Process Modeling and Simulation for Continuous Pharmaceutical Manufacturing of Diphenhydramine

Source: AIChE
  • Type:
    Conference Presentation
  • Conference Type:
    AIChE Annual Meeting
  • Presentation Date:
    November 10, 2015
  • Duration:
    30 minutes
  • Skill Level:
  • PDHs:

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Continuous Pharmaceutical Manufacturing (CPM) has been recognized as an increasingly promising multidisciplinary research domain, addressing the significant obstacles hampering sustainable profitability (increasing R&D costs, globalized competition, licensing protocols, legal and regulatory landscape changes). Introducing a viable alternative to traditional batch production processes, CPM has an expanding potential capable of achieving lower costs (Schaber et al., 2011), higher yields, more economical heat and solvent use, high mass transfer rates, rapid scalability and elimination of intermediate storage (Calabrese and Pissavini, 2011). The technical viability and process efficiency of CPM prototypes must however be investigated in detail, in order to ensure successful pilot-scale demonstrations (Mascia et al., 2013) which can be used toward reliable production-scale implementations keenly pursued by pharmaceutical corporations (Poechlauer et al., 2013).

Organic flow synthesis literature must thus be (and indeed, has been) extensively surveyed to identify a wide range of Active Pharmaceutical Ingredients (APIs) whose production has already been accomplished in continuous mode at laboratory scale. A wide range of promising API candidates have thus been identified as suitable for CPM implementation (Jolliffe and Gerogiorgis, 2015a), including ibuprofen and artemisinin, which have already been examined in recent publications (Jolliffe and Gerogiorgis, 2015b). Systematic flowsheet synthesis, process modelling and simulation are essential towards rapidly assessment of CPM potential, and are already widely applied for CPM case studies (Gernaey et al., 2012).

The present paper focuses on a plantwide process modeling and simulation study for the production of diphenhydramine, a first-generation antihistamine which has been developed and has anticholinergic, antitussive, antiemetic and sedative properties and is mainly used to treat allergies, drug-induced parkinsonism and other neurological symptoms; moreover, it has a strong hypnotic effect and is and FDA-approved nonprescription sleep aid, especially in the form of diphenhydramine citrate. Our process model is developed on the basis of a published continuous flow synthesis (Snead and Jamison, 2013), which demonstrates that this economically and societally important API can be produced using Plug Flow Reactors (PFRs) with molten ammonium salts, thereby allowing for heating heat well above the boiling point of all reaction components. Moreover, this method also achieves solvent and waste minimization, thereby reducing operating costs and suppressing hazards associated with excess and disposal of chemicals.

Process modelling and steady-state simulations have been conducted toward process design for the respective CPM routes, with novel kinetic expressions developed on the basis of published kinetic data from experimental campaigns and thermodynamic property estimations essential for process design. Economic evaluations of the respective plant construction and operation venture can accordingly be performed on the basis of plantwide mass and molar balances, in order to quantitatively evaluate the viability of a production-scale CPM process.


    1.     Calabrese, G.S., Pissavini, S., 2011. From batch to continuous flow processing in chemicals manufacturing. AIChE J., 57(4): 828-834.

    2.     Gernaey, K.V., Cervera-Padrell, A.E., Woodley, J.M., 2012. A perspective on PSE in pharmaceutical process development and innovation, Comput. Chem. Eng., 42(1): 15-29.

    3.     Jolliffe, H.G., Gerogiorgis, D.I., 2015a. Process modelling and simulation for continuous pharmaceutical manufacturing of ibuprofen, Chem. Eng. Res. Des., 97: 175-191.

    4.     Jolliffe, H.G., Gerogiorgis, D.I., 2015b. Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin, Comp.-Aided Chem. Eng. (in press).

    5.     Mascia, S., Heider, P.L., Zhang, H. et al., 2013. End-to-end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification and final dosage formation, Angew. Chem. Int. Ed. 52(47): 12359-12363.

    6.     Poechlauer, P., Colberg, J., Fisher, E., et al., 2013. Pharmaceutical roundtable study demonstrates the value of continuous manufacturing in the design of greener processes, Org. Proc. Res. Dev. 17(12): 1472-1478.

    7.     Schaber, S.D., Gerogiorgis, D.I. et al., 2011. Economic comparison of integrated continuous and batch pharmaceutical manufacturing: a case study, Ind. Eng. Chem. Res. 50(17): 10083-10092.

    8.     Snead, D.R., Jamison, T.F., 2013. End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts, Chem. Sci. 4(7): 2822-2827.

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