reactions in which the PGI is transformed into a more stable
species for more convenient analysis.15,16
resins.26-28 These studies suggested that a similar approach could
potentially be used for the removal of reactive PGIs. In this
study we investigate the use of nucleophilic reactive resins to
remove electrophilic PGIs. Several nucleophilic resins were
screened, and the resins with the highest efficiency of PGI
removal were selected. The selected nucleophilic resin can be
added to the final product stream, allowed to react with the PGI,
and then removed by filtration prior to crystallization. A standard
screening protocol with different resins is recommended for the
different PGIs. The kinetics of PGI removal, resin loading
capacity, solvent effects, and API matrix effects are also
demonstrated.
In general, impurities can be classified into five different
classes with respect to their genotoxic potential.5 Of these, alkyl
and aryl sulfonic acid esters are some of the most frequently
encountered PGIs in current pharmaceutical manufacturing
processes. Alkyl and aryl sulfonic acid esters are classified as
class 3 PGI (impurities that are considered as alerting structures
and could be linked to genotoxicity on the basis of their
structure). In fact, several studies17-21 confirmed genotoxicity
of several alkyl sulfonic acid esters, and Glowienke et.al.22
reported genotoxicity of other aryl sulfonic acid esters in two
in Vitro studies.
Methanesulfonic acid (MSA), benzenesulfonic acid (BSA),
and p-toluenesulfonic acid (pTSA) are commonly used in active
pharmaceutical ingredient (API) synthetic routes either as
counterions to form a salt or as acid catalysts. Esters of these
alkyl and aryl sulfonic acids may be formed in the presence of
alcoholic solvents such as methanol, ethanol, or isopropanol.
As the daily intake of these alkyl and aryl sulfonic acid esters
should be limited to <120 µg/day, any synthetic route involving
these species must be designed to control the formation of these
esters to low ppm levels.
Controlling the formation of PGIs (alkyl and aryl sulfonic
acid esters in this case) to low ppm levels poses a big challenge
for process chemists. In some cases, alternative synthetic routes
must be developed to avoid PGI formation. In other scenarios,
purification of the API is preferred to remove the PGI. Ideally,
PGI removal can be accomplished by crystallization of the API.
Final product crystallization is typically performed in most API
syntheses, and the simplest solution to PGI removal is to adjust
the crystallization conditions such that PGIs are reduced below
target levels. However, not all APIs are crystalline and not all
crystallizations are effective in rejecting PGIs. In cases where
crystallization is not possible, PGI removal by preparative
chromatography can sometimes be employed, despite the high
solvent consumption and additional time and cost required for
process development.
Results and Discussion
Figure 1 shows the structures of the various resins used in
this study. As shown, all resins have a nuclephilic site (amino
group or a thiol group). As opposed to adsorption or chromato-
graphic approaches, the removal of the sulfonic acid esters from
solution using nucleophilic resins is based on a chemical
reaction between the nucleophilic site of the resin and the
electrophilic PGI, as illustrated in Figure 2.
In order to assess the feasibility of this general approach, a
model study investigating the treatment of methyl p-toluene-
sulfonate with benzylamine (surrogate for the insoluble resin)
soon led to a decrease in methyl p-toluenesulfonate with
concurrent formation of methyl benzylamine as evidenced by
LC/MS (data not shown).
Solutions of methyl, ethyl and isopropyl p-toluenesulfonate
were treated with different nucleophilic resins for 30 min.
Several resins showed extensive removal of methyl p-toluene-
sulfonate, with multiple thiol- or amine-containing resins
affording greater than 80% impurity removal under these
conditions (Figure 3). These same resins were less effective in
removal of the ethyl and isopropyl esters, presumably owing
to the increased steric bulk of the ethyl and isopropyl esters
versus the methyl ester.29
The same screening experiment was performed with methyl,
ethyl, and isopropyl bezenesulfonates. Resins showing removal
of >50% for methyl ester and >10% for ethyl and isopropyl
esters were selected (data not shown). Similarly, the ethyl and
isopropyl esters showed lower reactivity relative to that of the
methyl ester.
We have previously reported approaches to the removal of
impurities such as utilizing selective adsorbents23-25 or reactive
(15) OSHA Analytical Methods Manual; U.S. Dept. of Labor, Occupational
Safety and Health Administration: OSHA Salt Lake Technical Center,
Salt Lake City, UT, 1990; Vol. 1, Publ. #4542; American Conference
of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH.
(16) Lee, C. R.; Guivarch, F.; Van Dau, C. N.; Tessier, D.; Krstulovic,
A. M. Analyst 2003, 128, 857.
In an analogous fashion, the screening experiment was
performed with methyl, ethyl and isopropyl methanesulfonate.
These studies showed some removal of methyl mesylate,
however, little or no removal of the ethyl or isopropyl mesylate
esters was observed, even when pH, temperature, and reaction
time were varied.
(17) (a) International Agency for Research on Cancer (IARC) Monographs
Program on the EValuation of Carcinogenic Risks to Humans (2004)
graphs.iarc.fr/ENG/Monographs/vol71/mono71-48.pdf (pages 1-20).
(b) IARC Monographs Program on the EValuation of Carcinogenic
Risks to Humans (2004) for Ethyl Methanesulfonate, 1974; Vol. 7, p
22).
(24) Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; DaSilva,
J.; Henderson, D.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.; Wang,
T. Org. Process Res. DeV. 2005, 9, 198.
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Childers, K.; Chung, J. Y. L.; Hartner, F. W.; Albaneze-Walker, J.;
Sajonz, P. Org. Process Res. DeV. 2008, 12, 81.
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(20) Snyder, R. D.; Regan, J. D. Mutat. Res. 1981, 91, 307.
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E. E. Mutat. Res. 1986, 159, 55.
(26) Welch, C. J.; Biba, M.; Sajonz, P. Chirality. 2007, 19, 34.
(27) Wong, A.; Welch, C. J.; Kuethe, J. T.; Vazquez, E.; Shaimi, M.;
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(22) Glowienke, S.; Frieauff, W.; Allmendinger, T.; Martus, H.; Suter, W.;
Mueller, L. Mutat. Res. 2005, 581, 23.
(28) Welch, C. J.; Biba, M.; Drahus, A.; Conlon, D. A.; Tung, H. H.;
Collins, P. J. Liq. Chromatogr. Relat. Technol. 2003, 26, 1959.
(29) Oh, H. K.; Kwon, Y. B. J. Phys. Org. Chem. 1993, 6, 357.
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Vol. 14, No. 4, 2010 / Organic Process Research & Development