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%.     

丙二醇对补骨脂黑色黏稠物的溶解度的影响

目的 优选丙二醇对补骨脂经醇提水沉后所得的不溶于水的黑色黏稠物的溶解条件。方法 正交试验法，以补骨脂素和异补骨脂素为指标，考察丙二醇的用量、丙二醇的浓度和吐温-80的用量3个因素。结果 丙二醇对补骨脂的水不溶物的最佳溶解条件为用6倍量50％的丙二醇溶解补骨脂的黑色黏稠物，所得溶液中补骨脂素和异补骨脂素的含量最高，吐温-80以不加入为佳。结论 丙二醇对补骨脂黑色黏稠物有较好的溶解度。吐温-80的加入不利于补骨脂素和异补骨脂素的溶出。     

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.     

Deviation from linearity of drug solubility in ethanol/water mixtures

A new empirical function that describes the deviation from linearity of solubility of a drug in an ethanol/water matrix is applied to the experimental data for 51 compounds. The proposed model is a more accurate predictor of the co-solvent solubility profile than a general third order polynomial with the same number of parameters. Both the root mean square error and average absolute error for the proposed model are significantly lower than those of existing models. The model also accurately predicts the fraction of co-solvent that gives maximum solubility (fmax).     

Prediction of drug solubility in water-propylene glycol mixtures using Jouyban-Acree model

A trained version of the Jouyban-Acree model was presented to predict drug solubility in water-propylene glycol mixtures at various temperatures. The model is able to predict the solubility in various solubility units and requires the experimental solubility of a solute in mono-solvent systems. The mean percentage deviation (MPD) of predicted solubilities was computed to show the accuracy of the predicted data and 24% was found as the average MPD for 27 data sets studied. The proposed model enables the researchers to predict solubiliy in water-propylene glycol mixtures at various temperatures and reduces the number of required experimental data from five to two points.     

Influence of propylene glycol as cosolvent on mechanisms of drug transport from hydrogels

The in vitro penetration of topical glucocorticoids (GC) betamethasone 17-valerate (BMV), hydrocortisone 17-butyrate (HCB) and hydrocortisone (HC) into an artificial lipid acceptor and excised human skin was examined using binary hydrogels with varying propylene glycol (PG) content. The relationship between the physicochemical properties of the model drugs in binary PG/water mixtures and the rate and extent of their penetration into artificial lipid membranes was studied. As a function of the drug solubility and partition behavior between lipid acceptor and PG/water mixtures, two directions were found in which PG affects the penetration of the GCs used. The lipophilic BMV, providing a higher solubility in the acceptor lipid than in PG/water mixtures of the formulations, penetrates thermodynamically controlled. In this case, PG acts only as cosolvent. For the more hydrophilic HC with higher solubilities in PG/water mixtures than in the acceptor medium, the amount penetrated increases with increasing PG content of the formulation. This result is surprising because of the expectation that the rate and extent of penetration decrease with decreasing partition coefficients. PG penetrates rapidly into the artificial acceptor and into excised human skin. It acts as both cosolvent and enhancer. In the case of HC transport, the enhancer effect is supposed to be a solvent drag effect of PG. HCB seems to penetrate thermodynamically controlled up to 40% PG. However, if PG contents of 60 and 80% are used in the gels the drag transport mechanism dominates. The results obtained from the studies with the lipophilic acceptor membranes were confirmed using excised human skin.     

Extended hildebrand solubility approach: satranidazole in mixtures of dioxane and water

The extended Hildebrand solubility parameter approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various dioxane-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility of satranidazole in the binary solvent, dioxane-water shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane-water mixture, and indicates that the solute-solvent interaction energy is larger than the geometric mean (δ(1)δ(2)) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy is obtained. In this case, the energy term is regressed against a polynomial in δ(1) of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in dioxane-water mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

Physicochemical properties of valsartan and the effect of ethyl alcohol, propylene glycol and pH on its solubility

The aqueous solubility and partition coefficient of valsartan were determined at room temperature. The effect of ethyl alcohol, propylene glycol and pH on its solubility was also investigated. It was found that both solvents increased the solubility of the drug in water. The solubilizing power of ethyl alcohol was found to be higher than that of propylene glycol. Valsartan solubility was also observed to increase at high pH values and its lipophilicity wasdemonstrated by the high positive value of the logarithm of partition coefficient.     

