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Efficient Determination of Trace Thionyl Chloride in the Antiepileptic Levetiracetam by Pyrolysis Combined with Ion Chromatography

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Shaorong Luan
Shaorong Luan
Shaorong Luan
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Pengyu Liu
Pengyu Liu
Pengyu Liu
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Fangfang Zhang
Fangfang Zhang
Fangfang Zhang
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Lijun Ni
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Abstract and Figures

A method involving pyrolysis pretreatment followed by ion chromatography was developed to determine the residual thionyl chloride in levetiracetam. Levetiracetam was combusted at high temperature. After the pyrolysis gas was absorbed, the sulfur in thionyl chloride was converted to sulfate, which were determined by ion chromatography with conductivity detector using potassium hydroxide as the mobile phase. The linearity, limits of detection and quantification, and recovery of the method were evaluated. The average rate of conversion of thionyl chloride to sulfate was 98.2%, indicating good conversion efficiency. The limit of detection for sulfate was 8.85 μg/L. The relative standard deviation of the amount of SOCl2 calculated based on the concentration of sulfate was 2.70%, indicating good repeatability. The recovery for sulfate was 96.0–104%. The results suggest that pyrolysis combined with ion chromatography is an effective method to determine residual thionyl chloride in levetiracetam.
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Vol.:(0123456789)
1 3
Chromatographia (2020) 83:1391–1395
https://doi.org/10.1007/s10337-020-03951-7
ORIGINAL
Ecient Determination ofTrace Thionyl Chloride intheAntiepileptic
Levetiracetam byPyrolysis Combined withIon Chromatography
ShaorongLuan1 · PengyuLiu1· FangfangZhang3· LijunNi1· QingchunHuang2
Received: 28 February 2020 / Revised: 14 May 2020 / Accepted: 1 September 2020 / Published online: 18 September 2020
© Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
A method involving pyrolysis pretreatment followed by ion chromatography was developed to determine the residual thionyl
chloride in levetiracetam. Levetiracetam was combusted at high temperature. After the pyrolysis gas was absorbed, the sulfur
in thionyl chloride was converted to sulfate, which were determined by ion chromatography with conductivity detector using
potassium hydroxide as the mobile phase. The linearity, limits of detection and quantification, and recovery of the method
were evaluated. The average rate of conversion of thionyl chloride to sulfate was 98.2%, indicating good conversion effi-
ciency. The limit of detection for sulfate was 8.85μg/L. The relative standard deviation of the amount of SOCl2 calculated
based on the concentration of sulfate was 2.70%, indicating good repeatability. The recovery for sulfate was 96.0–104%.
The results suggest that pyrolysis combined with ion chromatography is an effective method to determine residual thionyl
chloride in levetiracetam.
Keywords Thionyl chloride· Levetiracetam· Pyrolysis· Ion chromatography
Introduction
Epilepsy is a common disease that is widely distributed all
over the world [1]. Antiepileptic drugs are generally amide
nootropics or cholinergic agonists. To date, antiepileptic
drugs such as oxiracetam, aneracetam, praxitan, leveti-
racetam, neiracetam, and nefexitan have been developed [2].
Among them, levetiracetam is the only antiepileptic drug
that has been shown to combine with synaptic vesicle pro-
tein SV2A in presynaptic nerve endings, which can inhibit
abnormal discharge in the epileptic loop and block the epi-
leptic attack [3]. The antiepileptic effect of levetiracetam is
obvious, and the side effects are minor. Levetiracetam can be
rapidly and nearly completely (> 95%) absorbed with high
bioavailability and a good therapeutic index. Thus, leveti-
racetam is a widely used and patient-friendly drug, not only
for epilepsy, but also with axiolytic activity, distinguishing
it from other currently available antiepileptic [4,5].
The preferred route for levetiracetam synthesis in indus-
trialized production is to use
l
-methionine as starting mate-
rial to obtain levetiracetam through esterification, amidation,
cyclization, and desulfurization methylation, overcomes the
major disadvantages such as the racemization and excessive
hydrolysis [6,7]. Some new technology uses the 2-aminobu-
tanamide hydrochloride as raw material to act with 4-chlo-
rophenyl chloride. This route is convenient and cheaper for
the industrial production of levetiracetam. In the process
route, thionyl chloride (Fig.1) is used to protect the amino
group and remove the water produced during the esterifica-
tion reaction, thereby improving the yield of the reaction [8].
However, the residual thionyl chloride in levetiracetam is
harmful to the human body when the medicine is inhaled or
taken orally. Thus, effectively limiting and accurately quan-
tifying the content of thionyl chloride in levetiracetam are
of critical importance.
Many methods including argentometry, nephelometry,
and iodimetry have been established for the detection of
thionyl chloride. However, these methods are not accurate
for quantitative analysis and have poor specificity [9–11].
* Shaorong Luan
srluan@ecust.edu.cn
1 School ofChemistry andMolecular Engineering, East China
University ofScience andTechnology, Shanghai200237,
China
2 Shanghai Key Lab ofChemical Biology, School
ofPharmacy, East China University ofScience
andTechnology, Shanghai200237, China
3 Thermo Fisher Scientific (China) Co. Ltd., Shanghai201203,
China
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