An approach is developed by which the solubility of an organic compound in mixed solvents may be estimated. In this approach, an expression for the excess Gibbs free energy of mixing for multicomponent solvent systems was used to obtain parameters characteristic of the interaction between the solvents. A fairly simple equation which predicts the solubility of a solute in a binary solvent system over the entire solvent composition range was then derived. The equation may be partitioned into terms that contain (a) pure solvent solubilities, (b) solvent-solvent interaction contributions, and (c) contributions from the solute-mixed solvent interactions. The required data are the molar volume of the solute, the pure solvent solubilities, and, theoretically, one experimentally determined solubility in a solvent mixture. The equation can be easily extended for systems with three or more solvents.

Chemical Phenomena↗

PubMed1984

Excess free energy approach to the estimation of solubility in mixed solvent systems II: Ethanol-water mixtures.

The use of the reduced three-suffix solubility equation in characterizing solubility in ethanol-water mixtures is discussed. The equation states that ln xs2,m = z1 ln xs2,1 + z3 ln xs2,3 - A1-3z1z3(2z1 - 1)- (q2/q1) + A3-12z21z3(q2/q3) + C2z1z3, where xs2,1, xs2,3, and xs2,m are the mole fraction solubilities of the solute in ethanol (subscript 1), water (subscript 3), and in the mixture (m); A1-3 and A3-1 are solvent-solvent interaction terms; C2 is a solute-solvent interaction term; and the q- and z-values are molar volumes and solute-free volume fractions, respectively. The contributions of the various terms in the equation to solubility are examined, and the possible use of its derivative in indicating whether a maximum may exist in the solubility profile is discussed. Methods of obtaining the solvent-solvent interaction constant and the ternary constant C2 are described, and the general effectiveness of the equation in describing solubility is examined. The equation is shown to be applicable to 10 compounds with widely different physical properties and, thus, appears to combine both ease of use and general utility.

Chemical Phenomena↗

PubMed1984

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.

Chemical Phenomena↗

PubMed1984

Radiotelemetric method for evaluating enteric coatings in vivo.

A radiotelemetric method for the in vivo evaluation of enteric coating performance is described, and its advantages and disadvantages are compared with those of other available methods. Hydroxypropyl methylcellulose phthalate was used as the test enteric coating. Four dogs were administered several batches of enteric-coated tablets containing buffers. Tablet disintegration was determined by radiotelemetric detection of the pH drop in the upper intestine due to release of the buffer. Premature rupture of the coating in the stomach was detected by a rise and then a fall in gastric pH prior to gastric emptying. The average gastric emptying time was 80 +/- 18 min (SEM), while the average time for a tablet to disintegrate in the upper intestine was 14.2 +/- 2 min. The average disintegration time was not affected by a change in the batch (for a given tablet core pH) or the dog used, suggesting that the method yielded readily reproducible results. Although there was little correlation with in vitro disintegration times, the method gave results similar to those reported in the literature for the same enteric coating in a human study. Of the formulations tested, it was concluded that buffering the core to pH 4 was most suitable for studying enteric coating performance.

Animals↗

PubMed1984

Physicochemical model for dose-dependent drug absorption.

A two-tank perfect-mixing tank model was used to stimulate GI absorption. The effect of drug parameters (pK alpha, solubility, and intrinsic wall permeability) and system parameters (pH profile, volume of intestinal contents, and intestinal flow rate) on drug absorption were studied by numerical data stimulation. When the dose did not exceed the solubility of the drug in the intestinal lumen, the fraction absorbed depended on the transit rate relative to the absorption rate and the pK alpha relative to the pH profile, but was independent of drug dose. Saturation of one or both tanks led to dose-dependent absorption. The model was used to simulate absorption of chlorothiazide. Good agreement between simulated and experimental data led to the conclusion that the physical characteristics of chlorothiazide, rather than a saturable transport mechanism at the intestinal wall, may be responsible for the dose-dependent absorption observed for this drug. The model was also used to simulate hydrochlorothiazide absorption. By applying the same system parameters used for chlorothiazide, the model simulation correctly predicted the dose proportionality of hydrochlorothiazide absorption. The lack of dose dependency in this case may be attributed to the higher solubility and pK alpha of hydrochlorothiazide compared with chlorothiazide.