The influence of water mixtures on the dermal absorption of glycol ethers

Glycol ethers are solvents widely used alone and as mixtures in industrial and household products. Some glycol ethers have been shown to have a range of toxic effects in humans following absorption and metabolism to their aldehyde and acid metabolites. This study assessed the influence of water mixtures on the dermal absorption of butoxyethanol and ethoxyethanol in vitro through human skin. Butoxyethanol penetrated human skin up to sixfold more rapidly from aqueous solution (50%, 450 mg/ml) than from the neat solvent. Similarly penetration of ethoxyethanol was increased threefold in the presence of water (50%, 697 mg/ml). There was a corresponding increase in apparent permeability coefficient as the glycol ether concentration in water decreased. The maximum penetration rate of water also increased in the presence of both glycol ethers. Absorption through a synthetic membrane obeyed Fick's Law and absorption through rat skin showed a similar profile to human skin but with a lesser effect. The mechanisms for this phenomenon involves disruption of the stratum corneum lipid bilayer by desiccation by neat glycol ether micelles, hydration with water mixtures and the physicochemical properties of the glycol ether-water mixtures. Full elucidation of the profile of absorption of glycol ethers from mixtures is required for risk assessment of dermal exposure. This work supports the view that risk assessments for dermal contact scenarios should ideally be based on absorption data obtained for the relevant formulation or mixture and exposure scenario and that absorption derived from permeability coefficients may be inappropriate for water-miscible solvents.     

Influence of propylene glycol and isopropyl myristate on the in vitro percutaneous penetration of diclofenac sodium from carbopol gels

The influence of propylene glycol (PG) on the in vitro penetration of diclofenac sodium (DFS) through a synthetic membrane and abdominal rat skin from carbopol gels was investigated using Franz-type diffusion cells. The combined effect of isopropyl myristate (IPM) and PG was also evaluated. It was found that the penetration through the synthetic membrane was well described by the Higuchi model. The gel containing 40% PG showed the highest release rate, indicating that a releasing maximum exists for PG content which provides the fully solubilized drug in the vehicle. When using rat skin as the barrier, the penetration rate was controlled by the membrane. DFS flux decreased with increasing PG content of the gels due to an increase of the drug affinity to the vehicle. A cosolvent action of PG was evident. However, the combination of PG and IPM resulted in a synergistic enhancement of DFS flux. Maximum enhancing activity was obtained from gels containing 40% PG, which yielded an enhancement ratio of about 8. Increasing IPM content from 3 to 5% increased the flux and decreased the lag time taken to reach a steady-state level.     

Extended Hildebrand solubility approach: p-hydroxybenzoic acid in mixtures of dioxane and water

The extended Hildebrand solubility approach was used to reproduce the solubilities of p-hydroxybenzoic acid in a dioxane-water system. The solubility parameter of p-hydroxybenzoic acid was determined and found to be approximately 15 (cal/cm3)1/2. Residual plots (scattergrams) were used in conjunction with R2, F, and standard deviation values to determine whether a quadratic, cubic, quartic, or higher degree polynomial was required in the calculations. The earlier iteration method for back-calculations of solubilities was replaced by the more reliable root-finder method. The solubility profile of p-hydroxybenzoic acid in dioxane-water mixtures did not follow a log linear relationship even in the ranges where the solubility parameters of the water-cosolvent mixture might be expected to produce a straight-line function, as observed in other studies.     

Pharmacokinetics of propylene glycol in the rabbit

Propylene glycol (PG) is widely used as a drug solvent in the pharmaceutical industry. However, it has produced central nervous system toxicity during chronic administration. The current study was undertaken to describe the pharmacokinetics of propylene glycol during acute and constant-rate intravenous dosing, using the rabbit as an animal model. In the acute dosing experiment, metabolism of PG was the dominant disposition pathway, characterized by concentration-dependent metabolic clearance. Renal excretion of PG accounted for only 2.4 to 14.2% of the total dose following acute administration due to significant reabsorption in the rabbit kidney. An ascending-convex relationship exists between renal clearance and urine flow. During constant-rate intravenous infusion studies, there was a disproportionate relationship between infusion rate and steady-state concentration, providing further evidence for capacity-limited disposition kinetics. The ascending-convex relationship between renal clearance and urine flow was also apparent in the long-term infusion studies.     

Pharmacokinetics of propylene glycol in the rabbit

Propylene glycol (PG) is widely used as a drug solvent in the pharmaceutical industry. However, it has produced central nervous system toxicity during chronic administration. The current study was undertaken to describe the pharmacokinetics of propylene glycol during acute and constant-rate intravenous dosing, using the rabbit as an animal model. In the acute dosing experiment, metabolism of PG was the dominant disposition pathway, characterized by concentration-dependent metabolic clearance. Renal excretion of PG accounted for only 2.4 to 14.2% of the total dose following acute administration due to significant reabsorption in the rabbit kidney. An ascending-convex relationship exists between renal clearance and urine flow. During constant-rate intravenous infusion studies, there was a disproportionate relationship between infusion rate and steady-state concentration, providing further evidence for capacity-limited disposition kinetics. The ascending-convex relationship between renal clearance and urine flow was also apparent in the long-term infusion studies.     

