Texture analysis as a tool to study the kinetics of wet agglomeration processes.

In this work wet granulation experiments were carried out in a planetary mixer with the aim to develop a novel analytical tool based on surface texture analysis. The evolution of a simple formulation (300g of microcrystalline cellulose with a solid binders pre-dispersed in water) was monitored from the very beginning up to the end point and information on the kinetics of granulation as well as on the effect of liquid binder amount were collected. Agreement between texture analysis and granules particle size distribution obtained by sieving analysis was always found. The method proved to be robust enough to easily monitor the process and its use for more refined analyses on the different rate processes occurring during granulation is also suggested.

Scaling laws for the slip velocity in dense granular flows.

In this Letter, the two-dimensional dense flow of polygonal particles on an incline with a flat frictional inferior boundary is analyzed by means of contact dynamics discrete element simulations, in order to develop boundary conditions for continuum models of dense granular flows. We show the evidence that the global slip phenomenon deviates significantly from simple sliding: a finite slip velocity is generally found for shear forces lower than the sliding threshold for particle-wall contacts. We determined simple scaling laws for the dependence of the slip velocity on shear rate, normal and shear stresses, and material parameters. The importance of a correct determination of the slip at the base of the incline, which is crucial for the calculation of flow rates, is discussed in relation to natural flows.

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs.

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches. A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis). Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.

Formulation design for optimal high-shear wet granulation using on-line torque measurements.

An alternative procedure for achieving formulation design in a high-shear wet granulation process has been developed. Particularly, a new formulation map has been proposed which describes the onset of a significant granule growth as a function of the formulation variables (diluent, dry and liquid binder). Granule growth has been monitored using on-line impeller torque and evaluated as changes in granule particle size distribution with respect to the dry formulation. It is shown how the onset of granule growth is denoted by an abrupt increase in the torque value requires the amount of binder liquid added to be greater than a certain threshold that is identified here as 'minimum liquid volume'. This minimum liquid volume is determined as a function of dry binder type, amount, hygroscopicity and particle size distribution of diluent. It is also demonstrated how this formulation map can be constructed from independent measurements of binder glass transition temperatures using a static humidity conditioning system.