Studies on crystallization process for pharmaceutical compounds using ANN modeling and model based control

Abstract

Solvent selection and Controlling of operating parameters play a crucial role in batch cooling crystallization process. Choosing a best solvent for crystallization process involves more experimentation and time. To overcome this problem, an Artificial Neural Network (ANN) model technique is used to predict the carbamazepine form Ⅲ solubility by considering the thermodynamic properties of different solvents i.e. critical temperature, critical pressure, temperature, molecular weight, and acentric factor. The ANN model was trained and evaluated for solubility at various input data sets using experimental solubility data available in the literature. The ANN model with 20 hidden neurons has given the R2 value of 0.9943 which shows that the developed ANN model can be used for the selection of best solvent for batch crystallization process. Further, to determine the optimal cooling profile of batch cooling crystallization process, a multi-objective optimization problem is formulated by considering objectives as minimizing the coefficient of variation (CV) and maximizing the Number mean size (NMS) of crystals subjected to population balance equations using “method of moments” technique. Two types of temperature strategies i.e., piece-wise constant and piece-wise linear are developed and solved using NSGA-Ⅱ dynamic optimization procedure. The optimal NMS value attained through piece-wise linear strategy was 197.1 µm. This value has been increased by 28.3 µm from the nominal case (without optimization) and the coefficient of variation has decreased from 0.951 to 0.76. Further, optimal NMS value attained through piece-wise constant strategy was 205 µm. The value has been increased by 36.2 µm and the coefficient of variation has decreased from 0.951 to 0.73. This proves that the crystal attributes can be improved by optimal cooling temperature profile obtained by multi-objective optimization framework. For implementing the optimal cooling profile an advanced model-based control, i.e., Generic Model Control (GMC) was developed. It was observed that the GMC controller has the good tracking profile with no offset with/without disturbances and small value of root mean square error (RMSE) of 0.0016 using piece-wise constant as set point temperature. Using piece-wise linear as set point temperature, the RMSE value was 0.0018. In particular, it is advantageous to operate the batch cooling crystallization process with piece-wise linear strategy for set point trajectory tracking problems.