Issue link: https://www.e-digitaleditions.com/i/1138630
Tablets & Capsules July 2019 31 after blending (phase 1). At some point the reaction becomes self-limiting and an initial equilibrium is established. However, with some blends the reaction continues on a descending curve until the air fully evacuates and the blend is totally compacted (phase 2) [3]. At that point, blend compaction may be terminal, and the powder will no longer flow, even with addi- tional mechanical agitation. In addition to influencing tablet compression, under- standing the effect of both percolation phases is critical for reliable blend assay results. It is important to take powder samples for dosage uniformity purposes after the initial phase 1 air percolation has occurred. When this initial time point begins may vary from product to prod- uct and even from strength to strength within a specific product. For this reason, some companies establish a gen- eral waiting period, such as 30 minutes, before taking powder samples. There are documented cases where blend uniformity results were out of specification when samples were taken immediately after the blend was discharged into either drums or IBCs. Subsequent samples taken 30 to 60 min- utes later showed tight drug uniformity. Determining a formulation's optimal compression time As the percolation proceeds through phase 2, manu- facturers must determine when to compress the formula- tion into tablets. Understanding how the air percolates during phase 2 for a given material can provide insight into performance differences between batches com- pressed sequentially on the same tablet press. All fin- ished blends have a period of time after blending during wh ich flo w is o p tim al fo r tab let co m p ressio n . Compressing with the blend outside of this optimal time period often results in greater variations in tablet weight and content uniformity. If the material equilibrates shortly after phase 2 begins, a certain amount of air remains in the powder. This air must be subsequently dissipated by the tablet press through an optimized application of pre-compression punch entry and tablet thickness controls combined with the main compression or final punch entry setting. A more serious problem than equilibration is if the phase 2 air percolation continues until the blend becomes totally compacted. Some powder blends have unique air decreases over time when stored in a drum or interme- diate bulk container (IBC), while the level of other fin- ished blends remains essentially unchanged. This change in height comes from a phenomenon called "air percolation," which is the evacuation of air trapped in the material during blending [1]. Understanding this simple concept can be very helpful for achieving suc- cessful process validation and more reproducible results in tablet compression. Air percolation after blending All powders and powder blends percolate to some degree after blending. The amount of percolation largely depends on the nature of the powder or blend and the class of blender used. Pharmaceutical solid dosage manu- facturing processes almost always use tumble blenders, which tend to trap large quantities of air in the material during blending. Poor flow due to air percolation should not be confused with poor flow caused by static electric- ity, which should be addressed during blend discharge by properly grounding the equipment. How and when entrapped air dissipates from a blend should be of tremendous interest to tablet manufacturers. A hold-time protocol for a finished powder blend indi- cates how long the blend may be held prior to tablet compression or capsule filling. This is often misinter- preted to mean the maximum period of time allowed before the active pharmaceutical ingredient (API) changes or degrades, but it actually relates to air entrap- ment in the stored material and how that air influences flow and tablet compression. Figure 1 compares the flow- ability over time between a blend that compacts due to air percolation and a blend that doesn't. Air percolation from powder blends tends to occur in a dual phase model [2]. This means that most of the potential percolation occurs within the first 60 minutes Figure 1 Flowability over time for easily compacting blend versus non-compacting blend (expressed as a percentage of original potential) 100 90 80 70 60 50 40 30 20 10 0 Day 0 Day 2 Day 4 Day 6 Non-compacting blend Flowability (%) Easily compacting blend Some powder blends have unique air percolation profiles and mustn't be allowed to sit in a production or laboratory queue before tableting.