• British Pharmacopoeia Volume V
  • Appendices

Appendix VIII T. Methyl Ethyl and Isopropyl Methanesulfonate in Active Substances

(Ph. Eur. method 2.5.38)

The following general method has been validated for the determination of methyl, ethyl and isopropyl esters of methanesulfonic acid (in concentrations between 0.2 ppm and 5 ppm) in betahistine mesilate.

If it is intended to use the method for other active substances, particularly those that contain different concentrations of the methanesulfonic acid esters, the concentrations of the test solution and reference solution must be adjusted accordingly and the method must be suitably validated.

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).

Solution A Dissolve 30 mg of anhydrous sodium thiosulfate R and 60.0 g of sodium iodide R in water R and dilute to 50.0 mL with the same solvent.

Internal standard solution Dilute 10 µL of butyl methanesulfonate CRS (BMS) to 10.0 mL with the solvent mixture. Dilute 20 µL of the solution to 10.0 mL with the solvent mixture. Dilute 10.0 mL of this solution to 100.0 mL with the solvent mixture.

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, then seal the vial immediately with a polytetrafluoroethylene-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 methanesulfonate R (MMS), ethyl methanesulfonate R (EMS) and isopropyl methanesulfonate R (IMS) in toluene R and dilute to 5.0 mL with the same solvent. Dilute 50 µL of the solution to 25.0 mL with the internal standard solution.

Reference solution (b) Dilute 20 µL 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 polytetrafluoroethylene-coated silicon membrane and an aluminium cap.

Reference solution (c) Dilute 500 µL 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 polytetrafluoroethylene-coated silicon membrane and an aluminium cap.

Column: 

  • material: fused silica;
  • size: l = 30 m, Ø = 0.25 mm;

Carrier gas helium for chromatography R.

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.

Temperature: 

bp2012_v5_47_08_[appendix_viii_t]_ep7-3 2538methylethylandisopropylmethanesulfonateinac_1_2013_73_tb.png


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; alternatively a suitable electron-capture detector may be used:

  • — 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:
bp2012_v5_47_08_[appendix_viii_t]_ep7-3 2538methylethylandisopropylmethanesulfonateinac_2_2013_73_tb.png


Injection 1 mL of the gas phase of the test solution and reference solutions (b) and (c).

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).

Calculate the content in parts per million of each alkyl methanesulfonate using the following expression:

bp2012_v5_47_08_[appendix_viii_t]_ep7-3 2538methylethylandisopropylmethanesulfonateinac_3_2013_73_eq.png


A1

 = 

area of the peak due to each alkyl iodide in the chromatogram obtained with reference solution (c);

A2

 = 

area of the peak due to each alkyl iodide in the chromatogram obtained with the test solution;

C

 = 

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.