2-bromo butyric acid.
2-bromo butyric acid is a colorless liquid with a boiling point of 214–217 °C and density of 1.567 g/mL. 2-bromo butyric acid
was determined through derivatization with methanol to methyl-2-bromo butyrate. The method described earlier was used for
the determination of 2-bromo butyric acid.
For the derivatization of 2-bromo butyric acid with methanol, 32.45 μL of 2-bromo butyric acid standard was placed in a 100-mL
volumetric flask, and diluent was added up to the mark. The solution was refluxed for 4 h at 60–65 °C and then cooled to room
temperature. Next, 1.0 mL of refluxed solution was added to a 100-mL volumetric flask, and diluent was added up to the mark.
Figure 4: Selected concentration chromatogram for Bromo acetyl bromide and 1,6-dibromo hexane.
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Method for determining GTIs in salmeterol xinafoate.
Based on the route of synthesis for salmeterol xinafoate, bromo acetyl bromide and 1,6-dibromo hexane are suspected genotoxic
impurities. TTC values indicate the permitted level for both of these impurities is 1500 parts per million (ppm) (see Figure
4).
Bromo acetyl bromide and 1,6-dibromo hexane are colorless liquids with boiling points of 147 °C and 243 °C, respectively.
Their densities are 2.317 g/mL and 1.586 g/mL, respectively. Based on the properties of these impurities, wall-coated capillary
columns of various brands with various phases and dimensions were investigated. Nonpolar DB-WAX columns (30 m length, 0.53
mm i.d., Agilent J&W) with a stationary phase of polyethylene-glycol film of 1.0 μm are suitable for the determination of
bromo acetyl bromide and 1,6-dibromo hexane at these concentrations. A Perkin Elmer Clarus 500 autosampler was used for the
method development and validation. Oven temperature was maintained at 40 °C for 5 min, and a linear thermal gradient of 20
°C/min to 180 °C was used. A final hold lasted 10 min with 170 °C injector temperature and 250 °C detector temperature. Helium
was used as a carrier gas at a constant pressure flow rate of 3.0 psi. Operation mode was split (2:1).
Stock solutions of bromo acetyl bromide and 1,6-dibromo hexane were prepared and injected. Retention times were 1.988 min
for bromo acetyl bromide and 15.659 min for 1,6-dibromo hexane. The LOD and LOQ for bromo acetyl bromide were 30.33 ppm and
96.97 ppm, respectively. The LOD and LOQ for 1, 6-dibromo hexane were 100 ppm and 320 ppm, respectively. The LOD of bromo
acetyl bromide was 50 times lower than the selected concentration.
Figure 5: Chromatogram for mesylates.
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Method for determining GTIs in montelukast sodium.
The catalyst sulfonyl chloride is used to synthesize montelukast sodium, thus creating the possibility for the formation of
mesylates when reacted with alcohols. These mesylates are genotoxic, and permitted concentrations are at the 75-ppm level
(see Figure 5). Generally, mesylates are determined by gas chromatography–mass spectrometry–head-space sampling (GC–MS–HS)
at 1 ppm. Here, however, the permitted level is higher, so GC–MS–HS is unnecessary. GC–FID is suitable for the determination
of these GTIs in the selected concentrations. Depending upon the route of synthesis, the expected mesylates are methyl methane
sulfonate and isopropyl methane sulfonate.
Methyl methane sulfonate and isopropyl methane sulphonate are colorless liquids with boiling points of 202.5 °C and 220 °C
and densities of 1.3206 g/mL and 1.15 g/mL, respectively. Based on the properties of these impurities, wall-coated capillary
columns of various brands with various phases and dimensions were investigated. Nonpolar DB-1 columns (30 m length, 0.53 mm
i.d.) with a stationary phase of 100% and dimethyl polysiloxane film of 5.0 μm are suitable for the determination of mesylates
at these concentrations. A Shimadzu-2010 autosampler was used for method development and validation. Oven temperature was
maintained at 100 °C for 5 min, and a linear thermal gradient of 10 °C/min to 200 °C was used with a final hold of 5 min at
170 °C injector temperature and 250 °C detector temperature. Helium was used as a carrier gas at a constant pressure flow
rate of 3.0 psi. Operation mode was split (2:1).
Stock solutions of methyl methane sulfonate and isopropyl methane sulfonate were prepared and injected. Retention times were
10.021 min and 12.904 min, respectively. The LOD and LOQ were 4.38 ppm and 1.48 ppm for methyl methane sulfonate and 14.44
ppm and 4.87 ppm for isopropyl methane sulfonate, respectively.
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