Michel Buchmann

A New Predictive Equation for the Solubility of Drugs Based on the Thermodynamics of Mobile Disorder

The thermodynamics of mobile disorder rejects the static model of the quasi-lattice for liquids. Because of the perpetual change of neighbors, during the observation time of thermodynamics of the order of seconds, each molecule of a given kind in a solution has experienced the same environment and had at its disposal the same mobile volume. This domain is not localizable and not orientable. Each molecular group perpetually “visits” successively all parts of this domain. The highest entropy is obtained when the groups visit all the parts of the domain without preference. H-bonds are preferential contacts with given sites of the neighbors that cause deviations with respect to such “random” visiting, thereby decreasing the entropy. The quantitative development of these ideas leads to equations describing the effect of solvent–solvent, solute–solvent, and solute–solute hydrogen bonds on the chemical potential of the solute. A universal equation predicting the solubility of drugs in a given solvent is derived. The effect of H-bonds is governed not by “solubility parameters” but by stability constants from which the order of magnitude can be estimated. From the sole knowledge of the solubility of methylparaben in pentane, the method predicts correctly the order of magnitude of its solubility in 26 other solvents, including alcohols and water.

Comparison of the solubility of polycyclic aromatic hydrocarbons in non-associated and associated solvents: The hydrophobic effect

Abstract A remarkable improvement of the predictions of the solubility, Φ B , of a solute B in a solvent S is achieved by the theory of the mobile order of Huyskens. In this theory, the hydrophobic effect of the associated solvents like alcohols against inert substances is no longer considered as a result from a change in the energy of the molecular interactions, but as a decrease of the entropy due to temporary correlated displacements of two or more hydroxylic groups of solvent molecules. Such correlated displacements create a kind of mobile order. Quantitatively, the hydrophobic effect reduces ln Φ B by an amount of r S Φ S V B / V S . A direct consequence of this effect is that an increase in the ratio V B / V S of the molar volumes, which in non-H-bonded solvents is favourable for the solubility, becomes unfavourable in alcohols. For polycyclic aromatic hydrocarbons, the prediction of the solubilities in apolar, polar and associated solvents by the mobile order theory necessitates the knowledge of a single parameter only which can be deduced from one experimental solubility.

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

Abstract 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 cm 3 /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.

Enhancement of the solubilities of polycyclic aromatic hydrocarbons by weak hydrogen bonds with water

SummaryThe thermodynamics of mobile order is applied to predict the aqueous solubility of liquid and solid aliphatic and polycyclic aromatic hydrocarbons. The solubility values are mainly determined by the magnitude of the hydrophobic effect. However, contrary to the solubilities of the alkanes, the solubilities of polycyclic aromatic hydrocarbons in water predicted in absence of solute-solvent hydrogen (H) bonds are systematically too low. This shows the contribution of weak specific interactions between the OH groups and the π electrons of the aromatic substances. According to the theory, these interactions are characterized by a stability bility constant Ko which can be derived from solubility data. At 25°C, this constant amounts to 80 cm3/mol, the order of magnitude of which can be explained by the competition of these intermolecular bonds with the rather weak self-association bonds in the secondary chains of water.

Experimentally optimized determination of the partial and total cohesion parameters of an insoluble polymer (microcrystalline cellulose) by gas-solid chromatography

Abstract The partial solubility parameters of microcrystalline cellulose ( δ d = 9.5 ± 0.5, δ p = 6.2 ± 1.0, δ h = 15.3 ± 0.7 δ t = 19.2 ± 0.4) were obtained, on the basis of the Snyder/Karger-Hansen interaction model, where Δ E A = V i ( δ d i d d i + δ p i δ p j + δ h i d h j ). They were deduced from the internal adsorption energy of n -decane, carbon tetrachloride, benzene, acetonitrile, methanol and ethanol, determined by gas-solid chromatography. In order to get the highest accuracy and precision possible with minimal experimental work and the most appropriate solutes, the planification of the experiments was achieved by optimization of the experimental matrix. This revealed that the best results are obtained when 6 out of the 14 solutes were chosen.

Significance of Partial and Total Cohesion Parameters of Pharmaceutical Solids Determined from Dissolution Calorimetric Measurements

The total and partial adhesion-derived cohesion parameters of three solid pharmaceutical substances (caffeine, theophylline, and phenylbutazone) were determined from dissolution calorimetric measurements, a new technique devised for this purpose. Calorimetry has the advantage of leading directly to enthalpies, from which the solute cohesion parameter(s) is(are) deduced. An equation was developed that relates partial molar enthalpies of mixing (obtained by subtracting enthalpies of fusion from enthalpies of dissolution) to the cohesion parameters of the solute and of the solvents. Solvents were selected on the basis of their known cohesion parameters by applying the experimental research methodology.

Adsorption Isotherms of Water on a Set of Fractosils and on Avicel PH 101R by Frontal Analysis Chromatography

AbstractResidual water adsorbed on the surface of solids can modify significantly e.g.: stability of solids, properties of colloidal systems, compressibility of powders, oxidation phenomena, heterogeneous nucleation in the atmosphere, and may serve as a medium, favourable for the growth of numerous micro-organisms.The aim of this work is the characterization, by physical and thermodynamic parameters, of adsorbed water on the surface of a set of Fractosils and of Avicel PH 101R. Frontal analysis chromatography is used for the determination of adsorption isotherms. The analysis of the thermodynamic parameters of adsorbed water indicates that the water adsorption is either mobile or localized depending on the nature of the solids. The adsorbed water exists under three states: strongly bonded (up to the monolayer), weakly bonded and free (condensed water).

Ab initio quantum-chemical study on drug decomposition in solid state preparations: Part I. Potential reactivity of the interaction surface sites of silicas

Abstract Partly dehydroxylated silicas (aerosils) are frequently used as pharmaceutical excipients. In order to understand the behaviour of such surfaces toward water and reactive species, STO-3G calculations have been carried out on cluster models of increasing complexity. Analysis of the electronic properties allowed us to select the silanol group of the orthosilicic acid and the siloxane bond of the pyrosilicic acid to represent respectively the hydroxylated and the dehydroxylated part of silica surfaces. Moreover, the hydrophilic and hydrophobic nature of these interaction centres can be explained by their electrostatic potential, respectively Vmin(OH) — 67.5 kcal mol−1 and Vmin(SiOSi) — 48.5 kcal mol−1, characterizing the depth of the potential wells on the solid surface. These findings are supported by the calculations of interaction energies between the models and a water molecule.