Mixed aqueous solutions as dilution media in the determination of residual solvents by static headspace gas chromatography

Abstract

Static headspace (HS) sampling has been commonly used to test for volatile organic chemicals, usually referred to as residual solvents (RS) in pharmaceuticals. If the sample is not soluble in water, organic solvents are used. However, these seriously reduce the sensitivity in the determination of some RS. Here, mixed aqueous dilution media (a mixture of water and an organic solvent like dimethyl formamide, dimethyl sulfoxide or dimethyl acetamide) were studied as alternative media for static HS-gas chromatographic analysis. Although it has been known that mixed aqueous dilution media can often improve sensitivity for many RS, this study used a systematic approach to investigate phase volumes and the organic content in the HS sampling media. Reference solutions using 18 different class 1, 2 and 3 RS were evaluated. The effect of salt addition was also studied in this work. A significant increase in the peak area was observed for all RS using mixed aqueous dilution media, when compared with organic solvents alone. Matrix effects related to the mixed aqueous dilution media were also investigated and reported. Repeatability and linearity obtained with mixed aqueous dilution media were found to be similar to those observed with pure organic solvents.

Determination of volatiles in pharmaceutical certified reference materials

“…For less polar or apolar samples, high boiling point solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) 2,34 and N,N-dimethylacetamide (DMA) 36 may be used. Since organic diluents seriously reduce the method sensitivity, 2 water is usually added to the organic phase to reduce K and increase C g .…”

“…Several are the reasons for determining the mass fractions of water and residual solvents in pharmaceuticals, including their influence on the physicochemical [1][2][3][4][5][6][7] and microbiological stability of raw materials and finished products, their potential toxicity [1][2][3]8 and also economic aspects 9 since their presence results in analyte mass fractions smaller than 100%. Residual solvents may be introduced in active pharmaceutical ingredients (API) during their synthesis, especially if the final purification step is carried out by crystallization in different solvents, as well as during drug products formulation and manufacturing.…”

“…The dissolved sample 27,35 is heated in a closed vial, an equilibrium is established between upper gas phase and lower liquid phase, 2 and then a fixed gas phase volume (i.e., only volatile components) is injected into the GC column. 8 In equilibrium, the residual solvent concentration in the gas phase (C g ) is expressed as: 2,34 …”

“…Since organic diluents seriously reduce the method sensitivity, 2 water is usually added to the organic phase to reduce K and increase C g . 2,37 Another alternative is the addition of salt solutions, e.g., 1 mol L -1 NaCl, to promote a "salting-out" effect of residual solvents. 34,37 Diluents shall be purged with nitrogen prior to use for 3, 37 4 2 or 24 h; 34 (ii) volume of diluent in the headspace vial: larger solution volumes inside the vial (smaller β values) can reduce C g (equation 1), 2 which is not desired; (iii) headspace temperature: an increase in the headspace temperature increases C g .…”

“…34 However, in case of water, the temperature is usually set to 80 ºC, i.e., 20 ºC below the water boiling point to avoid overpressure in the headspace vial. 2,37,38 For diluents like DMF (b.p. 153 ºC), 35 DMSO (b.p.…”