Optimizing Tableting Processes with Quality by Design

A technical forum featuring Tim Freeman of Freeman Technology and Carl Levoguer of Malvern Instruments.
May 01, 2012

PharmTech: In your experience, What attributes besides particle-size distribution must be considered for tableting processes?

Tim Freeman
Freeman (Freeman Tecnology): As the industry focuses on better manufacturing efficiency, there is greater interest in identifying powder properties that directly influence tableting in-process performance and final product quality. Particle-size distribution is a critical primary particle characteristic of powders, but it is only one of many variables that impact bulk powder properties, which in turn dictate in-process behavior and product quality. Bulk property measurements can be an efficient way of accelerating and supporting process optimization studies because they quantify the net effect of all primary particle properties (e.g., size, shape, texture, surface energy and porosity), whether these can be measured directly or not. Furthermore, even if all primary particle properties that influence in-process behavior could be measured, the mathematical relationship between bulk powder behavior and particle characteristics remains elusive and highly complex. Hence, the most effective way forward is to measure process relevant characteristics of the bulk powder.

Tablet production can be divided into at least four discrete processes: discharge from the hopper; flow into and through the feedframe; die filling; and compression. Each of these processes subjects the powder to a specific set of environmental conditions (e.g., flow rates, stresses, and equipment surface properties), making different bulk properties more relevant at different stages. I would highlight the following as especially valuable:
  • Dynamic flow properties (including Basic Flowability Energy, Specific Energy, Aerated Energy, and Flow Rate Index): to optimise the flow regime in the feedframe and the efficiency of die filling, to investigate the effect of paddle geometry, to assess the likelihood of attrition, segregation and agglomeration.
  • Shear properties: for optimising flow from the feed hopper, where shear properties of powder–powder and powder–wall are important.
  • Permeability and compressibility: for assessing how easily the powder can transmit air and the impact of compression on the powder. Both characteristics are important during the filling and compression steps.

Carl Levoguer
Levoguer (Malvern Instruments): Success in tableting does indeed depend on many factors. It is important, for example, to control the flowability and compressibility of the tableting blend, as well as any tendency towards segregation, to ensure the production of uniform tablets at the required rate. Particle size and particlesize distribution are recognised as critical material attributes because they are known to directly impact these properties, as well as others such as solubility and bioavailability, which may define clinical efficacy as highlighted in ICH Q6A.

As analytical techniques evolve, however, it is becoming easier to identify other parameters that also impact behavior in the tablet press. Here I would highlight particle shape, a parameter that, like particle size, is known to affect powder flowability and segregation. In the past, shape information was gathered by microscopy, but the advent of automated imaging has made it much faster and easier to access statistically relevant data. Such information forms a foundation for scientific investigation of the impact of shape and supports the development of more successful tableting blends.