Process modelling and simulation for continuous pharmaceutical manufacturing of ibuprofen

• Ten Active Pharmaceutical Ingredients (API) have been evaluated for CPM potential.
• Steady state mass balances have been calculated for the entire upstream CPM flowsheet.
• Flowsheet synthesis and kinetic parameter estimation are based on published chemistry.
• Plug flow reactors (PFR) have been designed for all 3 continuous synthesis reactions.
• A final purification separation has been designed after evaluating several candidate solvents.

Pharmaceutical corporations face rapidly rising process research and development (R&D) as well as production costs due to globalised competition. Batch production processes are dominant in the pharmaceutical industry and have multiple advantages, including equipment flexibility, high-fidelity quality control and the ability to recall specific batches; they however suffer disadvantages such as limited heat transfer and mixing scalability and low operational asset efficiency. Continuous Pharmaceutical Manufacturing (CPM) has a documented potential to reduce cost, as continuous production techniques can be easier to scale up and can be designed to be more efficient in terms of both solvent and energy use: therefore, it is both timely and important to explore the expanding feasibility limits of this emerging technology. The literature has been extensively surveyed in order to identify a series of candidate Active Pharmaceutical Ingredients (API) for flowsheet synthesis, process modelling and mass balance simulation toward rapid assessment of CPM potential. Ibuprofen [2-(4-isobutylphenyl)propanoic acid], the widely used non-steroidal anti-inflammatory drug (NSAID), has emerged as an ideal CPM candidate because it is in high global demand and can generate significant profit margins. The flowsheet is based on a published organic synthesis pathway and produces 50 kg of ibuprofen annually using three plug flow reactors (PFRs) in series, followed by a final separation for purification. Kinetic and thermodynamic parameter estimation modelling has been employed in order to compute essential data for design, and all PFR reactors have been designed based on reported conversions of feed and intermediate organic molecules in the respective organic synthesis reactions. Theoretically computed reactor designs are in good agreement with experimental prototypes constructed for the same organic synthesis, as well as in with previously reported CPM systems. The developed continuous final separation performs very well in accordance with green chemistry principles, with relatively low environmental impact (E-factor  = 25.4).