Alcohol flux and effect on the delivery of theophylline from propylene glycol

The diffusion of alcohols and the back-diffusion of water through hairless mouse skin after the application of alcohols have been determined using ¹H NMR spectroscopy to quantitate the composition of the donor phases during diffusion cell experiments. After the alcohols were removed, a second application of a standard solute/vehicle (theophylline/propylene glycol-PG) was made. The diffusion of PG and the back-diffusion of water were determined using ¹H NMR spectroscopy to quantitate the composition of the donor phases while the diffusion of theophylline was determined using UV spectroscopy to quantitate theophylline in the receptor phases. The flux values for theophylline, PG and water were used as a measure of irreversible damage done to the skins by the initial application. The flux of the alcohols and the back-diffusion of water in the first application period decreased with increasing chain length of the alcohol. On the other hand, the flux of theophylline, PG and water in the second application increased with increasing chain length of the alcohol that had been applied initially. The results from the second application appear to be due to greater irreversible damage caused by the longer chain alcohols. There is a clear difference between the extent of damage caused by the C₁ to C₃ alcohols and that caused by the C₄ to C₈ alcohols.     

Influence of non-ionic surfactants, pH and propylene glycol on percutaneous absorption of piroxicam from cataplasm.

The influence of pH in the formulation, ethylene oxide chain length of polyoxyethylene (POE) non-ionic surfactants and addition of propylene glycol (PG) on percutaneous absorption of piroxicam (Px) from cataplasm was investigated in guinea-pig in vivo. The area under the plasma concentration of Px curve until 8 h after the application (AUC(0-8)) increased with increasing the cataplasm base pH up to 6.5 and then plateaued from pH 6.5 to 7.2. Px solubility in water increased markedly with increasing pH from pH 6 as Px is a weak acid and its pK(a) is 5.3. The ionic form of Px in the cataplasm was suspected to contribute to the percutaneous absorption of Px. The percutaneous absorption of Px from the cataplasms containing 5% of POE non-ionic surfactants with various POE lengths were examined. The parabolic relation between the Px absorption and the POE length was observed. POE length from 5 to 15 enhanced percutaneous absorption to a greater extent. An attempt was also made to examine the influence of the addition of PG to the formulation containing POE (9) lauryl ether. The addition of 20% PG to the formulation significantly increased the Px concentration in plasma, compared to 0, 5, 10 and 15% PG. Skin and cutaneous muscle concentrations significantly increased by addition of 20% PG, compared to those by 0% PG but not in deeper muscle.     

Bilinear model for the prediction of drug solubility in ethanol/water mixtures

A new bilinear function that accounts for the disparity between the log-linear and parabolic models for cosolvent solubilization is presented, where ethanol was used as the model cosolvent. This accounts for both the initial and terminal slopes in the ethanol/water solubility profiles of semi-polar solutes. The proposed model has only two fitted parameters sigmaA and sigmaB, which represent the initial and terminal asymptotes in the solubility profiles. The bilinear function can also model the ethanol/water solubility profile more accurately than the log-linear model and a general parabolic model.     

Limits on the use of propylene glycol in topical preparations

The authors define some limits for useful concentrations of propylene glycol (P.G.) by determination of inhibition produced in cell respiration from (crushed) mouse liver and in human cutaneous fibroblastic proliferation. They conclude that P.G. is able to inhibit both these physicological mechanisms from concentration as weak as 5.5% and 2% respectively. They give a method for analytical determination of P.G. in cosmetic and pharmaceutical products using gas liquid chromatography. This method is useful for a wide range of concentrations.     

Drug compatibility with the sponge phases formed in monoolein, water, and propylene glycol or poly(ethylene glycol)

The liquid sponge phase, a bicontinuous lipid-water system, formed in solvent-monoolein-water systems was investigated with respect to drug compatibility. The solvents propylene glycol and poly(ethylene glycol) swell the bicontinuous cubic phase of the monoolein-water system and form the sponge phase at constant water contents, 40 and 30% w/w, respectively. Amphiphilic drugs such as lidocaine participate in the bilayer and act on the interfacial curvature according to the amphiphilic packing concept. The interfacial curvatures increase/decrease depending on the salt/base forms of the molecules. The quantity of lidocaine that can be incorporated into the sponge phase depends not only on the form of lidocaine but also on the lipid content and the solvent used in the sponge phase. Addition of the water-insoluble gramicidin S to the sponge phase resulted in a stiff isotropic phase, possibly a cubic phase, indicating interaction of gramicidin S with the lipid bilayer. The in vitro release of lidocaine was significantly faster from the sponge phase in the propylene glycol system than from the corresponding cubic phase without solvent.