Chemical Phenomena↗

PubMed1983

Intestinal absorption of amino acid derivatives: structural requirements for membrane hydrolysis.

The intestinal absorption of L-lysine-p-nitroanilide, L-alanine-p-nitroanilide, and glycine-p-nitroanilide was studied in perfused rat intestine in the presence of a variety of potential competitive inhibitors. The results indicate that the hydrolysis site(s) show side-chain specificity, and that inhibitors require a free amino group in the alpha-position and must be in the L-configuration to be effective. Glycyl-L-proline, a peptide transport inhibitor, had no effect on the absorption rate.

Alanine↗

PubMed1983

Moisture sorption kinetics for water-soluble substances. I: Theoretical considerations of heat transport control.

A model based on heat transport control was developed to describe the uptake of water on a deliquescent solid in an atmosphere of pure water vapor. The model assumes the presence of a saturated liquid film on the surface of the solid. The decrease in the vapor pressure of water over the surface, brought about by the colligative effect of solid dissolved in the liquid film, is effectively offset by the increase in temperature of the film (and the solid) caused by the heat released on condensation of the water vapor. The thermal transients die out quickly and a steady-state analysis is valid. At steady state the temperature of the liquid film (and solid) is that temperature at which the vapor pressure of water above the saturated solution is equal to the chamber pressure. Consequently, water uptake occurs at a rate that depends on the heat flux away from the surface. The water uptake rate, W'h, is constant at a given relative humidity and is described by an equation of the form W'h = (C + F) . ln (RHi/RHo), where C and F are conductive and radiative coefficients, RHi the chamber relative humidity, and RHo the relative humidity at and above which continuous water uptake (deliquescence) occurs. The model contains no adjustable parameters and can thus be directly tested against experimental results.

Absorption↗

PubMed1983

Moisture sorption kinetics for water-soluble substances. II: Experimental verification of heat transport control.

The rates of water sorption as a function of relative humidity for water-soluble substances exhibiting deliquescence have been measured in an atmosphere of pure water vapor. The substances studied included a series of alkali halides, choline halides, and sugars. The results were compared with a theoretical model, previously described, which relates the rate of water uptake to the transport of heat produced during the process away from the surface. Taking into account the heat of water vapor condensation, heat of solution, and heat of hydration, when hydration occurs, the model allows excellent a priori prediction of water uptake rates as a function of relative humidity.

Absorption↗

PubMed1983

Moisture sorption kinetics for water-soluble substances. III: Theoretical and experimental studies in air.

As an extension of the model of heat transport control developed for the kinetics of water sorption by water-soluble substances from an atmosphere of pure water vapor, equations have been developed to account for limitations of diffusion on mass transport of water vapor when air is present. Although the inability to determine the vapor diffusion layer thickness prevents using these equations to predict sorption behavior a priori, minimum water sorption rates can be calculated by assuming a diffusion layer thickness equal to the sample chamber radius. Combining heat transport and mass transport produces equations which describe very well the observed sorption by three water-soluble salts in one atmosphere of air. As in the absence of air, sorption rates are predicted and observed to be constant at a given atmospheric relative humidity.

Absorption↗

PubMed1982

Intestinal absorption of amino acid derivatives: importance of the free alpha-amino group.

