Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement.

This review addresses the use of nonaqueous solvents as components of oral formulations in discovery and preclinical studies. Pharmacology, pharmacokinetic, and safety studies are frequently conducted with solution formulations that use a solvent to solubilize poorly aqueous soluble drugs. The physical chemical basis for solubilization and the precipitation of solubilized drug following administration both contribute to the utility of nonaqueous solvent solutions as oral vehicles. While many of these solvents are considered nontoxic, they are not completely inert biologically. The effects of common nonaqueous solvents on the structural integrity of the epithelia, the inherent permeability of and flux across the GI membrane, the activity of efflux and metabolic enzymes, and the effects on GI motility and GI transit times will be described through an examination of available literature. The practical relevance of these factors to the development of early formulations will be examined critically and suggestions made for the suitability of nonaqueous solvents for a variety of purposes.

Prediction of drug degradants using DELPHI: an expert system for focusing knowledge.

DELPHI is an expert system that has been developed to predict possible degradants of pharmaceutical compounds under stress testing conditions. It has been programmed with the objective of finding relevant degradation pathways, identifying degradant structures, and providing tools to the analytical chemist to assist in degradation identification. The system makes degradant predictions based on the chemical structure of the drug molecule and precedent from a broad survey of the literature. A description of DELPHI's treatment of molecular perception is described as are many features of the heuristic degradation rules it uses to capture and apply chemical degradation knowledge. DELPHI's utility for capturing institutional knowledge is discussed in relation to an analysis of degradation prediction results for 250 molecules of diverse chemical structure collected over 5 years of use. As such, it provides a reliable, convenient, and rapid tool for evaluating potential pathways of chemical instability of pharmaceuticals.

Silicon-29 NMR Studies of Tetraalkylammonium Silicate Solutions. 1. Equilibria, (29)Si Chemical Shifts, and (29)Si Relaxation.

The addition of tetraalkylammonium cations to aqueous silicate solutions enhances the abundance of symmetric, cagelike, polysilicate anions including the cubic octamer, Si(8)O(20)(8)(-). The equilibrium ratio of tetramethylammonium (TMA) cations to the octameric silicate anion is 8:1 for solutions with a concentration ratio [OH(-)]:[Si] >/= 1:1. Evidence indicates that organocations directly associate with cagelike polyanions to form a protective shell of hydrophobic hydration that impedes hydrolysis of the central anion.

Silicon-29 NMR Studies of Tetraalkylammonium Silicate Solutions. 2. Polymerization Kinetics.

The kinetics of formation of the silicate cubic octamer, Q(3)(8), in aqueous tetramethylammonium (TMA) silicate solutions was investigated by (29)Si NMR. The rate equation for solutions at pH 13.2-13.6 is d[Q(3)(8)]/dt = k(f) [H(+)](1.6)(+/-)(0.1)[TMA(+)](0.36)(+/-)(0.08)[Si](0.8)(+/-)(0.3) where k(f) = (2.2 +/- 0.8) x 10(16) mol(-)(1.8) kg(1.8) s(-)(1) at 296 K. The findings prove unequivocally that alkylammonium cations participate directly in the formation and subsequent stabilization of cagelike polysilicate anions. This implies a radically different mechanistic role than "templating" for alkylammonium cations in the synthesis of molecular sieves.