The integration of continuous unit operations imposes a challenge on the pharmaceutical companies aspiring to achieve plant-wide continuous manufacturing due to the additional complexity of the dynamic interactions, process control and quality assurance. To overcome this challenge, flowsheet modeling emerged as a viable tool to gain deeper process knowledge. In this work, the dynamic model of the integrated continuous manufacturing of acetylsalicylic acid (ASA) was formed based on real continuous unit operations. Furthermore, the surrogate model of the in vitro dissolution test of ASA capsules was integrated into the flowsheet model the first time to analyze the integrated manufacturing in light of the dissolution specifications of an immediate-release formulation. Systematic optimization studies were performed on the integrated process and on the continuous unit operations step-by-step, which clearly revealed the impact of the plant-wide dynamic modeling, as the integrated approach resulted in the threefold increase in the overall productivity and the parallel decrease in the required reactant excess. Sensitivity analyses of the operating conditions and the kinetic parameters were also performed. The crystallization temperature emerged as one of the most critical parameters, which variation could even result in the failure of the dissolution specification. Moreover, by calculating the time-varying sensitivity indices, the dynamics of the error propagation could be studied. These results could facilitate the integration of existing continuous units, the development of the control strategy, and encourage the implementation of dissolution surrogate models into process flowsheet simulations.

• Purdue University

• Modeling

1. Dissolution modeling
2. Dynamic flowsheet modeling
3. Integrated continuous manufacturing
4. modeling
5. Optimization
6. Research Article
7. Sensitivity analysis