(203b) Modeling of Pharmaceutical Milling Operations

Milling of active pharmaceutical ingredients (APIs) is an important operation that has not been analyzed in details. Recent stricter regulations on the properties of APIs creates a need for reliable modeling tools that enable a manufacturer to estimate a priori the properties of milled APIs, and to adjust the operating parameters to obtain product specifications efficiently and economically. This paper presents a general modeling approach for pharmaceutical milling. The model accounts for the mechanisms involved in the milling and handling of the particles during the operation. The general modeling approach is based on tracking the history of a single particle during the operation, and assigning a probability to successive milling actions during the operation. The approach is applicable to most milling methods (rolling mills, mortar mills, pin mills, etc.), both for dry and wet milling. Once the breakage mechanism is known and the method for handling of the particles is selected, the model applies known results from probability theory (renewal theory) to obtain the particle size and size distribution as a function of milling time. The model can be used to quantify the property distribution of the API, to identify and adjust key operating parameters, to develop a control strategy to regulate the operating conditions, and to determine the optimal and limiting milling operations.