Mixing of Pharmaceutical Pellets

Increasing demands on patient safety and reducing manufacturing costs have driven the pharmaceutical industry to adopt a new manufacturing paradigm: Continuous manufacturing. In order to implement it, all batch unit operations must be converted to their continuous equivalent and raw material feeding issues must be resolved.

The unit operation most commonly needed is done in a continuous blender. A homogenized powder mixture is required to produce oral solid dosage forms with minimum active pharmaceutical ingredients (API) content variability, under strict regulatory constraints. More specifically, the mixing performance of the continuous blender is used for formulations containing pellets. Pellets produced by hot melt extrusion are a means to solve solubility issues of many promising APIs.

The flow behaviour inside the blender can be characterized, using impulse stimulus response experiments and subsequent residence time distribution analysis. The effect of operational conditions, particularly material flow rate and the mixer’s rotation speed, on parameters like hold-up mass, mean residence time of pellets and shear intensity can thus be studied. Furthermore, the blender mixing performance can be assessed using the relative standard deviation as a mixing index.

The main results are as follows:

The hold-up mass decreases when increasing the rotation rate and decreasing the feeding rate. At low throughputs, the mean residence time of pellets increases when increasing rotation rate. The opposite effect is observed operating at higher feed rates. The extension of axial mixing and shear intensity increases when blender’s velocity is increased. No particular trend is observed by changing flow rate. A low rotation rate combined with a high feed rate shows the best mixing performance.

Continuous manufacturing can be realized when on-line process analytical technologies (PAT) are available. Efforts are done to implement on-line near-infrared spectroscopy (NIR) to monitor blend homogeneity. Where on-line methods do not give satisfactory results, an off-line method is subsequently used. Work is being done to provide insights about pellet behaviour in a continuous mixer under different process parameters and optimum conditions to achieve a homogenous blend.