Robert C. Mitchell

The Factors that Influence Skin Penetration of Solutes

In this study, human skin permeation data are analysed using a number of physicochemical descriptors.

Determination of solute lipophilicity, as log P(octanol) and log P(alkane) using poly(styrene–divinylbenzene) and immobilised artificial membrane stationary phases in reversed-phase high-performance liquid chromatography

Abstract A number of RP–HPLC systems have been characterized by the linear free energy relationship: (i) log SP=c+r.R 2 +s.π H 2 +a.∑α H 2 +b.∑β 2 +v.V x Here, SP is either log k′ or log kw for a series of solutes in a given system, where k′ is the capacity factor and kw is the capacity factor extrapolated to l00% water, and the solute descriptors are, R2 an excess molar refraction, π2H the dipolarity/polarizability, ∑α2H and ∑β2 the overall or effective hydrogen-bond acidity and basicity, and Vx the McGowan characteristic volume. Comparison of the coefficients in Eq. (1) with those for water-solvent partitions confirms that the modified electrostatically coated C18 phase of Pagliara et al. (J. Liq. Chromatogr., 18 (1995) 1721) can be used to obtain solute lipophilicities, as log Poct. For RP–HPLC systems based on poly(styrene–divinylbenzene), the coefficients in Eq. (i) are nearer those for the correlation of water–alkane partition coefficients, as log Palk, than for the correlation of log Poct, suggesting that the RP–HPLC systems with poly(styrene–divinylbenzene) phases could be used as a rapid method for determination of solute lipophilicity, as log Palk or as log Pcyc, where the latter is the water–cyclohexane partition coefficient. Eq. (i) has also been applied to RP–HPLC log k′ values obtained with an immobilized artificial membrane (IAM) phase. A good regression equation was obtained, but the coefficients in this equation are substantially different to those for regressions with log Poct, log Palk, or log Pcyc as the dependent variable. On the other hand, log k′ values from the RP–HPLC system of Miyake al. [J. Chromatogr., 389 (1987) 47], consisting of silica gel coated with dipalmitoyl phosphatidyl choline as a stationary phase, with aqueous acetonitrile mobile phases, yielded coefficients in Eq. (i) very similar to those for log Poct.

Hydrogen bonding part 46: a review of the correlation and prediction of transport properties by an lfer method: physicochemical properties, brain penetration and skin permeability†

A number of solute descriptors that relate to the ability of a solute to take part in solute-solvent interactions have been identified, quantified and incorporated into a multiple linear regression equation. This general solvation equation can then be used for the correlation and prediction of solute effects in transport processes, that is, processes in which the main step is either the equilibrium transfer, or the rate of transfer, of a solute from one phase to another. Examples discussed include the solubility of gases and vapours in water, various water-solvent partitions, blood-brain distribution, brain perfusion, and skin permeability.

Algorithms for Skin Permeability Using Hydrogen Bond Descriptors: the Problem of Steroids*

Several algorithms that use hydrogen bond descriptors have been published for the permeation of compounds from aqueous solution through human stratum corneum. In the present work, all the skin permeability coefficients, Kp in cm s−, used in these algorithms for non‐steroids have been correlated through the Abraham equation to give a new algorithm:

PHYSICOCHEMICAL ANALYSIS OF THE FACTORS GOVERNING DISTRIBUTION OF SOLUTES BETWEEN BLOOD AND BRAIN

Abstract An equation is described that relates the equilibrium distribution of compounds between blood and brain to various solute descriptors, for 57 varied compounds. It is shown that the main factors influencing the distribution are solute size that favours brain, and solute dipolarity/polarisability, hydrogen-bond acidity and hydrogen-bond basicity that favour blood. The descriptors can be obtained from measurements on compound substructures, so that the blood-brain distribution can be predicted for drug molecules without the necessity for synthesis.

Infrared spectroscopic studies of vancomycin and its interactions with N-acetyl-D-Ala-D-Ala and N,N′-diacetyl-L-Lys-D-Ala-D-Ala

The infrared (IR) spectrum of vancomycin, in D2O solution, has been assigned by recording spectra at different pD values and by comparing them with the spectrum in H2O at pH 5. The effects of self association on the spectrum of vancomycin at pD 5 have also been investigated. Details of underlying components of the broad bands in the spectra were revealed using resolution enhancement and second derivatives. The IR spectra of two peptide models, N-Ac-D-Ala-D-Ala and N, N′-Ac2-L-Lys-D-Ala-D-Ala, have also been assigned in D2O solution. The interactions of these peptides with vancomycin, in pD 5 solution, have been studied by infrared spectroscopy and the above assignments used to interpret the observed spectral changes; the solubilities of the vancomycin-peptide complexes at pD 5 were determined to facilitate these studies. The IR spectra of the complexes show substantial increases in intensity of a component at about 1588 cm 1. Using 13C labelled N-Ac-D-Ala-D-Ala this was found to be due to the asymmetric stretch of the carboxylate group of the peptide, showing that this group undergoes a substantial perturbation on binding to vancomycin.