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Tablets & Capsules July 2020 25 profiles of the key components measured just below the pile's top surface, as shown in Figure 1. With this concentration data, you can determine the segregation magnitude by computing the standard devi- ation of the concentration data for each component along the pile relative to the mean concentration. This gives a segregation intensity value that represents the percent deviation from the mean concentration of any one component. Consider a fictitious piece of process equipment or bin in which material forms a pile that induces a radial segregation profile. If the process were to empty in such a way as to discharge the all the material just below the pile's center first and then progress away from the cen- ter towards the perimeter of the pile, the time sequence concentration out of this fictitious process or bin would mimic the segregation pattern measured on the pile, with the material at the top of the pile's slope exiting first and the material at the bottom of the pile's slope exiting last. However, no real process discharges in this manner. Even in a funnel-flow bin, the region just above the out- let empties and then the remainder of the material exits the bin by sloughing down the inverted conical pile that forms during the discharge event. Some mixing always occurs. This implies that, assuming no fluidization segre- gation or other additional segregation is induced during the emptying process, the measured pile segregation pro- file would be the worst-case scenario during a process- emptying step. Because the segregation intensity number is the stan- dard deviation relative to the mean concentration, mul- tiplying this number by 3 gives a practical approximate bound on the expected concentration limits for that com- ponent. For example, suppose the segregation test gave a segregation index number that was 3 percent. This would imply that 99.7 percent of all the measured points on the pile would fall between the mean value plus or minus about 9 percent of the mean. In other words, a segregation intensity number of just over 3 percent would create a product that was always Because a formulation's composition influences prod- uct quality and performance, achieving and maintaining content uniformity in the final product is critical. Con- tent uniformity is expressed as a component's actual con- centration in a mixture divided by its desired expected average concentration in the mixture. In a perfect mix- ture, the content uniformity would be 100 percent. The limit on content uniformity is usually expressed as some percent deviation above or below 100 percent (± some percentage) and is considered the allowable percent change from the average. For pharmaceuticals, the API typically must have a content uniformity between 95 and 105 percent for Euro- pean products and between 90 and 110 percent for many US products. However, some US companies are begin- ning to adopt the European content uniformity standards. Excipients may have less stringent content uniformity ranges. To ensure that their products are within content uniformity limits for all important components or ingre- dients, drug product manufacturers must design their for- mulations and processes to minimize or mitigate segrega- tion during production. Segregation mechanisms Segregation is a mechanistic phenomenon in which components of a blend separate by particle size, shape, density, or other characteristic. Understanding the mag- nitude, pattern, and cause of segregation is extremely important to mitigating its effects. If a material is rela- tively free-flowing, finer particles can sift down through a matrix of coarse particles, causing the fine particles to separate from the coarse particles during processing, packaging, and usage. If the fines are small enough, they may become entrained in air currents generated by free fall or pneumatic conveying during processing. These air- borne fines can then be carried into the freeboard space of process equipment and deposited wherever the air velocity drops low enough for them to settle. As a formulation fills a bin in a process, the material forms a pile with sloping sides. Particles with different characteristics such as size, surface friction, or shape can slide down the pile at different rates, causing segrega- tion in the pile. Each segregation mechanism results in a unique pattern along the slope of the pile. With sifting segregation, fines tend to accumulate at the top of the slope, while air entrainment may cause fines to accumu- late at the bottom of the slope. Each of these mechanisms may occur at different intensities in the same blend, and their combined effect for each component can give the overall magnitude of segregation on a component- by- component basis. Measuring segregation The first step to mitigating a segregation problem is to measure the mixture's component segregation profile and component segregation intensity. You can do this by forming a pile in a slice box and then using near-infra- red (NIR) spectroscopy to determine the concentration Figure 1 Segregation measurement using a slice box Measurement zone on pile View port Individual measurement