Chim Yong Chin

Simulated Moving Bed Equipment Designs

Abstract Simulated Moving Bed or SMB chromatography is a continuous adsorption technique that increases throughput, purity and yield relative to batch chromatography. SMB utilizes a series of columns with periodically moving inlet and outlet ports. This technique has been applied for the production of petrochemicals and sugars, and to a limited extent, pharmaceuticals. The recent surge in SMB research has led to various novel SMB schemes or configurations. This review presents a survey and comparison of SMB schemes and equipment, specifically SMB valve designs, which are needed to implement the various schemes. Illustrated examples include SMBs with three, four, five, eight, nine, or twelve zones, Varicol scheme, Japan Organo process, fast startup and shutdown, and online decoupled regeneration. The SMB valve designs reviewed are classified into central and distributed valves designs, which include two‐way‐valve designs and rotary‐valve designs. We also present a novel SMB design, the Versatile SMB or V‐SMB, which can implement all the novel schemes by using a one‐rotary‐valve‐per‐column design. Select‐Trapping valves are used to interrupt the stream between the columns and to act as a junction that allows streams to be partially or totally added or removed, or to flow through to the next column. The streams can also be redirected to another SMB zone. Compared to other SMB valve designs, the V‐SMB: (1) can be configured for open‐loop, multi‐zone and zone bypass operation; (2) does not require a carousel for column rotation; (3) does not contribute to product contamination; (4) allows independent port switchings, which is required for certain schemes; (5) allows additional columns to be added easily; and, (6) requires only constant speed pumps. The V‐SMB has successfully purified enantiomers, sugars, organic acids, an antibiotic, and biosynthetic human insulin.

A parallel pore and surface diffusion model for predicting the adsorption and elution profiles of lispro insulin and two impurities in gradient-elution reversed phase chromatography.

Lispro insulin (LPI), a widely used insulin analog, is produced on tons per year scale. Linear gradient reversed phase chromatography (RPC) is used in the production to separate LPI from two impurities, which differ from LPI by a single amino acid residue. A chromatography model for the ternary separation in this RPC process is unavailable from the literature. In this study, a parallel pore and surface diffusion model is developed and verified for LPI and the two impurities. The LPI can be recovered with high yield (≥95%) and high purity (>99.5%). A new method, which requires a small amount of materials and an order of magnitude fewer experiments, has been developed to estimate the solvent-modulated isotherm parameters. A modified reversed phase modulator model is developed to correlate the adsorption isotherms of LPI and impurities. A strategy has been developed for estimating the intrinsic pore diffusivity and surface diffusivity. Since the adsorption affinities decrease by more than three orders of magnitude as organic fraction (φ) increases from 0.19 to 0.40, the apparent diffusivities based on a pore diffusion model or a surface diffusion model can also vary by several orders of magnitude. For this reason, a pore diffusion model or a surface diffusion model with a constant apparent diffusivity cannot predict closely the chromatograms over the same range of organic fractions, concentrations, and loadings. The parallel pore and surface diffusion model with constant diffusivities can predict closely the frontal and elution profiles over a wide range of organic fractions (0.19-0.40), LPI concentrations (0.05-18 g/L), linear velocities (<10 cm/min), and loading volume (0.0004-13 CV). For large loading stepwise and linear gradient elution, the peaks of LPI and the impurities are strongly focused by self-sharpening and gradient focusing effects as a result of the steep decrease of adsorption affinity from the loading φ (0.19) to elution φ (≥0.27). When the ratio of diffusion rate to convection rate is greater than 10, spreading due to diffusion is largely compensated by the focusing effects. As a result, a pore diffusion model with a constant pore diffusivity can predict closely the elution profiles in stepwise and linear gradient elution. The experimental yield values (≥95%) can be predicted to within ±1% by the model.

Simulated Moving Bed Technologies for Producing High Purity Biochemicals and Pharmaceuticals

Adsorption and Simulated Moving Bed (SMB) processes can be used to purify many chemicals, biochemicals, and pharmaceuticals. 5MB processes usually have significantly higher yield, higher throughput, and lower eluent consumption than batch chromatography. Conventional 5MB systems have been developed for binary separations. Many major products, however, need to be purified from complex multicomponent mixtures. We have developed comprehensive new technologies for multicomponent separation, which include design methods, versatile 5MB equipment, and software tools for process design, simulation, and optimization. The technologies have been tested for the separation of various biochemicals and pharmaceuticals, and are expected to reduce significantly the cost of 5MB process development and purification. This article introduces the fundamental principles of 5MB and investigates the splitting strategies and design method for multicomponent separations. Insulin purification from a ternary mixture is used as an example. Rate model simulations show that the standing wave design can ensure high purity and yield for all splitting strategies. The simulations also show that mass transfer effects must be considered in 5MB design to meet purity requirements and achieve high yields. A decoupled regeneration strategy is developed to avoid gel fouling, and a long-term 5MB experiment proves that the 5MB process with decoupled regeneration for insulin purification is stable.