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EUROPEAN PHARMACOPOEIA 8.

2.5.40. MTS, ETS and ITS in active substances

04/2015:20540 Column :
material : fused silica ;

2.5.40. METHYL, ETHYL AND


ISOPROPYL TOLUENESULFONATE IN
ACTIVE SUBSTANCES

size : l = 30 m, = 0.25 mm ;
stationary phase : polar-deactivated polyethyleneglycol R
(lm thickness 1 m).
Carrier gas : helium for chromatography R.

The following general method has been validated for the


determination of methyl, ethyl and isopropyl esters of
toluenesulfonic acid (in concentrations between 0.2 ppm and
5 ppm) in sultamicillin tosilate dihydrate.
If it is intended to use the method for other active substances,
particularly those that contain different concentrations of
the toluenesulfonic acid esters, the concentrations of the test
solution and reference solutions must be adjusted accordingly
and the method must be suitably validated.

The use of an inert inlet liner without glass wool significantly


reduces the effect of carry-over between the injections.
Flow rate : 0.5 mL/min.
Split ratio : 1:20.
Static head-space conditions that may be used :
equilibration temperature : 60 C ;
equilibration time : 30 min ;
transfer-line temperature : 120 C.

METHOD
Head-space gas chromatography (2.2.28) coupled with mass
spectrometry (2.2.43). Prepare the test solution and reference
solutions immediately before use.
Solvent mixture : water R, acetonitrile R (20:80 V/V). The use
of acetonitrile of appropriate purity is essential.
Solution A. Dissolve 30 mg of anhydrous sodium thiosulfate R
and 60.0 g of sodium iodide R in water R using sonication and
dilute to 50.0 mL with the same solvent.
Internal standard solution. Dilute 10 L of butyl
methanesulfonate CRS (BMS) to 10.0 mL with the solvent
mixture. Dilute 20 L of the solution to 100.0 mL with the
solvent mixture.
Blank solution. Introduce 0.5 mL of solution A and 0.5 mL of
the internal standard solution into a headspace vial and seal
the vial immediately with a polytetrauoroethylene-coated
silicon membrane and an aluminium cap.
Test solution. Weigh 25.0 mg of the substance to be examined
into a 20 mL headspace vial. Add 0.50 mL of solution A and
0.50 mL of the internal standard solution and seal the vial
immediately with a polytetrauoroethylene-coated silicon
membrane and an aluminium cap.
Following the derivatisation reaction, a precipitate may be
observed, however this does not affect the validity of the
quantification.
Reference solution (a). Dissolve 25.0 mg each of methyl
toluenesulfonate R (MTS), ethyl toluenesulfonate R (ETS) and
isopropyl toluenesulfonate R (ITS) in toluene R and dilute to
5.0 mL with the same solvent. Dilute 50 L of the solution to
25.0 mL with the internal standard solution.
Reference solution (b). Dilute 40 L of reference solution (a)
to 20.0 mL with the internal standard solution. Introduce
0.50 mL of this solution and 0.50 mL of solution A into a
20 mL headspace vial and seal the vial immediately with
a polytetrauoroethylene-coated silicon membrane and an
aluminium cap.
Reference solution (c). Dilute 500 L of reference solution (a)
to 20.0 mL with the internal standard solution. Introduce
0.50 mL of this solution and 0.50 mL of solution A into a
20 mL headspace vial and seal the vial immediately with
a polytetrauoroethylene-coated silicon membrane and an
aluminium cap.
General Notices (1) apply to all monographs and other texts

Temperature :

Column

Time
(min)
0-1

Temperature
(C)
40

1 - 10

40 130
220

Injection port
Detector

transfer line

280

source

250

analyser

200

At the end of analysis the temperature of the column is raised


to 240 C and maintained at this temperature for 7 min.
Detection : mass spectrometer as described below ; adjust the
detector settings so as to comply with the system suitability
criteria :
quadrupole mass spectrometer equipped with an electron
impact ionisation mode (70 eV) ;
mass spectrometer parameters for the fragmentometric
mode (single-ion monitoring (SIM)) set as follows :
Quantitation ion
(m/z)
184

Qualication ion
(m/z)
127

Methyl iodide (MeI)*

142

127

Ethyl iodide (EtI)*

156

127

Isopropyl iodide (iPrI)*

170

127

Substance
Butyl iodide (BuI)*

* formed from BMS, MTS, ETS and ITS in the derivatisation reaction.

Injection : 1 mL of the gas phase of the test solution, reference


solutions (b) and (c) and of the blank solution.
Relative retention with reference to the internal standard
(BuI) (retention time = about 8.5 min) : MeI = about 0.51 ;
EtI = about 0.63 ; iPrI = about 0.68.
System suitability :
resolution : minimum 1.5 between the peaks due to EtI
and iPrI in the chromatogram obtained with reference
solution (c) ;
signal-to-noise ratio : minimum 10 for the peak due to each
alkyl iodide in the chromatogram obtained with reference
solution (b).

4501

EUROPEAN PHARMACOPOEIA 8.4

2.5.40. MTS, ETS and ITS in active substances

Calculate the content in parts per million of each alkyl


toluenesulfonate using the following expression :

A1
A2
C

4502

= area of the peak due to each alkyl iodide in


the chromatogram obtained with reference
solution (c) ;
= area of the peak due to each alkyl iodide in the
chromatogram obtained with the test solution ;
= percentage content of each ester ;

I1

= area of the peak due to the internal standard


in the chromatogram obtained with reference
solution (c) ;
I2
= area of the peak due to the internal standard in the
chromatogram obtained with the test solution ;
W1 = mass of each ester used to prepare reference
solution (a), in milligrams ;
W2 = mass of the substance to be examined in the test
solution, in milligrams ;
0.05 = dilution factor.

See the information section on general monographs (cover pages)