Tableting Complexity
Underestimating complexity underlies common problems in tableting. Modified release tablets are more complex than immediate release but no tablet is simple enough to never fail. A definition of complexity relevant to tableting is: –
The repeated application of simple rules, to systems with many degrees of freedom, leads to emergent behaviours not encoded in the rules.1
Tablet formulators using fixed formulae and processes, who rely solely on compliance with sales specification to control raw materials, can expect surprises. Most excipients are complex, and their specifications may not be relevant to a particular tablet application. For example, failure of modified-release tablets may be because the specified dilute solution viscosities, used to differentiate polymer grades, do not reflect the high concentration rheologies in such applications. It is better to identify Critical Material Attributes (CMAs) up front rather than after commercial product failures. Excipient variability introduces many degrees of freedom beyond that which is controlled by specification. How the excipient is manufactured, its variability and potential CMAs should be discussed with the excipient maker early in the development of the tablet.
Tablets themselves are systems with many degrees of freedom due to inherent criticalities, which are points of transition from one state to another. Criticalities are not built in by design, being unanticipated, and often scale-dependent. Criticalities can introduce nonlinearity, discontinuity, or a tipping point into tablet performance. The impact may be disproportionate if a hitherto unremarkable excipient variability interacts with a criticality.
Criticalities within tablets arise from percolation thresholds, conflicting technological objectives, or formulating too close to a minimum effective level of an excipient.
In powder blends a major component can form a contiguous network within the tablet and its’ properties dominate above a threshold concentration, below which a second component with different properties suddenly dominates. A simple example would be trying to directly compress too high a loading of uncooperative active. As observed by Leuenberger, “non-robust formulations can be obtained close to the percolation threshold.”2
A more subtle percolation threshold is due to inhomogeneous force transmission during compaction. A contiguous high-density region within the tablet will give a higher tablet breaking strength or hardness. Hardness should never be used as a critical quality attribute, being dependent on other factors including tooling geometry, lubrication, and compaction force, the latter often unknown if using an un-instrumented tablet press.
A tablet is a perfect example of conflicting technological objectives, in which compactability, dissolution and lubrication must be balanced.
Univariate change control using compliance data is not predictive and may not detect product or process drift. If an excipient variability interacts with a product criticality sudden product failure may result. The excipient variability itself is not causative but starts to control transition at the criticality. Such emergent behaviours are otherwise known as special cause variation.
The IPEC QbD Guide3 therefore recommends that multivariate monitoring, using attributes complementary to compliance data, be used for continued process verification. This increases the detectability of drift, which, although not harmful in itself, is a harbinger of product failure. The IPEC QbD Guide3 divides excipients into two categories. Performance excipients are those, which, by design, have immediate direct impact on tablet performance. An example would be HPMC for modified release. Such excipients are titrated into the formula for specific performance. In contrast, basic excipients, above a minimum level, have less impact. As performance excipients dominate experimental results there is a tendency to simplify development by focusing on the performance excipients and paying less attention to the basic excipients such as filler-diluents. This is especially hazardous for tablets, where, unlike capsules or liquids, the level and type of diluent imparts properties to the dose form other than simply bulking up. It is easier to determine the CMAs for a performance excipient than for a basic excipient. The CMAs will either be tighter limits on specified attributes or new attributes added to the specification.
The effect of decreasing the concentration of individual basic excipients should be evaluated during development. If the tablet is still feasible after a 10-20% decrement it is more robust than a formulation where a small decrement (<5%) causes problems. The smaller the problematic decrement the more likely the proximity to a criticality, and the greater the risk of product drift and failure.
Processing conditions during development should simulate the desired commercial production.
The ratio of elastic to plastic effects increases with speed leading to problems such as lamination and capping. Lubricated blends are shear sensitive so mixing intensity and times should be evaluated before scaling up as larger blends can experience greater shear and consequent decrease in compactability. Evaluation methods also need to be appropriately selected. Particle sizes and distributions are apparent quantities which depend on the method used, and which may or may not be predictive of product performance. Powder flow methods give different rankings and should be chosen on relevance to actual powder handing conditions. Tablet complexity is best addressed during development and via the Control Strategy. A simple design and development program is superficially attractive but lifecycle management will be more complex due to special cause variation, lack of robustness and product failures.
References
[1] Complexity and Criticality” Christensen K, Moloney NR Imperial College Press, London, UK 2005
[2] Leuenberger H. Adv Powder Technol 10 323-352 1999
[3] International Pharmaceutical Excipients Council 2020
Incorporation of Pharmaceutical Excipients into Product Development using Quality-by-Design (QbD)
