CO2_2016 - page 26

Chimica Oggi - Chemistry Today
- vol. 34(2) March/April 2016
tetrazole functions. In our
laboratory, resolution of the
racemic precursor shown was
~20x more efficient. At nearly 2
kkd (kilograms of racemate per
kilogram of stationary phase per
24-hour day) this process would
be considered as a reasonable
commercial approach to
the API if an enantiospecific
synthesis were not available.
Use a Different Feedstock
Many times chiral
chromatography is viewed
only as a means to resolve
stereoisomers. This can be
limiting, as it implies that good
results are only obtained when
the separation deals only with
the isomeric peaks. Chemists
often believe that their racemic
product must be completely
free of reactants, other
products, and impurities. This
can be difficult to achieve while
scaling up a novel synthesis or
the time pressures of an active
program, and limits the utility of
the chromatography solution.
Our view is that “dirty”
feedstocks should be examined
as part of an ongoing effort
to serve the program’s
needs. Figure 2a shows just
such a sample; well-resolved
enantiomers contaminated with
a number of impurities. In this
case, the target enantiomer
was known, and was the early-
eluting peak “E1” in the pair.
In chiral preparative
chromatography, an isocratic
method for separation is
developed and the feedstock
sample is injected repeatedly –
as frequently as possible – while
collecting bands base on their
elution time. Figure 2b is a
“stacked injection run” of the
sample in 2a, illustrating the repeated collection of a pure E1
peak. The efficiency of the method comes from “stacking” the
injections with such a frequency that the later eluting impurities
contaminate the E2 peak in the following injections. Knowing
that only E1 must be captured at high purity reduces the
injection cycle to about 1/3 of the time required to purify both
Highly acidic and basic compounds often interact with
silanol groups on the silica solid support of a chromatography
column’s stationary phase. The “silanol effect” (5) results
They actually represent not
costs, but possible leverage
points or influences on the
program’s planned spending:
Speed (to get a needed
quantity of drug);
Control (predictability of the
Short Term Need (for
profiling and de-risking
assessment work while
process development
Future Potential (chances
that the drug will fail prior to
or early in production);
These factors may help
understand the risks of
investing in a better
production process. As
chromatographers, we also
look at the ways in which an
existing chromatographic
resolution may be improved
to limit risks and maximize
Resolving a key
Working with a different
feedstock for batch
Using a derivatization or
Working with an enriched
Pre-enriching the sample
using chromatography.
These strategies often require
a close collaboration with
a chemistry team, but they
can be productive. We
have seen enhancement of
chromatographic process
efficiency of greater than 5x,
translating to a corresponding
reduction in cost. The new
cost-effectiveness balance can
and should have an influence
on the development path and
While not every synthesis lends itself to this approach, it’s not
uncommon that a precursor to an active pharmaceutical
ingredient may be resolved into pure enantiomers more
efficiently than the API. An example is shown in Figure 1.
Valsartan is a commercial product that is produced as a single
isomer by several commercial syntheses (4), generally with
inexpensive L-valine as the source or the chiral center. The
API final product is separable chromatographically, but the
separation is inefficient due to the highly active acid and
Figure 1.
Comparison of preparative chiral chromatography
productivity for Valsartan and a synthetic precursor.
Figure 2.
(a) isocratic analytical SFC separation of a racemic
compound with impurities at ~25% of total UV absorbance, (b)
isocratic preparative SFC “stacked injection” chromatogram.
Injections are timed such that the later eluting impurities
elute under or near the E2 peak from the following injection,
allowing accumulation of clean and enantiopure desired E1.
Fully resolving the impurities would result in a much less efficient
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