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G L Mosher

Publications and source records attributed to G L Mosher.

6 recordsLinked to original sources
PubMed1994

The determination of interfacial transfer constants using side-by-side diffusion cells.

A side-by-side diffusion cell setup has been used to determine the pH 7.4 buffer-octanol interfacial transfer constants for twelve compounds. The compounds are a diverse selection of pharmaceuticals, amino acids, and small organics which covers a log distribution coefficient (K) range of -3 to 2. A model based on the resistance summation approach, which deals explicitly with the various barriers, involves in the transport process, was used to derive transfer constants from the transport data for each compound. The model gave constants that were well behaved in a published model describing the correlation of the forward and reverse transfer constants to equilibrium K values (r2 = 0.999). These studies demonstrate the utility of side-by-side diffusion cells for the determination of interfacial transfer constants. This type of setup offers the advantages of controlled interfacial area, measurable hydrodynamic effects, and a commercially available apparatus.

Diffusion↗
PubMed1991

Photoreactivity of LY277359 maleate, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, in solution.

Compound LY277359 maleate undergoes a photoinduced solvolysis reaction in water to generate the corresponding hydroxylated product and release chloride. Attempts to stabilize a parenteral formulation of the compound led to an investigation of possible reaction mechanisms. The data are consistent with a mechanism involving homolytic cleavage of the aryl-chloride bond followed by electron transfer to give an aryl cation intermediate. The cation thus formed reacts with surrounding nucleophiles to give the substituted product. A kinetic expression for reaction rate was derived from the mechanism, and various components of the rate constant were evaluated experimentally. The reaction is slowed with the addition of chloride, presumably via a common ion effect (enhanced retroreaction). In the absence of added chloride, the reaction can be described kinetically by an initiation term. An inner filter effect is also observed, where increasing amounts of the hydroxylated product slow the reaction. Experimental data for observed rate constants as a function of starting concentration and light intensity are fit with good correlation to an equation describing the filter effect. Additional studies evaluated the effects of various structural features of the parent compound on the rate of the reaction in glass containers. It was determined that reactivity was dependent on two features: (1) the ortho positioning of the carboxyl and ether groups, which shifted an absorption band above the container cutoff; and (2) the para orientation of the chloro group to the ether, which is para activating in the photoexcited state.

Benzofurans↗
PubMed1986

Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters.

Various novel diesters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the aim of improving the ocular delivery characteristics of the drug. The pilocarpic acid monoesters previously studied cyclized spontaneously to pilocarpine in aqueous solution and although they showed enhanced corneal permeability when compared with pilocarpine these monoesters suffered from poor solution stability. The present study shows that this problem can be totally overcome by blocking the free hydroxyl group in the monoesters. Diesters of pilocarpic acid were obtained by esterification of this group. Such compounds were found to possess a high stability in aqueous solution (shelf lives of more than 5 years at 20 degrees C were estimated) but at the same time were readily converted to pilocarpine under conditions simulating those occurring in vivo through a sequential process involving enzymatic hydrolysis of the O-acyl bond followed by spontaneous lactonization of the intermediate pilocarpic acid monoester. Rate data are given for the conversion of the diesters in human plasma and in various rabbit eye homogenates. The pH-solubility profile was derived for a diester and lipophilicity parameters were determined for the compounds. All diesters were markedly more lipophilic than pilocarpine and the corresponding pilocarpic acid monoesters. The results suggest that pilocarpic acid diesters may be potentially useful pilocarpine prodrugs as they combine a high solution stability with an adequate rate of conversion to pilocarpine under in vivo conditions.

Animals↗