The determination of residual solvents (RS), formerly called organic volatile impurities (OVI), in pharmaceutical products is probably the most important application of gas chromatography in pharmaceutical quality control. Recently, methods described in the U.S. and European Pharmacopoeia have been reviewed, updated, and harmonized according to ICH guideline Q3C (R3).1
Approximately 60 different solvents are typically in use in pharmaceutical manufacturing. This set of solvents covers a wide range of boiling points and polarities. According to ICH guideline Q3C, these solvents are divided into three classes. Class 1 includes benzene, carbon tetrachloride; 1,1-dichloroethane; 1,2-dichloroethylene; and 1,1,1-trichloroethane. These solvents are toxic and their use should be avoided. Class 2 solvents are less toxic, but their use should be limited. It is hoped that class 1 and 2 solvents will be replaced by class 3 solvents, which have low toxic potential to humans. Taking into account their relative toxicity, these solvents should be monitored in pharmaceutical products, including drug substances (or active pharmaceutical ingredients [API]) and drug products (formulations) at various levels, ranging from 2 ppm (2 μg/g drug substance) for benzene (class 1) to 0.05% (w/w = 5000 ppm) for class 3 solvents. Consequently, the analytical method(s) used to monitor these residual solvents in pharmaceutical products must also cover this range.
For the analysis of residual solvents, gas chromatography in combination with flame ionization detection (GC-FID) is normally used. Sample preparation and introduction is via static headspace (SHS).2,3 In this way, the (mostly) volatile solvents are introduced selectively, and the analytical system (inlet, column, and detector) is not contaminated by the (mostly) nonvolatile drug substance or drug product. For the separation, a thick-film, medium polar column (e.g., G43) is employed. Quantification is done versus an external standard.
Excellent quantitative data, including low limits of detection (LODs), high repeatability, and very good linearity, were obtained using the Agilent G1888 static headspace sampler (Agilent Technologies, Wilmington, DE) in combination with an Agilent 7890 GC.4 However, since no column can guarantee a unique retention time for a given solvent, confirmation analysis by GC-FID on a capillary column coated with a different stationary phase (e.g., G16) was performed. More recently, GC-MS was used successfully for confirmation/identification purposes.5,6
This paper describes a system configuration and operation conditions that allow the analysis of 56 solvents in a single run. Some solvents listed in the ICH guideline are not volatile (enough) and not amenable to SHS-GC analysis. Examples are formic acid, acetic acid, dimethyl sulfoxide (often used as method solvent), formamide, ethylene glycol, and sulfolane. The analysis of these impurities should be performed using other (liquid injection) methods, and their analysis is not discussed here.
For the analysis of residual solvents in pharmaceutical products, the drug substance or drug product is typically dissolved in a low-volatility (high-boiling) solvent such as dimethyl sulfoxide (DMSO); dimethyl acetamide (DMAC); or 1,3-dimethyl-2-imidazolidinone (DMI). For water-soluble drug substances, dissolution in water can also be used. In this work, a 100-mg drug substance was dissolved in 2 mL DMSO or DMSO:water (1:1) in a 20-mL headspace vial. Recently dedicated GC headspace-grade solvents were made available from Sigma-Aldrich (St. Louis, MO). DMSO, which is suitable for GC-SHS (cat. no. 51779), was used in this work. Calibration solutions were prepared in the same solvent at 0.15–15 ppm level for class 1 and 6–600 ppm level for class 2 and 3 solvents. All concentrations (ppm = μg/g) refer to the amount of drug substance (100 mg). The actual concentration of the standard in solution (μg/mL solvent) was a factor of 20 lower.
Figure 1 - SHS-GC-FID-MS system configuration.
The samples were analyzed using the SHS-GC-FID-MS configuration presented in Figure 1. Static headspace was performed using a G1888 HS autosampler. The transfer line of the headspace sampler was coupled to a standard split/splitless inlet. Separation was done on a J&W DB-1301 column (equivalent to G43). The column effluent was split using a purged splitter Capillary Flow Technology device to the FID and MS (Agilent 5975 MSD). The vial pressure was regulated by an Agilent AUX EPC channel. The purge at the splitter was also regulated by the AUX EPC (second channel). A 63 cm × 0.1 mm i.d. deactivated fused-silica capillary was used to connect the splitter to the mass selective detector (MSD); a 40 cm × 0.1 mm i.d. capillary was used to connect the splitter to the FID. Flows in both capillaries were approximately 1.4 mL/min, and the retention time was also similar (small offset between FID and MS retention times). The analytical parameters are summarized in Table 1.
Table 1 - SHS-GC-FID-MS analytical parameters