Page 278 - Chiral Separation Techniques

10.2 Chromatographic processes 257

10.2.2 Illustrations of SMB Processes

The concept of using continuous chromatography for the separation of stereoisomers
or “optical isomers” is very old and was probably proposed for the first time by Mar-
tin and Kuhn in 1941 [28]. The suggested implementation was different from today’s
SMB technology, though the basic concept is the same. The chromatographic media
is moved continuously in a conveyor belt, the feed is injected continuously at a fixed
point, and the pure enantiomers are recovered at fixed points. In the idea of Martin
and Kuhn, benefits were taken from the possibility of modulating the adsorption of
the products at different temperatures.
Hotier and Balannec published one of the first real proposals to use SMB as a pro-
duction tool for the pharmaceutical industry, and thus to scale down a process
already used on a production scale [29]. The first commercially available plant
(Licosep) SMB system was offered by Separex in 1991 and was exhibited for the
first time in June 1991 during the Achema Exhibition. The system consisted of 24
stainless steel columns with adjustable lengths between a few centimeters up to
almost 1 meter, HPLC pumps, and mulitpositional valves. To improve the robustness
of the system, a rotary valve replaced two-way valves and the pumps were modified.
Early scientific publications detailed experimental results for the enantiosepara-
tion of phenyl-ethyl alcohol [30] and on threonine [31]. Sandoz released the first
announcement for the development and use of SMB on an industrial scale [32], this
separation has been described by Nicoud et al., 1993 [25].
Following these announcements, the first wave of publications addressing the use
of SMB for the manufacture of pharmaceutical products of interest was published.
The separation of a chiral hetrazepine [26], WEB 2170 6-(2-chlorophenyl)-8-9-di-
hydro-1-methyl-8-[(morpholinyl)-carbonyl]-4H,7H-cyclopenta[4,5]-thieno[3,2-
f][1,2,4]triazolo[4,3-a][l,4]diazepine. WEB 2170 is a chiral hetrazepine from
Boehringer-Ingelheim. The enantioseparation of WEB 2170 was performed using
cellulose triacetate (CTA) from Merck (Darmstadt) as the CSP and with pure
methanol as eluent.
A precursor in the synthesis of a promising calcium sensitizing agent from E.
Merck [33], a chiral thiadiazin-2-one EMD 53986, 3,6-Dihydro-5-[1,2,3,4-tetrahy-
dro-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one [26]. The study was performed
®
using Celluspher , a CSP prepared from cellulose tri(p-methylbenzoate) according
to a patent from Ciba-Geigy [34]. The spherical particles had a mean particle diam-
eter of 20–43 µm and the mobile phase was pure methanol.
Other examples of enantioseparations include the separation of the antihelmintic
drug, prazinquatel [35], which used a 4-column SMB system composed of columns
of 12.5 mm i.d. packed with CTA and with methanol as the eluent. Ikeda and Murata
separated the enantiomers of β-blockers [36].
A second wave of publications describes SMB in simplistic terms, while integrat-
ing economical calculations [37–40]. Moreover, some users (researchers in pharma-
ceutical companies) disclosed the design and applications of SMB in their own lab-
oratories [41–45].