Optimizing Tableting Processes with Quality by Design - Pharmaceutical Technology

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Optimizing Tableting Processes with Quality by Design
A technical forum featuring Tim Freeman of Freeman Technology and Carl Levoguer of Malvern Instruments.


Pharmaceutical Technology
Volume 36, Issue 5, pp. 48-55

PharmTech: What challenges exist with regard to understanding bulk-powder attributes?

Freeman (Freeman Technology): I think it is reasonable to say that the pharmaceutical industry's ability to understand how bulk powder properties impact process behavior has been constrained by a lack of reliable bulk powder property data. The reproducible measurement of defining powder characteristics, such as flowability, has long been a goal, but the results have been mixed. Traditional techniques, such as flow through an orifice and tapped density methods, are not ideal for the extended, detailed experimental work required to support QbD. Shear-cell measurements are ideal for understanding flow in hoppers, but are less useful for understanding lower stress processes, such as mixing, filling and aerosolization. Here, different measurement techniques are required.

Powder testing has developed considerably in the past decade, including the introduction of dynamic testing. Dynamic characterization reproducibly and directly measures powder flowability, for conditioned powders and for those that are consolidated or aerated, thereby generating reliable and valuable information for process development. Used in combination with bulk and shear property measurement, dynamic testing enables the kind of multifaceted powder characterization required to fully rationalise in-process behavior.

With these techniques in place, it is now possible to develop a detailed understanding of the way bulk properties influence tableting, granulation and many other frequently employed unit operations. This type of knowledge development remains a work in progress, but the goalposts shift too. Faster tableting speeds are one example, but the long-term objectives of continuous production in integrated manufacturing suites adds another layer of complexity, requiring testing strategies that provide the deepest and most comprehensive information.

Levoguer (Malvern Instruments): Generally speaking, my area of expertise is the measurement of particle properties rather than bulk powder attributes of the material, such as flowability and permeability. However, I've recently observed that some of our more experienced laser diffraction customers within the pharmaceutical sector are now using particle size analyzers to directly access information about the cohesivity of the sample because this is a useful property for tablet blend optimization.

Sample dispersion is an essential element of laser diffraction particle-size analysis. In dry measurement, dispersion conditions are established by conducting a pressure titration, which involves gradually increasing the pressure of the dispersing gas until a steady particle size is measured and/or the results obtained are identical to those generated with wet dispersion. Agitation and sonication are applied to achieve wet dispersion. In either case, the development process used to develop a robust method yields parameters that effectively quantify the strength of particle-particle interactions within the powder sample.

In state-of-the-art laser diffraction systems, dispersion conditions can be very precisely controlled and this measure of cohesive strength can therefore be sufficiently sensitive to give useful information for tablet blend optimization.

PharmTech: What technological gaps exist among the industry for fully understanding the material properties of powders used in a tableting process?

Freeman (Freeman Technology): Particles exhibit a wide range of mechanical and chemical properties. Several of these are commonly recognized as being highly influential with respect to in-process performance and product quality, and are often well defined as part of the specification. However, other properties, which may be even more important in some instances, such as particle shape, roughness, porosity and stiffness, to name just a few, are rarely considered in a specification because they are either too difficult to measure directly or can't be measured at all. Nevertheless, that doesn't exclude them from influencing the overall bulk material properties and, consequently, the in-process performance of the powder and the final product quality.

Direct measurement of many of these properties will only be achieved with further technological advances, but they will be required if the goal of "mathematical QbD" (accurately predicting tablet or granule properties from a knowledge of a range of particle properties) is to be achieved. In the interim, recent advances in bulk powder measurement techniques, simulating the conditions powders observe in the process environment and quantifying their response to those conditions, are likely to provide the best opportunity for understanding the relationship between bulk material properties, process parameters and final product attributes.

Levoguer (Malvernns Itruments): As I've previously suggested, one of the reasons why our customers measure parameters, such as particle size and shape, is because they are known to correlate with processability issues such as flowability, compressibility and the likelihood of blend segregation. These relationships are widely recognized, but my understanding is that they are not yet quantified in ways that help to establish optimal bulk powder properties. I would, therefore, point to lack of knowledge in the area of correlating particle and bulk powder properties as a gap that needs to be filled in the future.

As I noted previously, the advancement of automated imaging has made it much easier to access the shape data needed to extend our understanding in this important area and we have done some work in this area ourselves with Freeman Technology looking at the effect of particle size and shape on the bulk properties of lactose (1). This is an interesting area of research and one that I'm sure will receive further attention from the pharmaceutical industry as it works to extend understanding of how to make powders behave as required.


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