466304 Systematic Technoeconomic Comparison of Separation Solvents for Green Continuous Pharmaceutical Manufacturing of Diphenhydramine

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Samir Diab and Dimitrios I. Gerogiorgis, Institute for Materials and Processes (IMP), School of Engineering, University of Edinburgh, Edinburgh, United Kingdom

Continuous pharmaceutical manufacturing (CPM) has been shown to provide significant cost savings and enhanced material efficiencies compared to the currently used, yet inefficient, batch methods [1]. With the highest research and development costs of all industrial sectors, and historically increasing commercialisation costs [2], technological innovation is essential for pharmaceutical firms to remain profitable and sustainable [3]. For the benefits of CPM to be realised by industry, demonstration of its feasibility and viability via systematic process evaluation is paramount [4].

Continuous flow synthesis is the key to all candidate CPM processes, which has been demonstrated for several active pharmaceutical ingredients (APIs) to date. Several promising API candidates have already been identified as suitable for CPM implementation, including ibuprofen and artemisinin, which have already been examined in recent publications [5][6]. Systematic flowsheet synthesis, process modelling and simulation are an essential method for rapid assessment of potential processes and have already been widely applied for CPM case studies [7].

Diphenhydramine, a first-generation antihistamine API with hypnotic and anti-depressant uses [8] has been shown to be a promising candidate API for CPM implementation. Our previous work developed a process model on the continuous upstream processing of diphenhydramine [9] on the basis of a published continuous flow synthesis route which demonstrates that this economically and societally important API can be synthesised in plug flow reactors with molten ammonium salts [10]. This method achieves solvent and waste minimisation, achieving low total costs, enhanced material efficiency, and reduced hazards of chemical waste disposal.

The present paper illustrates a comprehensive technoeconomic analysis of various separation solvents for the continuous purification of diphenhydramine in this novel CPM process. This work provides a systematic methodological framework toward assessing liquid-liquid extraction (LLE) performance and material efficiency of the CPM process using different separation solvents. The inefficiencies incurred by each solvent at varying feed ratios on plant capacity, unit operation sizes and the corresponding capital, operating and total costs are also calculated here and compared to the CPM process with a batch separation train.

It is shown that whilst there is significant variation in process equipment sizes, costs and material efficiencies for CPM with different separation solvents, there is a clear trade-off between greatest cost savings, improvements in material efficiency, solvent toxicity and green, sustainable CPM operation. Original results indicate small computed reactor volumes and considerable heating requirements for the plant capacity. Chloroform emerges as a potent extraction agent in comparison to other candidate solvents, allowing the highest material efficiency (environmental factor of 3.43, total cost savings of 49.5%), but its high toxicity prohibits CPM use. Methyl-cyclohexane is the next strongest performer (environmental factor of 31.06, total cost savings of 37.3%) whose chemical properties render it significantly more acceptable for CPM implementation.

The present study exhibits the potential for technological innovation available via CPM in an effort to facilitate the transition from batch production methods in the pharmaceutical industry; by demonstrating the technoeconomic feasibility and economic viability for CPM of diphenhydramine via a rigorous comparison of a wide range of continuous separation options, we highlight the importance of systematic process systems engineering methods toward facilitating promising transitions from batch to CPM processes.


1. Plumb, K., 2005. Continuous processing in the pharmaceutical industry - Changing the mind set, Chem. Eng. Res. Des. 83(A6): 730–738.

2. Morgan, S., Grootendorst, P., Lexchin, J., Cunningham, C., Greyson, D., 2011. The cost of drug development: A systematic review, Health Policy 100(1): 4–17.

3. Behr, A., Brehme, V.A., Ewers, C.L.J., Gron, H., Kimmel, T., Kuppers, S., Symietz, I., 2004. New developments in chemical engineering for the production of drug substances, Eng. Life Sci., 4(1): 15–24.

4. Teoh, S.K., Rathi, C., Sharratt, P., 2016. Practical assessment methodology for converting fine chemicals processes from batch to continuous, Org. Process Res. Dev., 20(2): 414-431.

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

6. H. G. Jolliffe and D. I. Gerogiorgis, D.I., 2016. Process modelling and simulation for continuous pharmaceutical manufacturing of artemisinin, Chem. Eng. Res. Des. (in press, available online).

7. K. V Gernaey, K.V., Cervera-Padrell, A.E., Woodley, J.M., 2012. Development of continuous pharmaceutical production processes supported by process systems engineering methods and tools, Future Med. Chem. 4(11): 1371–1374.

8. Richardson, G.S., Roehrs, T.A., Rosenthal, L., Koshorek, G., Roth, T., 2002. Tolerance to daytime sedative effects of H1 antihistamines, J. Clin. Psychopharmacol. 22(5): 511–515.

9. Diab, S., Gerogiorgis, D.I., 2015. Process modeling and simulation for Continuous Pharmaceutical Manufacturing (CPM) of diphenhydramine, Proceedings of the AIChE Annual Meeting, Salt Lake City, UT, USA.

10. 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.

Extended Abstract: File Not Uploaded
See more of this Session: Poster Session: Pharmaceutical
See more of this Group/Topical: Pharmaceutical Discovery, Development and Manufacturing Forum