E. Tomlinson

Enthalpy-entropy compensation analysis of pharmaceutical, biochemical and biological systems

Abstract Although linear free-energy relationships are familiar research tools in pharmaceutical and biochemical science, the analysis of data in terms of a further extrathermodynamic analysis, namely enthalpy-entropy compensation, is little used. This review attempts to draw attention to this latter procedure and describes the advantages and disadvantages of the method by using examples taken from the recent literature. Consideration is first given to the manner in which the analysis should be performed, and to the significance of found compensation relationships. Secondly, the analytical procedure is applied to data derived from a number of phenomena of pharmaceutical and biochemical interest, including, liquid-liquid distribution, Chromatographic retention, aqueous solubility, complexation, film spreading, liposome-water partitioning, biological membrane permeation and receptor/enzyme-small molecule interactions. Results indicate that enthalpy-entropy compensation analysis, when performed using the statistically correct coordinate plane of enthalpy versus free-energy, can be a most valuable tool for examining the effect of physicochemical structure on various phenomena, for verification of similarity in behaviour, and for indicating outliers from general relationships.

Correlations between alkane/water and octan-1-ol/water distribution coefficients and isocratic reversed-phase liquid chromatographic capacity factors of acids, bases and neutrals

Abstract For a large number of acid, base and neutral liquids and solids (including drugs) general relationships between both octan-1-ol/water distribution coefficients and isocratic reversed-phase liquid chromatography capacity factors and solute aqueous activity coefficients have been shown. These have lead to highly significant correlations being found between octan-1-ol/water distribution coefficients and isocratic Chromatographie capacity factors determined using aqueous methanol/alkylsilica phase systems. In contrast, only for a series of neutral and basic solutes could a limited linear relationship be found between isocratic capacity factors and aliphatic alkane/water distribution coefficients, (with acids — and alcohols — being displaced irregularly from this relationship). It is suggested that capacity factors determined using methanol-water (volume fraction organic modifier = 0.50)/ octadecylsilane could be used as a priori descriptors of solute physicochemical character in, for example, drug design and preformulation studies.

Potential use of albumin microspheres as a drug delivery system. I: Preparation and in vitro release of steroids

Abstract Albumin microspheres were prepared by two different stabilization processes: chemical denaturation and heat denaturation. The extent of stabilization was characterized by the solubility and the swelling properties of the microspheres. In vitro drug (prednisolone) release rates were determined for the different microsphere preparations and the results were correlated to the stability of the microspheres. Heat denaturation had a significant effect on the in vitro release rates; the more denatured the albumin, the slower the drug release rate. Chemical denaturation, using glutaraldehyde, did not have a marked effect on drug release from the microspheres. Two of the major limitations of albumin microsphere systems i.e. poor drug entrapment and premature release (“burst effect”) have been overcome using prednisolone loaded heat denatured microspheres.

Thermodynamics of functional groups in reversed-phase high performance liquid-solid chromatography

Abstract The behaviour of functional groups having differing physicochemical characteristics have been examined in reversed-phase high performance liquid-solid chromatography using aqueous methanolic eluents. The effects of temperature, mobile phase organic modifier concentration and stationary phase on extrathermodynamic group values have been determined. Results fit into the framework of solvophobic theory with extrapolated group parameters being related to other extrathermodynamic terms. Group values exhibit linear enthalpy-entropy compensation behaviour as examined using ΔH-ΔG coordinates. A unique relationship between solute retention and the enthalpy of transfer for all solutes and phase systems examined is exhibited, and the overall study indicates that attempts to relate chromatographic retention data to drug liquid-liquid distribution is thermodynamically valid.

Isocratic chromatographic retention data for estimating aqueous solubilities of acidic, basic and neutral drugs

For 108 compounds of diverse chemical character (including drug molecules) isocratic reversed-phase liquid chromatographic retention parameters have been used in modifications of the Hildebrand-Scott equation to estimate compound aqueous solubility. The relationships found are valid for both liquids and crystalline solids, as well as for stronger (pKa > 6.5) bases that are chromatographed in a partially ionized state. It is observed that there is a significant constant difference in behaviour between acid and alcohol molecules and neutral and base molecules. This difference can be empirically corrected for during solubility estimations. Comparison of the use of octan-l-ol/water distribution coefficients in these equations shows that the use of isocratic chromatograhic retention parameters lead to significantly better estimations of compound aqueous solubility.

