CO2_2016 - page 28

ways to make chromatography an economical option.
The advantages of doing so are related to the risks to the
program. Chromatographic resolution of a racemate is
an expedient solution at early development stages, and
likely already available. Other options may be more cost
effective at clinical and commercial scale, but what are
the risks that the compound will not reach that stage of
development?
Finally, the approaches suggested here generally require
an in-depth collaboration between chromatographers
and project team chemists. This collaboration may not
be necessary in early phases of R&D, but it could become
a critical time and money-saving component to a team
successful in full drug development.
REFERENCES
1. Nguyen L.A., Hua, H., Chuong P.; Int. J. Biomed. Sci. 2(2)
85-100 (2006)
2. Agranat, I.; Caner, H.; Caldwell, J.; Nat. Rev. Drug Discov. 1,
753–768 (2002)
3. Aboun-Enein H.Y., Ali. I. in Introduction: Chiral Separations by
Liquid Chromatography and Related Technologies; Edited by
Aboun-Enein H.Y. and Ali. I. Marcel Dekker, New York NY (2003)
4. a. Goosen L., Meltzer B.; J. Org. Chem. 72 (19), 7473–7476
(2007) b. Harel Z., Rukhman I., United States Patent US7378531
B2; May 2008 c. Ghosh S., Kumar A.S., Mehta G.N.; Beilstein J.
Org. Chem. 6(27) 2010
5. Welsch T., Frank H., Vigh G.; J. Chromatogr. A 506, 97-108
(1990)
6. Bank R.A., Jansen E. J., Beekman R., te Koppele J. M.; Anal.
Biochem. 240(2), 167–176 (1996)
7. E.g. Regis Technologies (Morton Grove, IL):
registech.com/chromatography/chiral-chromatography/
pirkle-type-chiral-columns (last checked February 15 2016).
AD-H, Daicel/ Chiral Technologies, West Chester PA) at
a quantity per injection which produced a resolution
(R
s
) of 1.5. Processing time was determined and the
chromatographic efficiency in kkd was calculated.
The isolated (R) and (S) warfarin were used to prepare
stock samples of enantiomer mixtures ranging to 10:90
and 90:10. Processing of these mixtures was performed
according to the same strategy and kkd efficiencies
determined. The results are tabulated in Table 1.
Perhaps surprisingly, the processing rate of feedstock
is nearly 2.5 times greater for 90:10 E1:E2 material as
compared with racemate, while the productivity of
production of E1 is over 4 times greater from the enriched
feedstock. Production of E2 is also more efficient from
enriched stock, but the advantage is closer to 2 times.
This suggests that overloading the racemate – causing
the enantiomers to overlap and fractions to be enriched
at lower than target level - may save time. Overloading
by a factor of 5 reduced the warfarin separation to R
s
= 0.7, so that head and tail cuts of the incompletely
resolved chromatogram recovered material at 80%
enrichment in one-fifth of the time. The final processing
was approximately 2-2.5 times faster than racemic, for an
overall time savings for a two-pass purification of 35%.
CONCLUSIONS
There are a number of ways by which batch
chromatography cost can be minimized. Generally,
chromatographers look for optimal stationary phase,
mobile phase, and system conditions to achieve a high
efficiency separation. We suggest that, if that work has
been done and a separation is available, a team tasked
with managing a chemistry program can still look at other
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