(200x) Single-Step Continuous Purification from Liquid-Liquid-Solid Mixture: Design and Experimental Implementation for an HIV Drug Intermediate

An objective in pharmaceutical manufacturing is to increase process efficiency and yield, while reducing capital and operating costs (e.g., am Ende 2010; Simon et al., 2015). As a typical pharmaceutical manufacturing process consists of multiple chemical reactors that are separated by multiple other types of separations such as solids filtration, liquid-liquid extraction, evaporation, crystallization, and precipitation, a strategy for reducing both capital and operating costs is to redesign the process to reduce the number of unit operations. Moving from batch to continuous unit operations creates opportunities for reducing the number of unit operations, such as demonstrated for the end-to-end manufacturing of aliskiren hemifumarate which reduced the number from 21 to 14 (e.g., Mascia et al., 2013). As such, the capital and operating costs can be reduced substantially from the use of continuous-flow technologies.

While much progress has been made in the development of effective continuous-flow options for some unit operations, such as for crystallization (e.g., Nagy and Braatz, 2012; Simon et al., 2015), other continuous unit operations, such as filtration, are less well developed (e.g., Gursch et al., 2015). One of the guiding principles during the design of continuous-flow processes is to avoid the creation of conditions in which particles are present unless suspended within a liquid (e.g., Mascia et al., 2013). The reasoning behind this principle is that particle-particle interactions are much less predictable and more likely to cause processing problems when liquid is not present. Particles suspended within a liquid, however, can be transported through a continuous-flow process in the same manner that liquids are transported. As such, there is an especial interest when reducing the total number of unit operations to also avoid the use of unit operations such as filtration that involves particles that are not suspended in a liquid.

This presentation describes a unit operation for controlled continuous-flow separation that improves manufacturing efficiency while reducing the number of unit operations. The unit operation replaces the typical process sequence of solids filtration followed by liquid-liquid extraction, while having particles interact with particles only while being suspended within liquid. As such, the unit operation is highly reliable and robust. The unit operation does not require high pressure for its operation and does not employ any form of membrane or filtration media, and so cannot clog. The controlled continuous-flow separation does not involve crystallization nor precipitation on a surface (e.g., Zhou et al., 2015), and has high efficiency by retaining a high surface area to volume ratio for the particles throughout the process. The process also operates at low temperature, which minimizes potential oxidation or generation of impurities during processing.

The unit operation is experimentally demonstrated for the purification of an intermediate (Compound #9 in Wang et al., 2015) in the manufacture of a potent HIV integrase inhibitor. The process is controlled by a combination of a physical feedback control system designed into the process and a computer-controlled feedback control system implemented using open-source hardware commonly used by the Maker Community (Lahart, 2009). The cost of the computer-controlled system is less than $200. The actuator and sensor are also inexpensive off-the-shelf equipment. The use of commodity equipment common to the Maker Community results in very low cost for the controlled continuous-flow separation. The presentation will describe the unit operation in some detail, including the design strategies that led to its development and the specific equipment and software used in its experimental implementation.

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