The intestinal absorption of L-lysine-p-nitroanilide, L-alanine-p-nitroanilide, and glycine-p-nitroanilide was studied in the presence of competitive inhibitors in a perfused rat intestine. It ws observed that L-lysine-p-nitroanilide absorption was inhibited by L-lysine methyl ester and L-arginine-beta-naphthylamide but not by N alpha-acetyl-L-lysine methyl esters. L-Alanine-p-nitroanilide absorption was inhibited by L-alinine methyl ester but not by beta-alanine methyl ester. It was further observed that N alpha-benzoyl-L-arginine-p-nitroanilide and N alpha-succinyl-L-phenylalanine-p-nitroanilide were poorly absorbed. It was concluded that the peptidase in the brush border region that serves as the hydrolysis site requires a free alpha-amino group (an aminopeptidase), and that passive absorption of these compounds occurs only to a small extent.

Amino Acids↗

PubMed1982

Pharmacokinetics of probenecid following oral doses to human volunteers.

The pharmacokinetics of probenecid were examined following single 0.5-, 1.0-, and 2.0-g oral doses to healthy male volunteers. Doses were administered following overnight fast, according to a randomized design. Plasma levels of probenecid were determined by high-pressure liquid chromatography (HPLC), using sulfamethazine as the internal standard. Mean peak probenecid levels of 35.3, 69.6, and 148.6 micrograms/ml were obtained at 3-4 hr following the 0.5-, 1.0-, and 2.0-g doses, respectively. Probenecid levels from the 0.5- and 1.0-g doses declined in apparent monoexponential fashion, with mean elimination half-lives of 4.2 and 4.9 hr. Interpretation of the 2.0-g data by a kinetic model incorporating first-order elimination resulted in a plasma drug half-life of 8.5 hr. When first-order elimination was replaced by a Michaelis-Menten-type function, the mean value of the resulting Vm/Km ratios was 0.20, equivalent to a plasma drug half-life [0.693/(Vm/Km)] of 3.8 hr. Plasma probenecid curves from all three dosages were successfully fitted to the saturable elimination model using nonlinear regression and numerical integration routines. The results suggest that probenecid elimination may be saturable at therapeutic dose levels.

Administration, Oral↗

PubMed1982

A theoretical model for the use of functional antagonism to estimate dissociation constants for agonists.

Explore the source record for details and available documents.

Models, Theoretical↗

PubMed1981

Physicochemical property modification strategies based on enzyme substrate specificities I: rationale, synthesis, and pharmaceutical properties of aspirin derivatives.

A rationale is developed for drug physicochemical property modification based on making derivatives that are substrates for known enzymes. The approach requires knowledge of the enzyme-substrate specificities to select the appropriate derivative. As a class, the digestive enzymes represent possible reconversion sites. It is shown that by using only known specificities of these enzymes, the physicochemical properties of a drug may be modified in almost any manner desired by appropriate derivative choice, with enzymatic regeneration remaining effective. The strategy is applied to making a stable aspirin derivative that is activated in vivo. Of the derivatives made, aspirin phenylalanine ethyl ester was shown to be stable in suspension form for over 4 years. It was also shown that aspirin is regenerated form the derivative in the presence of the enzymes alpha-chymotrypsin and carboxypeptidase in vitro. This biochemical approach to drug physicochemical property modification offers a new and powerful rationale for improving drug product efficacy.

Amines↗

PubMed1981

Physicochemical property modification strategies based on enzyme substrate specificities II: alpha-chymotrypsin hydrolysis of aspirin derivatives.

Three aspirin derivatives, aspirin phenylalanine ethyl ester, aspirin phenylalanine amide, and aspirin phenyllactic ethyl ester, were investigated with respect to their hydrolysis by alpha-chymotrypsin. Of the three compounds, aspirin phenylalanine ethyl ester was the best substrate, with kcat = 25 sec-1 and Km = 1.3 x 10-6 M at pH 8.0. The results for all substrates were in the range of expectation based on kinetic data for other substrates. The apparent latitude in the nature of the acrylamide substituent of alpha-chymotrypsin substrates makes this enzyme a good potential reconversion site for many drug derivatives.

Aspirin↗