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 \u2018minimum liquid volume\u2019. This minimum liquid volume is determined as a function of dry binder type, amount, hygroscopicity and particle size distribu- tion 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

The development of a novel formulation map for the optimization of high shear wet granulation

With a view to describing the powder agglomeration process, particles have often been considered as inert material and the solid\u2013liquid interactions have rarely been contemplated. The present research aims to fill the gap in understanding how the nucleation and the early stage of the granule growth depend on some important formulation properties. The glass transition concept coupled with on-line impeller torque monitoring and measurements of the time evolution of the particle size distribution was used to give a description of the early stage of the agglomeration process in high shear wet granulation. A mixture of commonly-used pharmaceutical powders, which are amorphous and crystalline in nature, was processed. Accordingly, a new formulation map is presented which describes the onset of significant granule growth as a function of the key formulation components (i.e. diluent, dry and liquid binder). From this map, the minimum amount of liquid binder required to induce appreciable granule growth is determined as a function of the type, quantity, hygroscopicity and particle size distribution of the diluent and the solid binder. This map can be obtained from a priori glass transition measurement using a static humidity conditioning system and by fitting the experimentally obtained data using a modified Gordon\u2013Taylor equation

Characterization of platelet adhesion under flow using microscopic image sequence analysis

A method for quantitative analysis of platelet deposition under flow is discussed here. The model systemis based uponperfusion of blood platelets on an adhesive subtrate immobilized over a glass coverslip acting as the lower surface of a rectangular flow chamber. the perfusion apparatus is mountedonto an inverted microscope equipped with epifluorescentillumination and intesified CCD vide camera. Characterization is based on information derived from a specific image analysis method applied to continuous sequences of microscopical images. Platelet recognition across the sequence of images is based on a time-dependent bidimensional, gausssian-like pdf. Once a platelet is located, the variation of its position and shaped as a function of time (i.e., the platelet history) can be determined. Analyzing the history we can establish if the platelet is moving on the surface, the frequency of this movement and the distance traveled before its resumes the velocity of a non-interacting cell. Therefore, we can determine how long the adhesion would last which is correlated to the resistence of the platelet-substrate bond. This algorithm enables the dynamic quantification of trajectories, as well as residence times, arrest and release frequencies for a high number of platelets at the same time. Statstically significant conclusions on platelet-surface interaction can be obtained. An image analysis tool of this kind candramatically help the investigation and characterization of the thrombogenic properties of artificial surfaces such as those used in artificial organs and biomedical devices

von Willebrand factor-mediated platelet adhesion in flowing blood is influenced by hematocrit.

We have studied the influence of hematocrit on the capture and rolling of platelets on von Willebrand factor (VWF) as well as the biomechanical properties of the interaction. When fluorescently-labeled platelets in whole blood (in the presence of anti-aIIbb3 MoAb LJ-CP8 to avoid platelet stable arrest) were perfused onto immobilized VWF through rectangular flow chambers, platelets formed numerous rolling attachments. The characterization is based on information obtained from a tailored-specific image analysis method applied to continuous sequences of microscopical images. Platelet movement on the surface, the duration of each arrest (lifetime), the frequency of this movement, and the distance traveled before its resumes the velocity of a non-interacting cell were measured. Our data indicated that hematocrit influenced not just the rate of capture from the flowing stream, enhancing platelet diffusivity to the wall, but also the ability to sustain interactions with the surface. Possibly due to the augmented intercellular collisions, as the hematocrit was increased from 5% to 40% the frequency of attachment increased 1.5 times. The removal rate constant was faster at high hematocrit (29.5 s-1 at 40% Hct and 21.1 s-1 at 5% Hct). Variation of hydrodynamic forces was used to sample the on-rate and bond resistance, ultimately resulting in different association and dissociation constants. The number of adhering platelets revealed a bell-shaped dependence on the wall shear rate, also affected by the hematocrit. Increasing hematocrit, platelets showed a faster saltatory movement, i.e., stayed on the surface for shorter durations, traveling longer distances. In rapid flow conditions (3000 s-1), increasing the hematocrit from 5% to 40%, the mean translational velocity increased exponentially (from 0.03 to 0.21 \ub5m/s). Our findings support the concept of transport-enhancing capability of red cells but also suggest their influence on platelet rolling on immobilized VWF before adhering firmly to form thrombi