The samples were allowed to equilibrate for at least 48h. The filtered sample was injected directly on an analytical HPLC column through a manual injector interface, and analyzed at an appropriate solute wavelength via HPLC. The solutes display diverse physico-chemical properties and yielded solubility values that ranged over four orders of magnitude. In general, a linear-linear solubility relationship was observed as the fraction of ethanol increased. The effects on solubilization ranged from 1.3 to 99.4 times when 20% (w/w) ethanol was introduced, relative to pure HFA-134a. A regression equation utilizing a solute's hydrogen bonding potential resulted in a significant correlation to the slope obtained from a linear model for solubility in HFA-134a with 0-20% (w/w) ethanol, and may be useful for pre-formulation studies.     

The effect of solvent polarity on the accumulation of leachables from pharmaceutical product containers.

Material/water equilibrium interaction constants (E(b)) were determined for 12 organic model solutes and a plastic material used in pharmaceutical product containers (non-PVC polyolefin). An excellent correlation was obtained between the measured interaction constants and the organic solute's octanol/water partition coefficient. The effect of solvent polarity on E(b) was assessed by examining the interaction between the plastic and selected model solutes in binary ethanol/water mixtures. In general, logE(b) could be linearily related to the polarity of the ethanol/water mixture. This information, coupled with the interaction model, was used to estimate the levels to which container leachables could accumulate in contacted solutions. Such estimates were made for six known leachables of the polyolefin material and compared to the leachable's measured accumulation levels in binary ethanol/water systems. In general, the accumulation level of the leachables increased with increasing solution polarity. For most of the leachables, the measured accumulation level was less than the calculated levels, suggesting that equilibrium was not achieved in the leaching portion of this study. This lack of equilibrium is attributable to the layered structure of the material studied, as such layering retards the migration of the leachables that are derived from the material's non-solution contact layers.     

Deviations of drug solubility in water-cosolvent mixtures from the Jouyban-Acree model--effect of solute structure

Deviations of the predicted solubilities using the Jouyban-Acree model from experimental data were correlated to the structural descritptors of the drugs computed by HyperChem software. The proposed models are able to predict the solubility in water-cosolvent mixtures and reduced the mean percentage deviations (MPD) of predicted solubilities from 24%, 48%, and 53% to 16%, 33% and 38%, respectively for water-propylene glycol, water-ethanol and water-polyethylene glycol 400 mixtures, with the overall improvement in prediction capability of the model being approximately 13%.     

Influence of solute structure on deviations from the log-linear solubility equation in propylene glycol:water mixtures

The solubilities of the methyl, ethyl, propyl, and butyl esters of p-hydroxy- and p-aminobenzoates have been determined in propylene glycol:water mixtures. The log of the observed solubility data in propylene glycol:water mixtures was examined for deviations from the following equation: In Xi = f In (Xc) + (1 - f) In (Xw), where Xi is the calculated mole fractional solubility of the solute, f is the volume fraction of cosolvent, Xc is the observed mole fractional solubility in the neat cosolvent, and Xw is the solubility in water. In each case, the deviations from the predicted solubilities demonstrated a characteristic pattern. Positive deviations were observed at high volume fractions of cosolvent, while negative deviations were observed at low volume fractions. The magnitude of the deviations at low volume fractions of cosolvent was related to the carbon chain length within each group of esters. A similar phenomenon was not observed at high volume fractions of cosolvent; however, the magnitude of the deviations was dependent on the nature of the polar group on the ester. The data are interpreted in terms of the possible effects of solvent structure on the solubility of the solutes.     

Solubility and polarity parameters of polyoxyethylene glycol dialkyl ethers

Solubility parameters were estimated for model individual polyoxyethylene glycol dialkyl ethers and correlated with polarity parameters determined by gas chromatography. The effects of the length of the polyoxyethylene chain and of the terminal alkyl groups on the values of the parameters investigated and on the obtained relationships are discussed. It was found that polarity parameters can be estimated from the total solubility parameter with relatively low errors (approximately 1% for the retention index of ethanol and methanol and for the polarity index of ethanol). The polarity index of methanol and the relative retention of alcohols can be estimated with errors of approximately 3-4%. Using the total solubility parameter, polyoxyethylene glycol dialkyl ethers can be arranged in the same order of increasing polarity as in the case of polarity parameters determined by gas chromatography.     

Rapid, small-scale determination of organic solvent solubility using a thermogravimetric analyzer

A rapid gravimetric method for determining drug candidate solubility in organic solvents has been developed. The scale, speed, precision, and accuracy of the method make it ideal for solubility screening of pharmaceutical compounds during early development. The method utilizes a thermogravimetric analyzer to automate drying and weighing. Results for model compounds compare favorably with literature values.     

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.