Multivariate modelling of the tablet manufacturing process with wet granulation for tablet optimization and in-process control

Abstract

The process of tablet manufacturing with granulation is described as a two-step process. The first step comprises wet granulation of the powder mixture, and in the second step the granules are compressed into tablets. For the modelling of the pharmaceutical process of wet granulation and tableting, two models are constructed and compared. The first model relates the crushing strength (CS), disintegration time (DT) and ejection force (EF) of the tablets with process variables from both the wet granulation and tableting steps and the composition variables of the powder mixture. In addition to these predictor variables, the second model also uses physical properties of the intermediate granules to improve the predictive properties of the first model. Model 1 has to be used at the start of the process to find settings for the process variables and the composition of the tablet mixture that produce tablets with specific properties. Model 2 is used, in everyday production, for each new granulation batch. The granule properties may differ from batch to batch due to uncontrolled sources such as air humidity, temperature or other unknown features. With Model 2 these differences are taken into account, and the CS and DT are predicted better than with Model 1. The advantage of incorporating the measured granule properties in the second model is not only an improvement of the predictive power, but the second model offers also the possibility to use a control scheme for the second step of the process. This control scheme adjusts the variables of the tableting step to produce tablets that better meet the specifications. Because the granule properties are highly collinear and also dependent on the process variables of the first step, a partial least squares regression method has been used for the modelling.