Nonsynchronous CCC

There is a current increase in the research emphasis of pharmaceutical companies into the rapid, cost effective manufacture of a new generation of biopharmaceutical therapies and in particular to facilitate 'downstream processing with fewer process steps that preserves macromolecular structure and integrity.' (DTI BIGT report: 'Bioscience 2015'). Dynamic Extraction (DE) is a liquid-liquid separation technique that, unlike traditional chromatography, does not need a solid support. Instead, it uses two immiscible (usually aqueous/organic) liquids; one liquid is retained in the coiled column by centrifugal force, while the other is continuously pumped past it. Rotation of the coiled tubes relative to the rotor itself causes the mixing and settling of the two immiscible liquids that results in the partition/distribution process. If the equipment could be improved to enable the separation of biopharmaceuticals using non-organic solvents, DE could become a 'green', low-cost alternative for conventional high-resolution separations both at laboratory and industrial scale. In principle, the column can be rotated at any speed relative to the rotor. However a further feature that makes DE centrifuges ideal for bio-separations is the 'flying-lead', an anti-twist mechanism that allows external equipment to be connected to the spinning column by a continuous flexible tube thus avoiding problems of over-heating of sensitive biological molecules and contamination. This is achieved by spinning the coiled column in a synchronous planetary motion generated by a 1:1 simple planet-gear drive. Attempts to move towards the use of 'green' solvents in DE have met with some problems; the small density difference between, and high viscosity of, suitable 'bio-friendly' liquids means that a large centrifugal force is required both to retain them in the tube and to separate them. Unfortunately, the current 1:1 flying-lead mechanism requires that the coiled tube rotates at the same speed as the rotor and the resulting rapid mixing and settling may both damage bio-molecules and emulsify the solvent liquids instead of keeping them as two separate layers. The aim of this project is to overcome these problems and establish the basis for extending the capabilities of the DE process to enable the efficient recovery and purification of next generation of bio-therapeutics. It will involve the design and construction of a new generation of DE device that incorporates non-synchronous rotation between the main rotor and the coiled tube (i.e. where the mixing speed is decoupled from the centrifugal force) but which retains all the other intrinsic advantages of the technology, such as the flying lead connection. We have devised a novel way of making such a non-synchronous centrifuge by incorporating a second anti-twist mechanism between the gear for the centrifuge rotor and the coiled tube, allowing them to spin at different speeds. This arrangement, and the simple manner in which we achieve the additional anti-twist, are the basis for the novelty of our proposed scheme.

Dynamic Extraction (DE) is a liquid-liquid extraction technique that has been shown to provide a 'green', low-cost alternative to conventional HPLC for high-resolution separations both at laboratory and industrial scale. In DE centrifuges, separation occurs due to small differences in the solubility of a compound in two immiscible liquids; one liquid is retained in the coiled column by the rotor's centrifugal force, while the other is continuously pumped past it. The column is spun in planetary motion, causing the liquids to mix and settle and thus enable the migration of a compound into its 'preferred' phase. The other feature that makes DE centrifuges ideal for biological separations is the 'flying-lead', a simple anti-twist mechanism that allows external equipment to be connected to the spinning column by a continuous flexible tube, thus avoiding the heating and contamination problems associated with rotating seals. The improved resolution of the DE process would be particularly useful for protein separations but the low density difference and high viscosity of suitable 'bio-friendly' liquids means that a large centrifugal force is required to retain and separate them. Unfortunately, the flying-lead mechanism requires that the column rotates at the same speed as the rotor and the resulting rapid mixing and settling may damage cells and emulsify the liquids. A centrifuge is required where the mixing speed is decoupled from the centrifugal force whilst maintaining the flying-lead connection. We have devised a novel way of making such a non-synchronous centrifuge. In our proposed design, the anti-twist between the case and a column's planet gear is handled in exactly the same way as standard DE machine, but between the planet gear and column is a second anti-twist mechanism that allows them to spin at different speeds. This arrangement and the simple manner in which we achieve the additional anti-twist are the basis for the novelty of our proposed scheme.