Challenges faced by the pharmaceutical industry: training graduates for employment in pharmaceutical R&D.

There is a shortfall between output from universities and demand by the pharmaceutical and health care industries for science and engineering graduates able to rapidly contribute to success in the business environment. Against a changing infrastructure of pharmaceutical research, the development of new chemical entities by major companies accounts for a high proportion of R&D expenditure. Allocation of staff is divided fairly evenly between discovery, non-clinical and clinical research activities and in all categories the new sciences are likely to be used extensively. In dealing with the shortfall the challenge comes from balancing education in basic science with training in the emerging areas of science and technology. There is a need for a 'partnership' that includes not only industry and academia but also government, since these three bodies have both synergistic and diverging interests in scientific education. On the education-training continuum, industry should recognise what it most values from academia and provide as much input and support as possible. At the same time universities must question their ability to fulfil their traditional educational role in the face of current rates of adoption of new sciences and technology. While disciplinary excellence remains vital for PhD students, multi-disciplinary programmes are becoming increasingly important to enable graduates to function effectively in the modern, globalised pharmaceutical industry.

Dissolution and ionization of warfarin.

It has been shown in recent studies that warfarin exists in the solid state and in some nonaqueous solvents as a cyclic hemiketal. The present study was undertaken to investigate the ionization and ionization kinetics of warfarin, to confirm the probable existence of the cyclic hemiketal in aqueous solution, and to determine the possible consequences of the cyclic hemiketal to acyclic enol equilibrium and ionization kinetics on the dissolution rate of warfarin. The equilibrium aqueous solubility of un-ionized warfarin acid at 25 degrees C and ionic strength 0.5 (with potassium chloride) was found to be 1.28 X 10(-5) M, and its observed macroscopic pK alpha was 5.03-5.06, depending on the method of determination. By comparing the aqueous pK alpha of warfarin to phenprocoumin, a hydroxycoumarin that cannot exist in the cyclic hemiketal form, the hemiketal-acyclic enol ratio was estimated to be approximately 20:1. By stop-flow spectrophotometry, the ionization rate of warfarin (pH 3.5 jumped to pH 6.5) was found to have t1/2 less than 1-2 X 10(-3) s. The dissolution rate of warfarin from a rotating disk (600 rpm), as a function of pH, was measured under nonbuffered but pH-stat conditions (mu = 0.5 with potassium chloride). The pH-dissolution rate profile for warfarin agreed with that calculated from an equation derived previously to describe the dissolution of instantaneous ionizing acids, i.e., the profile was not perturbed from that expected from an acid of aqueous solubility 1.28 X 10(-5) M (un-ionized form) and pK alpha 5.06.

Dissolution kinetics of phenylbutazone.

This study investigated the possible effects of simultaneous, noninstantaneous, reversible chemical ionization of carbon acids on the dissolution of a typical pharmaceutical carbon acid, phenylbutazone, and its deutero analog. The dissolution rate versus pH profile for phenylbutazone was consistent with phenylbutazone acting as if it were an acid where the ionization can be considered instantaneous. In view of the dissolution behavior of phenylbutazone under various conditions, it is unlikely that the noninstantaneous ionization kinetics demonstrated for this compound play a major role in determining the dissolution rate, either in vitro or in vivo, since the average residence time in a typical aqueous diffusion layer for phenylbutazone dissolution is longer than the reaction time for its ionization. Slowing the reaction time with a primary isotope effect by deuterium substitution for the ionizable proton caused significant deviation from classical behavior for d-phenylbutazone.

Dissolution kinetics of carboxylic acids I: effect of pH under unbuffered conditions.

The dissolution behavior of benzoic acid, 2-naphthoic acid, and indomethacin from rotating compressed disks into aqueous solutions of constant ionic strength (mu = 0.5 with potassium chloride) at 25 degrees was investigated. The pH of the bulk aqueous medium was maintained during dissolution by means of a pH-stat apparatus. A model for the initial steady-state dissolution rate of a monoprotic carboxylic acid was derived from Fick's second law of diffusion. This model assumed that diffusion-controlled mass transport and simple, instantaneously established reaction equilibria existed across a postulated diffusion layer. Using previously determined intrinsic solubilities, pKa values, and diffusion coefficients, the model was found to predict the dissolution rates of these acids accurately as a function of the bulk solution pH. Hydroxide ion and water were the only reactive base species present in the bulk solution. The concentration profiles of all of the species across the diffusion layer were generated for a given bulk pH. Furthermore, the model generated values for the pH profile within the microclimate of the diffusion layer and the pH at the solid-solution boundary.

Dissolution kinetics of carboxylic acids II: effect of buffers.

The dissolution behavior of 2-naphthoic acid from rotating compressed disks into aqueous buffered solutions of constant ionic strength (mu = 0.5 with potassium chloride) at 25 degrees was investigated. A model was developed for the flux of a solid monoprotic carboxylic acid in aqueous buffered solutions as a function of the solution pH and the physicochemical properties of the buffer. The model assumes a diffusion layer-controlled mass transport process and simple, instantaneously established reaction equilibrium between all reactive species (acids and bases) across the diffusion layer. Using intrinsic solubilities, pKa values, and diffusion coefficients, the model accurately predicts the dissolution of 2-naphthoic acid as a function of the bulk solution composition. The concentration profiles of all species across the diffusion layer are generated for each buffer concentration and bulk solution pH, including the pH profile within the microclimate of the diffusion layer and the pH at the solid-solution boundary.