Publications

Authors: Rohit Ramachandran

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Abstract: The overarching goal of this study is to quantitatively understand the interactions between material properties, process parameters, equipment design and environmental conditions to predict product performance of granules as product performance is critical to the value of granulated products. In this study, multi-scale predictive models are presented for granulation processes combining key material properties and process parameters with transport phenomena. Results obtained from the study enables a more quantitative and predictive understanding of granulation. Furthermore, the improved multi-scale model formulations can be used to alleviate labor- and capital-intensive experimentation that currently plagues industrial processes.

Authors: Rohit Ramachandran, Jeyrathan Arjunan, Anwesha Chaudhury & Marianthi G. Ierapetritou

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Abstract: This study is concerned with enhanced model-based control of a continuous direct compression pharmaceutical process. The control-loop performance is assessed in silico and results obtained will be incorporated into the pilot plant facility of the continuous direct compaction process at the NSF Engineering Research Center of Rutgers University. The models used in the study are obtained via system identification from a combination of first principles-based dynamic models, experimental data, and/or literature data. The main objective of the paper is to formulate an effective control strategy at the basic/regulatory level, for the integrated continuous operation of the direct compaction process, and to maintain the process at the desired set-points, taking into account the multivariable process interactions and disturbances. Simulations show that that at very mild interactions, the proposed regulatory control strategy is able to maintain set-points at desired values. However, at moderate to high process interactions, oscillatory behavior of controlled variables is seen. The presence of disturbances also resulted in poor control-loop performance. Results also lend credence to the development of advanced control strategies in such scenarios and will be addressed in future work. Optimal control tuning parameters are obtained from a derivative-free optimization algorithm.

Authors: Spencer D. Schaber, Dimitrios I. Gerogiorgis, Rohit Ramachandran, James M. B. Evans, Paul I. Barton, and Bernhardt L. Trout

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Abstract: The capital, operating, and overall costs of a dedicated continuous manufacturing process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estimated for a production scale of 2000 t of tablets per year, with raw material cost, production yield, and API loading varied over broad ranges. Costs are compared to batch production in a dedicated facility. Synthesis begins with a key organic intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of $100 to $3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuous process has not been built at large scale, so Wroth factors and other assumptions were used to estimate costs. Capital expenditures for continuous production were estimated to be 20 to 76% lower, depending on the drug loading, KI cost, and process chosen; operating expenditures were estimated to be between 40% lower and 9% higher. The novel continuous process with recycling coupled to a novel direct tablet formation process yields the best overall cost savings in each drug loading/KI price scenario: estimated savings range from 9 to 40%. Overall cost savings are also given assuming the yield in the continuous case is 10% above and 10% below that of the batch process. Even when yields in the continuous case are lower than in the batch case, savings can still be achieved because the labor, materials handling, CapEx, and other savings compensate.

Authors: F. Boukouvala, R. Ramachandran, A. Vanarase, F.J. Muzzio and M.G. Ierapetritou.

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