Partition coefficients and surface areas of some alkylbenzenes.

The experimentally measured log P values (logarithms of partition coefficients) of a number of alkylbenzenes are shown to be quantitatively related to the hydrocarbon surface area HSA of the molecule by pi = 0.0275 X HSA - 0.863 (correlation coefficient =0.996, standard deviation = 0.071). The use of surface area as a correlating parameter eliminates the need for correction factors to account for branching, cyclization, ring fusion, and "backfolding". Futhermore, surface area calculations provide a conceptual basis for understanding how conformation can effect partitioning.

Solubility and partitioning. VII: Solubility of barbiturates in water.

The solubility equation of Yalkowsky was used to estimate the aqueous solubility of 33 barbiturates in the temperature range of 5 to 45 degrees C. The equation was extended by adding a term which accounts for the effect of pH on the solubility of the drug. The extended equation is successful in estimating the aqueous solubility of this series of drugs under different conditions of temperature and pH. The results indicate that the extended equation can be used to estimate the aqueous solubility of nonelectrolytes as well as weak electrolytes.

Solubility and partitioning. IX: Solubility of hydantoins in water.

An expression for estimating the aqueous solubility of weak electrolytes under different conditions of temperature and pH has been proposed in a previous publication. The expression, based on the additivity of free energy, separates solubility into three independent contributions. In the present work, the equation is tested with a different set of 18 solutes within the range of temperature of 20 to 50 degrees C and of pH of 1 to 10. The results show that the theoretical relationship between aqueous solubility and the three independent contributions used in the equation is in excellent agreement with the experimental data.

Solubility and partitioning I: Solubility of nonelectrolytes in water.

On the basis of a semiempirical analysis, an equation was obtained that enables the estimation of the aqueous solubility of either liquid or crystalline organic nonelectrolytes: (see formula in text) where log PC and delta Sf are estimated from the chemical structure and MP is either known or experimentally determined. Analysis of this equation provides a means of assessing the role of crystal structure [as reflected by the melting point (MP) and the entropy of fusion (delta Sf)] and of the activity coefficient [as reflected by the octanol-water partition coefficient (PC)] in controlling the aqueous solubility of a drug. Techniques are also provided for estimating the entropy of fusion of organic compounds.

Solubility of organic solutes in ethanol/water mixtures.

The log-linear solubilization model was applied to the experimental solubility data of 109 organic compounds in ethanol/water mixtures. It is found that the extent of solubilization strongly depends on the solute hydrophobicity and the ethanol concentration in the solvent mixture. Patterns of deviation from the log-linear model are related to the structure and hydrophobicity of the solutes. Predictive equations were obtained by regression of the experimental data with solute octanol/water partition coefficient (log Kow). The logarithms of the solubilization and the solute log Kow range over 11 orders of magnitude. The solubilities of chrysene, perylene, benzo[a]pyrene, pentachlorobenzene, and hexachlorobenzene in ethanol/water mixtures were experimentally determined, and the results fit well into the model.

UPPER III: unified physical property estimation relationships. Application to non-hydrogen bonding aromatic compounds.

The UPPER scheme uses four additive and two nonadditive parameters and several well-known equations to calculate 21 physical properties of organic compounds strictly from molecular structure. The scheme allows reasonable estimations of melting and boiling points, aqueous and octanol solubilities, air-octanol, air-water, and octanol-water partition coefficients, vapor pressure, and other properties. In this report non-hydrogen bonding aromatic compounds are used to evaluate a portion of the UPPER scheme.

Predicting the total entropy of melting: application to pharmaceuticals and environmentally relevant compounds.

Experimental entropy of melting values for physical property estimation schemes, such as solubility and vapor pressure, are not readily available. In this study a semiempirical equation, which contains two molecular parameters, is used to estimate the total entropy of melting for a variety of pharmaceutically and environmentally relevant compounds. A database of experimental entropy values consisting of over 370 different compounds was compiled from literature. A molecular rotational symmetry number and a molecular flexibility number for each compound were defined. The simple equation does very well in predicting the total entropy of melting for the complex set of molecules with an average error of 21%.

Stability of E-type prostaglandins in triacetin.

A drug delivery system for E-type prostaglandins is described. In this system, consisting of drug dissolved in triacetin and filled into soft gelatin capsules, normally unstable prostaglandins show excellent stability at room temperature.

A novel thermogravimetric method for estimating the saturated vapor pressure of low-volatility compounds.

Thermogravimetric analysis is used to measure accelerated vaporization rates at elevated temperatures and reduced pressures for several compounds. Multiple linear regression is used to generate empirical coefficients of an equation that relates these parameters. The vaporization rates of the compounds at standard ambient temperature and pressure (SATP) are estimated by extrapolation to 10(5) Pa (1 atm) and 298 K. The estimated vaporization rates are then correlated with literature values of saturated vapor pressure (Psat). The results of twenty four compounds with vapor pressures that span 10 orders of magnitude indicate that p25 degrees C (sat) is directly proportional to the rate of vaporization at SATP. The average error of an estimate of p25 degrees C (sat) based on this relationship is less than a factor of 2.1.

Effect of hydroxypropyl-beta-cyclodextrin and pH on the solubility of levemopamil HCl.

