Challenges for Low-Dose Product Development and their Assessment Methods

4 CHALLENGES FOR LOW-DOSE PRODUCT DEVELOPMENT AND THEIR ASSESSMENT METHODS 

The active pharmaceutical ingredient in a low-dose formulation is typically a small molecule, designed to meet a small particle size requirement for uniformity purposes, and can be susceptible to effects of static charge and segregation. The impact of static charge on the accuracy of blend uniformity measurements (i.e., sampling bias) is discussed in the next section. 

Fluidization Segregation. In order for fluidization segregation to occur, particles in a blend must have different particle sizes and/or a broad particle size distribution as well as different particle densities. This type of segregation may occur when a bulk powder or blend is pneumatically conveyed, filled or discharged at high rates, or if 

Fine particles (mean particle size 100 (jliti) generally have a lower permeability than coarse particles and therefore tend to be retained in the air longer. Thus on filling a hopper, the coarse particles are driven into the bed while the fine particles remain fluidized near the top surface. This can also occur after tumble blending if the material is fluidized during blending. 

With dilute formulations, segregation can result in unacceptable variations in tablet or capsule potencies. While one approach to achieving API content uniformity is to 

---