Issue link: https://www.e-digitaleditions.com/i/1331851
28 January/February 2021 Tablets & Capsules More difficult than detecting the endpoint of granu- lation is achieving reproducible endpoints by controlling a range of process variables. For a given set of processing parameter values, the granulation endpoint is determined by measuring the strength, rheological properties such as density, and physical properties such as mean particle size distribution of the granules. This requires an endpoint measurement technique that can provide accurate and reproducible results, taking into account changes in pro- cessing parameters, such as mixer geometry, blade speed, batch size, and the amount and method of binder addition. It is also important to consider the different phases of HSM granulation when determining the granulation end- point. The HSM process follows three principle phases: dry mixing, spraying or binder addition, and wet mixing. The wet mixing phase has the greatest impact on the endpoint, but the binder addition phase and the method of binder addition also play important roles in granule formation, including granule nucleation, densification, and growth. Hence, predicting the granulation endpoint requires consideration of the binder addition phase as well as the wet mixing phase. Current methods for determining the endpoint in HSM granulation Wet mixing duration. One of the oldest methods for endpoint determination is based on the duration of the wet mixing phase, which follows the binder addition phase. The limitation of this method is that it may lead to inaccurate results if the properties of the starting mate- rials vary due to a supplier change or some other circum- stance. Also, manually adding binder can introduce errors in addition time and binder quantity that may cause vari- ations in the final granulation lot. Power consumption. Another popular endpoint determination method is based on measuring the power consumed by the mixer motor (in amperes). This is a cost-effective method, and the results obtained can be correlated to granule growth. A change in the consis- tency of the powder mixture increases the resistance on the granulator blades, which in turn, affects the motor's power consumption. This method has certain limitations. The readings are affected by various factors such as the formulation, equipment type, and process variables, as well as by the amount of wear and tear on components such as the impeller motor, bearing, and gear box. A major drawback of the power consumption method is that the load is measured on the motor rather than on the impeller where the process is conducted. These measure- ment readings fluctuate over time and depending on the condition of the motor, regardless of the load. Calculated torque. Another means of endpoint determination is to use the motor current to calculate the torque on the mixer's impeller. However, HSMs usually have induction motors that use an alternating current. This causes fluctuations in measurement read- ings and poses limitations. The basis of evaluation is the measured current, which is then converted to calculated Although technological advances have made a con- siderable impact on many industries, pharmaceutical operations, such as the granulation step in tableting, have often remained conventional. Pharmaceutical man- ufacturers employ an array of methods to determine the granulation endpoint, including wet mixing dura- tion, power consumption, calculated torque, reaction torque, torque rheometer, acoustic emission, near-infra- red (NIR) spectroscopy, and focused beam reflectance measurement (FBRM). However, these methods are not exact, and the read- ings they provide may fluctuate. In contrast, direct torque measurement provides more accurate endpoint detection and fewer reading fluctuations, making it a reliable option for overcoming FDA scrutiny of endpoint determination in HSM granulation processes. Before discussing how direct torque measurement works, however, it's import- ant to understand the challenges involved and endpoint determination methods currently in use. Challenges of endpoint determination in HSM granulation The endpoint of a granulation process is the time at which the process forms granules with desirable tableting properties, including strength, bulk density, particle size distribution, and flowability. Over the years, researchers have devised various ways of predicting the results of HSM granulation processes. Simultaneously, granulation equipment manufacturers have improved their machines to provide more reliable results. Despite these efforts, HSM granulation relies heavily on empirical methods to determine its endpoint. Because precise endpoint determination is so challeng- ing, most formulations are either under- or over-granu- lated, leading to a range of problems during downstream processes. Operators still often follow a traditional hand test to check granules, which is highly subjective and can lead to extreme inaccuracies. As a result, the FDA has insisted that manufacturers establish a precise method for determining the granulation endpoint. Direct torque measurement provides more accurate endpoint detection and fewer reading fluctuations, making it a reliable option for overcoming FDA scrutiny of endpoint determination in HSM granulation processes.