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Ind. Eng. Chem. Res. 2000, 39, 2175-2182 2175 Evaluation of Spinning Disk Reactor Technology for the

Manufacture of Pharmaceuticals

Paul Oxley,† Clemens Brechtelsbauer,*,† Francois Ricard,† Norman Lewis,† and Colin Ramshaw‡

SmithKline Beecham Pharmaceuticals Research & Development, Old Powder Mills,

Tonbridge, TN11 9AN, United Kingdom, and Centre for Process Intensification and Innovation, University of Newcastle upon Tyne, Merz Court, Newcastle upon Tyne, NE1 7RU, United Kingdom

A continuously operating spinning disk reactor (SDR) displayed distinct advantages over batch processing techniques when several commercially relevant processes for the manufacture of pharmaceuticals as test reactions were investigated. It proved to be a useful tool for revealing intrinsically fast kinetics as well as for optimizing processes with such kinetics. Very encouraging results were achieved for a phase-transfer-catalyzed (ptc) Darzen’s reaction to prepare a drug intermediate and the recrystallization of an active pharmaceutical ingredient (API). In comparison to presently used batch processes, the ptc reaction resulted in a reaction with 99.9% reduced reaction time, 99% reduced inventory, and 93% reduced impurity level. The recrystal- lization yielded particles with a tight particle size distribution and a mean size of around 3 μm. Reactor modeling was in good agreement with the experimental results and highlighted the advantages of the process-intensified equipment with a production capacity of around 8 tonnes/ year.

Introduction

Recently, the spinning disk reactor (SDR) was brought forward as an alternative to traditional stirred tank processing technology,1,2 claiming to offer distinct ad- vantages with respect to mixing characteristics, heat transfer, and residence time distribution. Following an industrial/academia collaboration sponsored by the Innovative Manufacturing Initiative in the United Kingdom, the Process Chemistry Department, at Smith- Kline Beecham (SB) Chemical Development, Tonbridge, evaluated with support from Newcastle University the applicability of this continuous processing technol- ogy to drug manufacturing processes currently in de- velopment. The aim of the study was to determine whether this novel reactor would prove to be of advan- tage over presently applied manufacturing techniques. A prototype of the equipment was constructed by Newcastle University and then loaned to and later purchased by SB. It was installed at SB pilot plant premises at Tonbridge for the duration of the evaluation study.

In this report, we will describe the results of this evaluation, determining whether the spinning disk reactor proved to be an attractive and commercially viable alternative to conventional batch processing.

Theory

Background. Most pharmaceuticals and fine chemi- cals are manufactured in stirred vessels which are simply scaled-up versions of the beaker in which the process was originally devised. Unfortunately, the heat-/

* To whom correspondence should be addressed. E-mail: Clemens_Brechtelsbauer-1@sbphrd.com. Tel.: +44 1732 372110. Fax: +44 1732 372104.

† SmithKline Beecham Pharmaceuticals Research & Devel- opment.

‡ University of Newcastle upon Tyne.

mass-transfer and mixing characteristics of a stirred vessel deteriorate rapidly at larger sizes because the surface-to-volume ratio decreases and the circulation time of contents increases while the corresponding mixing intensity decreases at constant impeller tip speed. Thus, large vessels will tend to impede reactions which may be intrinsically fast and highly exothermic. If a more intense fluid dynamic environment could be created, the intrinsic reaction kinetics can be given free rein. Where these are fast, the reaction can in principle be completed within a few species half-lives, provided heat-/mass-transfer and mixing limitations are relaxed. In practice, the fluid residence times on an SDR are in the range of 1-5 s compared with a few hours in a stirred vessel. Hence, reactions with half-lives in the 0.1-1 s range may be expected to be completed on the disk. Noting the qualitative equivalence of mixing intensity and fluid shear stress, the SDR is capable of generating a far higher mixing intensity than a stirred vessel and should therefore be capable of maintaining uniform concentration profiles within a rapidly reacting fluid. Thus, better control should be exerted over the reaction trajectory than that achieved in a conventional stirred tank. Bearing in mind the pharmaceutical industry’s drive to shorten development times, it is apparent that the SDR, with its high potential produc- tive capacity may allow the laboratory scale to be the full scale and hence avoid the inevitable delays in authenticating various levels of scale-up. In addition, the small reactor holdup (<100 mL) and the excellent fluid temperature control make the SDR particularly suited for highly hazardous reactions.

Operating Principle. The working principle of the continuously operated SDR can be taken from Figure 1. The spinning disk is a horizontally oriented plate that can be heated or cooled and rotated via an air motor at speeds up to 5000 rpm. Liquid feed streams, supplied to a well in the center of the plate, travel rapidly across

10.1021/ie990869u CCC: $19.00

Published on Web 05/27/2000

© 2000 American Chemical Society

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