Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project.

OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.

Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.

Power consumption profiles in high-shear wet granulation. II: Predicting the overwetting point from a spreading energy.

Granulation is an important process in the pharmaceutical industry for the preparation of solid dosage forms. For high-shear wet granulation, the process endpoint is monitored using the device power consumption. However, granulation is very sensitive to variations in the feed product physicochemical properties and, in some cases, power consumption profiles can not be used for process control. In this paper, a model is proposed to predict the granulation overwetting point from the spreading energy of the liquid binder on the powder. This energy is independently calculated from measurements of the powder true surface area, liquid binder surface tension, and liquid contact angle on the powder surface.

Power consumption profiles in high-shear wet granulation. I: Liquid distribution in relation to powder and binder properties.

Wet granulation processes frequently rely on the device power consumption profile to monitor the process endpoint. This work shows how the observed power consumption relates to the physical properties of the mass. The liquid binder was traced with a fluorescent marker and the liquid distribution could be followed during the process. It was found that primary agglomerates form in the reactor, the shape and composition of which depend on the wettability of the starting powders by the liquid binder. An increase of the device power consumption is conditional to the disruption of these primary agglomerates. Increasing the viscosity of liquid binders up to 250 mPa. s had no significant effect on the power consumption. Eventually, the lower surface tension liquid binders yielded greater energy consumption, indicating that interparticle friction forces had a great impact on the device power consumption.

Modeling the Evolution and Rupture of Pendular Liquid Bridges in the Presence of Large Wetting Hysteresis.

A model has been developed to predict the shape evolution, rupture distance and postrupture liquid distribution of a pendular liquid bridge between two unequally sized spherical particles in the presence of wetting hysteresis. Two different simplifications of the bridge geometry were considered: a toroidal and a parabolic approximation. The liquid bridge was assumed to rupture through its thinnest neck leaving liquid distributed on each sphere. Experimental measurements showed that the rupture distance was well predicted by both profile approximations by assuming that rupture occurred when the liquid-vapor interfacial area of the bridge and the postrupture droplets was equal. Both bridge profile approximations only correctly predicted the evolution of the apparent contact angle and the extent of postrupture liquid distribution when the solid-liquid interfacial area measured throughout the separation was included in the calculations. This is because during the pendular liquid bridge elongation, the three-phase contact line usually begins to slip on at least one of the spheres. The parabolic profile approximation was slightly more accurate than the toroidal one. The toroidal approximation is more difficult to use because one of the parameters passes through infinity as the bridge changes from convex to concave in shape. In some cases the toroidal approximation was also unable to generate a solution. Copyright 2000 Academic Press.

Modeling Pendular Liquid Bridges with a Reducing Solid-Liquid Interface.

Liquid bridges formed between particles of dissimilar surface properties are important in many processes involving the handling of powders in mixtures. For instance, growth kinetic models for wet granulation frequently incorporate the evolution and resistance to breakage of individual liquid bridges between particles in a statistical form. These models generally propose a confusing definition of liquid-to-solid contact angles. Taken as a single thermodynamic value, they typically neglect the influence of wetting hysteresis on the liquid bridge. In this paper, a simple model based on the interfacial energies is proposed for the evolution of liquid bridges when one solid-liquid interface reduces. This receding process is well described by a balance between the adhesion energy of the bridge liquid on the particle surface and the capillary energy stored by the liquid free surface. The extent of solid-liquid interfacial area reduction can hence be predicted from the initial liquid bridge configuration. The liquid bridge shape is approximated by a parabolic curve, which is validated from the good agreement between measured and calculated contact angles or liquid-vapor interfacial area. Copyright 2000 Academic Press.

Powder dynamic contact angle data in the pharmaceutical industry.

Formulation scientists generate physicochemical data that are used in process modelling and in the prediction of end-product quality. In this respect, contact angles are of particular importance as the surface energy of substances influences their processability and bioavailability. Dynamic contact angle (DCA) analysis represents a straightforward wettability assay. Now fully adapted to powders, DCA analysis also proves to be more efficient than other methods for wettability determination.

On the use of ion-pair chromatography to elucidate doxorubicin release mechanism from polyalkylcyanoacrylate nanoparticles at the cellular level.

The major hypothesis underlying the remarkable efficiency of polyalkylcyanoacrylate particles loaded with doxorubicin against multidrug resistant tumor cells in vitro, is based on the ion-pair association of doxorubicin with soluble hydrolysis products of polyalkylcyanoacrylate. In an attempt to demonstrate the validity of this hypothesis, we have used ion-pair reversed-phase high-performance liquid chromatography and a laboratory-synthetized compound, i.e., the 2-cyano-2-butylhexanoic acid, as a model for polyalkylcyanoacrylate highly polydispersed degradation products. It is shown that, compared to a counter-ion, like heptane sulfonic acid, 2-cyano-2-butylhexanoic acid exhibits an effective ion-pairing effect at different pH values and organic mobile phase conditions. Moreover, at pH close to physiological conditions and at low mobile phase organic modifier percentage, this effect is experimentally observed, which strongly supports the initial hypothesis.