Understanding the segregation potential of pharmaceutical dry powders and granules is an important aspect of solid oral-dosage form development. Powder segregation demixes a homogenous powder blend. Further processing of this heterogeneous mixture can result in final-product quality deficiencies such as variable dosage-form potency, variable tablet or capsule fill weight, variable tablet hardness, and nonuniform appearance. Segregation also can affect manufacturing process robustness through erratic or unstable powder flow, under- or overcompression, variation in tablet-core tensile strength, and unacceptable blend uniformity (1).
Fluidization segregation is a common segregation mechanism for pharmaceutical dry-powder and granule systems (1). It can occur during unit operations such as blender-to-bin transfers, bin discharge, pneumatic conveyance, bin-to-tablet press transfer, and fluidization in a fluid bed. The fluidization segregation mechanism is illustrated in Figure 1 using the example of a bin discharge unit operation. Before discharge, the particles in the bin are arranged homogeneously (see Figure 1a). During discharge, the particles are entrained in a counterflow air stream (see Figure 1b). Smaller particles and less-dense particles will be carried higher in the air stream. They also have a lower terminal velocity and will settle at a slower rate compared with larger particles. These particles also can be deflected easily by air turbulence, further increasing settling time. This results in a layer of small particles on top of a bed of larger particles or a particle-size gradient in the settled pile (see Figure 1c).
The extent of fluidization segregation is dependent upon a combination of material properties, process equipment characteristics, and process conditions. Material-selection guidelines that can help minimize fluidization segregation risk have been discussed, but it is not always possible or desirable to modify the properties of mixture components because of material limitations and regulatory considerations. The particle factors often cited in the guidelines include particle size, particle-size distribution, particle shape, and true density for which, in general, segregation risk is minimized when the properties of a mixture's individual components are most similar. Cohesion also plays an important role where sticking together of individual and dissimilar particles can minimize segregation by limiting demixing. Methods exist to measure this property, but the threshold value where it has an effect on segregation is not well understood. Equipment characteristics such as chute angles, material of construction, and powder-drop heights also can cause segregation to occur (2). This multitude of factors with potential interaction terms makes it difficult to predict a priori the tendency of a given powder blend to segregate, although the guidelines give a good starting point for formulation and process design.
A test method that gauges fluidization segregation potential in the early stages of solid oral-dosage form development would be a valuable tool for the development scientist. The method must have the following characteristics:
- use a minimal amount of material because a finite quantity of the active pharmaceutical ingredient (API) is typically available during early drug product development;
- be rapid to allow the screening of numerous formulation options;
- be reproducible to ensure a meaningful comparison of test results.
One test method that is standardized through ASTM International is the Jenike and Johanson (J&J, Tyngsborough, MA) fluidization segregation tester (FST) (3, 4). The tester fluidizes a powder sample in a column of air, allows the particles to settle in the column, and has a mechanism to retrieve top, middle, and bottom samples of settled powder. These samples can then be analyzed to determine if there is a property gradient within the column. The operation of this equipment is described as an ASTM standard practice (4). Though the test equipment reproduces the fluidization mechanism, it has several disadvantages which include a limited data set of three samples per test, the need to riffle each sample before analysis, operator dependence on setting the airflow needed to achieve fluidization, and the use of a relatively large amount of material compared with what is available during the early stages of development.