HPLC for Pharmaceutical Scientists 2007 (Part 21)

Directly from its beginning—now 100 years ago, when Michail Tswett developed the principles [1, 2] with the isolation of chlorophyll—chromatography has always been a preparative technology, and its value in producing compounds of high purity cannot be overemphasized. It was Paul Karrer [3] who stated very early “. . . it would be a mistake to believe that a preparation purified by crystallization should be purer than one obtained from chromatographic analysis. In all recent investigations chromatographic purification widely surpassed that of crystallization.” and Leslie Ettre, although not distinguishing between analytical and preparative separations, denoted chromatography as “the separation...
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HPLC for Pharmaceutical Scientists 2007 (Part 21)21TRENDS IN PREPARATIVE HPLCErnst Kuesters21.1 INTRODUCTIONDirectly from its beginning—now 100 years ago, when Michail Tswett devel-oped the principles [1, 2] with the isolation of chlorophyll—chromatographyhas always been a preparative technology, and its value in producing com-pounds of high purity cannot be overemphasized. It was Paul Karrer [3] whostated very early “. . . it would be a mistake to believe that a preparation puri-fied by crystallization should be purer than one obtained from chromatographicanalysis. In all recent investigations chromatographic purification widely sur-passed that of crystallization.” and Leslie Ettre, although not distinguishingbetween analytical and preparative separations, denoted chromatography as“the separation technique of the 20th century” [4]. From a historical point ofview, the beginnings of preparative isolation of natural compounds were cum-bersome. For example, it is reported [5] that six years of work and processingof 30 tons of strawberries was needed to finally obtain 35 mL of an oil, theessence of the fruit. This situation changed dramatically in the 1960s with thetheoretical understanding of the chromatographic process, the developmentof high-performance liquid chromatography, and the synthesis of highly selec-tive stationary phases. As a result of these improvements, the isolation ofnatural compounds with preparative chromatography on production scale(e.g., drug substances from fermentation processes) is still state of the art, evenafter 100 years. Today, preparative HPLC has also become a powerful technology in phar-maceutical development and production either for isolation of impurities, forHPLC for Pharmaceutical Scientists, Edited by Yuri Kazakevich and Rosario LoBruttoCopyright © 2007 by John Wiley & Sons, Inc. 937938 TRENDS IN PREPARATIVE HPLCTABLE 21-1. Order of Magnitude and Purpose of Purified Amounts Obtained fromPreparative Chromatography Amount of Stationary Amount ofColumn Type I.D. (mm) Purpose Phase (g) Product (g)Analytical 1–5 Isolation of reference 0.2–3 0.0002–0.003 substances (MS or NMR)Analytical— 5–10 Starting materials 0.003–25 0.003–0.1 semipreparative for toxicologySemipreparative 10–40 Intermediates for 25–100 0.1–5 —preparative lab synthesisPilot plant 100–300 Manufacturing of 100–1000 20–5000 drug substances for pharmaceutical developmentProduction 300–1,500 Manufacturing of 1,000–4,000,000 kg-tons trade productschromatographic purifications, or as part of a scale-up process and subse-quently has been reviewed in a lot of monographs [6–10]. The term prepara-tive amount thus covers the range from milligram quantities (amounts forstructure elucidation, analytical characterization, toxicology, or referencematerial) to large-scale production of tons of intermediates and drug sub-stances. The separations therefore can be performed on all types of columns,starting from analytical ones up to production scale columns with 1-m i.d andseveral meters in length. Typical applications are summarized in Table 21-1. The success of preparative HPLC on a production scale has been made pos-sible because of significant improvements made in several areas like (i) columntechnology (today, mainly compressed columns are used), (ii) packing mate-rials (pressure stable spherical particles with high homogeneity, either non-chiral or chiral), and (iii) the understanding of the nonlinear process inpreparative HPLC (overloaded conditions) which resulted in new methods todetermine the adsorption isotherms and which consequently led to new con-cepts like displacement chromatography and simulated moving bed (SMB)chromatography, where the knowledge of such adsorption isotherms is a pre-requisite for the design of the corresponding separation process. The aim of this chapter is to highlight current developments in these variousfields of preparative HPLC, with particular emphasis on applications that havebeen developed at Chemical & Analytical Development at Novartis PharmaAG. Drug substance purifications from biological and synthetic sources arepresented, along with the separation of chiral and/or achiral molecules onchiral stationary pha ...