Levemopamil was solubilized by varying the concentration of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and by the alteration of pH. The drug molecule has two sites for possible complexation with HPbetaCD, creating the possibility of either 1:1 or 1:2 complexation. The solubility as a function of HPbetaCD concentration of the charged and uncharged forms of the drug follows the A(L) and Ap complexation models, respectively. This suggests that the charged drug forms a 1:1 complex, whereas the neutral drug forms both 1:1 and 1:2 complexes.

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.

Convective diffusional analysis for drug transport through a tubular polymeric membrane.

The transport of three p-aminobenzoate esters (ethyl, butyl, and hexyl) through a tubular dimethyl polysiloxane membrane into a flowing liquid was investigated. The tubular configuration permits the exact determination of the convective diffusional contribution to membrane transport with models that account for fluid hydrodynamics. The observed transport behavior ranged from complete convective diffusion control for the hexyl ester to complete membrane control for the ethyl ester; the butyl ester exhibited a change in control with flow rate. The implications of convective diffusional considerations to intestinal absorption and dissolution studies are discussed.

Multiple-hole approach to zero-order release.

We describe an approach to zero-order drug delivery systems that utilizes a device consisting of multiple holes uniformly distributed in an impermeable membrane. The interior of the device is filled with a suspension of a drug in a polymeric matrix. Near zero-order release is attained by using the proper density and configuration of holes on the surface of the device.

Solubilization by cosolvents I: organic solutes in propylene glycol-water mixtures.

An equation describing solubilization in aqueous systems by cosolvents was developed by treating a mixed solvent as a linear combination of its components. This equation can successfully explain both the exponential increases and the exponential decreases in aqueous solubility that are frequently observed with the addition of cosolvent. It also provides a means of estimating to what extent a particular drug can be solubilized and how much cosolvent would be required to accomplish a particular degree of solubilization.

Water solubility: a critique of the solvatochromic approach.

The reasoning and some of the assumptions behind the solvatochromic approach to water solubility are evaluated, particularly in relation to its claims. It is shown that the contribution of the pi term is uncertain, and that it can be dropped from the correlation without substantially affecting the degree of fit. The solvatochromic method is compared with the long-standing relationship between solubility and the octanol-water partition coefficient, and it is demonstrated that the latter offers a far superior route to solubility estimation.

Effect of Brij-78 on systemic delivery of insulin from an ocular device.

An ocular insert is developed for the controlled systemic delivery of insulin. Commercially available Gelfoam absorbable gelatin sponge, USP, is used in the fabrication of the ocular insert in the form of a matrix system. Two eyedrop formulations and 13 eye device formulations were evaluated. The efficacy of insulin ocular delivery was quantitated by monitoring the changes in its pharmacological response (i.e., blood glucose lowering). The in vivo results from devices containing 0.5 or 1.0 mg of insulin with 20 micrograms of polyoxyethylene-20-stearyl ether (Brij-78) give a substantial improvement in insulin activity and a significant prolongation in its duration compared with the eyedrops. In addition, the mean blood glucose concentration returns to nearly normal levels within 60 min after the removal of the device. Overall, the application of the Gelfoam device makes it feasible to obtain a prolonged systemic delivery of insulin within the desired therapeutic levels without the risk of hypoglycemia.

A method for the rapid estimation of sublimation rates of organic compounds at standard temperature and pressure.

A method for the rapid estimation of the sublimation rates of organic compounds at standard temperature and pressure (STP; 298 K and 101.3 kPa, respectively) is presented. Thermogravimetric analysis was used to obtain accelerated sublimation rates for anthracene at a series of elevated temperatures and reduced pressures. An empirical equation relating these parameters was used to extrapolate to the STP sublimation rate. This value is in good agreement with the measured value.

Solubilization of flavopiridol by pH control combined with cosolvents, surfactants, or complexants.

This study investigates the roles of both ionized and un-ionized species of flavopiridol in solubilization by complexation, micellization, and cosolvency. Control of pH was used in combination with surfactants (polysorbate 20 and polysorbate 80), cosolvents (ethanol and propylene glycol), as well as uncharged and anionic complexing agents [hydroxypropyl beta-cyclodextrin (HPbetaCD) and sulfobutyl ether beta-cyclodextrin (SBEbetaCD)] to solubilize flavopiridol. These combined techniques increase not only the solubility of the un-ionized flavopiridol but also the solubility of the ionized drug. This study confirms that previously developed equations effectively characterize the roles of pH, pK(a), and either complexation constant, micelle partition coefficient, or cosolvent solubilizing power in determining drug total aqueous solubility.

Solubilization of fluasterone.

Solubilization of nonpolar drugs constitutes one of the most important tasks in parenteral formulations design. This study investigates and assesses the solubility enhancement of Fluasterone by various techniques including cosolvency, micellization, and complexation. Of the solubilizing agents used, the modified beta-cyclodextrins were found to be the most effective. The solubility of Fluasterone is 1.55 x 10(-4) mM, 3.13 mM, and 4.04 mM in water, 20% sulfobutyl ether-beta-cyclodextrin (SBEbetaCD), and 20% hydroxypropyl-beta-cyclodextrin (HPbetaCD), respectively.

Fusion of disubstituted benzenes.

The entropy of fusion of 84 disubstituted benzenes was essentially constant and independent of the participation of the compounds in intramolecular or intermolecular hydrogen bonding. It was also independent of the shapes, sizes, and dipole moments of the rigid molecules studied. While the entropy of fusion was independent of these parameters, the melting point and the heat of fusion showed a direct dependence on molecular properties.