Document Detail

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.
MedLine Citation:
PMID:  21074775     Owner:  NLM     Status:  In-Process    
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.
Pei-Lun Chung; Jennifer Galvez Bugayong; Chim Yong Chin; Nien-Hwa Linda Wang
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Publication Detail:
Type:  Journal Article     Date:  2010-10-07
Journal Detail:
Title:  Journal of chromatography. A     Volume:  1217     ISSN:  1873-3778     ISO Abbreviation:  J Chromatogr A     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9318488     Medline TA:  J Chromatogr A     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  8103-20     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier B.V. All rights reserved.
School of Chemical Engineering, Purdue University, 480 Stadium Mall Drive, West Lafayette, IN 47907-2100, USA.
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