(408b) An Efficient Approach for Chemical Process Development Using Kinetic Modeling in Batch and Continuous Mode

Traditionally active pharmaceutical ingredients are manufactured in batch mode, however the pharma companies express increasing interest in continuous processing. Continuous manufacturing is an attractive alternative due to its benefits such as reduced development time, greater process safety when employing hazardous chemistries or extreme conditions, reduced operating costs, improved process control and product quality.

Kinetic modeling plays an important role in development stages of chemical processes regardless of the operation mode. Precise knowledge of the kinetic parameters is necessary for the scale up from laboratory to industrial scale and for the design of robust and safe processes.

This work describes an efficient approach for the development of a reaction in an API synthesis. The approach includes screening of the reaction conditions, estimation of the kinetic parameters both in batch and flow mode and their comparison, and also fine-tuning optimization applying Design of Experiments.

In the screening phase, we tested both conventional and microwave heating to find the most favorable conditions resulting in 99% conversion and we analyzed the possibilities for a continuous process. Specific sets of experiments were performed in both operation modes, kinetic curves and parameters were then obtained and assessed to determine if the studied variables impacted the impurity formation. The model was used to predict conversion values and impurity levels for different conditions. In the last stage optimization studies were carried out in order to determine the Design Space ensuring the product quality within specifications.

We demonstrate our methodology applied for a case study following the Quality by Design concept, including experimental data and also simulations. This approach can be used for the development of batch or continuous processes in the future. The use of kinetic modeling allowed deeper understanding of the reaction mechanism and its influential factors, resulting in shorter development time and enhanced confidence level regarding the impurity formation.