Drug liquid-liquid distribution based on the fundamentals of segmented flow

A method for the rapid determination of drug liquid—liquid distribution properties, (partition coefficients, ion-pair extraction constants, etc.), is described. The approach is based on fast solute phase equilibration in oil/water segmented flow through helically coiled tubes, with phase splitting based on dissimilar phase wetting of hydrophobia and hydrophilic surfaces. The method has a capacity for up to 45 determinations per hour with a precision error of less than 2%, and is shown to be suitable for either single ‘oneoff’ determinations of Kd etc., or for more detailed studies examining various constitutional and environmental factors, (e.g. pH, ionic strength, temperature), which can affect distribution. The rapidity of determination makes the method appropriate for examining the distributive properties of unstable drugs.

Physicochemical description of the absorption rate of a solute between water and 2,2,4-trimethylpentane

The apparent rate of absorption, kapp, for steady-state flux of solutes of varying physicochemical character from an aqueous compartment (pH = 7), through a membrane filled with 2,2,4-trimethylpentane, to a 2,2,4-trimethylpentane sink compartment, can be given by a simple bilinear relation. It is clearly demonstrated that experimentally, and in concordance with the theoretical model, a reduction in the aqueous diffusion layer thickness leads to a displacement of the bilinear log kapp versus log kd curve both upwards and to the right. However, it can also be shown that at lower Kd values the interfacial transfer step can become rate limiting. In addition, there seems to be a linear relationship between the interfacial transfer rate constant and the log Kd value. This indicates that the simple bilinear model for describing the absorption rate has to be expanded to adequately describe drug rate of absorption.

Ion-pair and complex-coaeervate effects on large ion flux through polyamide-6 membrane

Abstract Using a simple two-compartment diffusion cell it has been demonstrated that the transport of a model large organic ion (sodium cromoglycate), across a polyamide membrane can be altered by the presence of hydrophobic monovalent quaternary ammonium ions added to the bulk donor phase. There is an initial enhancement of ion flux at low quaternary ion concentration, which is directly related to ammonium ion concentration and hydrophobicity. The flux falls markedly at the aqueous solubility product between the two ions (where a complex coacervate forms). Results are consistent with previous findings using in vivo absorption systems

Local composition models in pharmaceutical chemistry. I. Liquid-liquid distribution coefficients from COMMON UNIQUAC parameters

Abstract A literature compilation of COMMON UNIQUAC parameters has been employed to correlate mutual solubilities in binary and ternary systems on one side and distribution coefficients between water and organic solvent of infinitely diluted liquid solutes, Kd, on the other. The following organic solvents were considered: butan-1-ol, 2-methylpropan-l-ol, ethyl acetate, chloroform, octan-1-ol. benzene, hexane, cyclohexane, heptane, octane and 2,2,4-trimethylpentane. Satisfactory Kd predictions were observed for various solutes in 2-methylpropan-l-ol/water and butan-1-ol/water and ethyl acetate/water. For all other systems, the reliability of predicted Kd values decreased with decreasing mutual saturabilities, outliers being most frequently found among alkane/water distribution coefficients of hydrogen-bonding and acidic solutes. These results are comparable to those of previous empirical correlation studies and much better than those produced by a solubility parameter concept.

Theoretical and experimental studies on the origin pH-absorption shifts

Abstract The in vitro pH-absorption profile of aniline has been examined using a rotating diffusion cell assembly. With 2,2,4-trimethylpentane as the lipoidal phase, it has been found that a reduction in the thickness of the diffusion layers leads to a higher apparent rate of absorption. For the physical model studied a theoretical relationship has been derived between the apparent rate of absorption and the speed of rotation of the diffusion cell used. Studies at different values of pH have been used to test a new theoretical approach for evaluating the influence of an aqueous diffusion layer on the pH-absorption rate profile. It is found that although the aqueous diffusion layer is responsible for a pH-absorption shift, the extent of any shift depends entirely upon the experimental conditions both in front and behind the membrane.