Simultaneous Analysis of Class 1, 2A and 2B Residual Solvents in Pharmaceuticals via HS-GCMS

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Residual solvents in pharmaceuticals are defined as volatile organic chemical substances used or generated in a drug substance or pharmaceutical additive and formulation processes. They are classified for administrative purposes from Class 1 to Class 3 based on their risk to human health.
In the GC-HS method prescribed in the United States Pharmacopeia (USP) General Chapter <467>, Residual Solvents, analysis of solvents must be performed three times for each class. However, using the HS-GCMS method introduced here allows solvents in all three classes to be analyzed in a single measurement. This method also provides qualitative information about unknown peaks.

Due to the mass selectivity offered by GC-MS, the HS-GCMS method achieves quantitation of peaks that cannot be separated sufficiently by GC. A set of chromatograms is shown in Fig. 1. Favorable results were obtained by SIM analysis with repeatability of 1.3 to 3.9 % RSD (Table 1).

Fig. 1 TIC Chromatogram of 27-Compound Mixture

Table 1 Repeatability of 27 Compounds

   Name  Abbreviation  Class  R.T.  Conc. (μｇ/ml)  AREA RED (%)
1  Methanol  MeOH  CLASS　2A 2.321 3.03 3.83
2  1,1 Dichloroethylene  11DCEy  CLASS　1 3.618 0.018 2.79
3  Acetonitrile  AcNt  CLASS　2A 4.107 2.85 3.29
4  Dichloromethane  DCM  CLASS　2A 4.411 27.0 2.78
5  trans-1,2 Dichloroethylene  trans-12DCEy  CLASS　2A 4.908 14.6 2.60
6  Hexane  C6  CLASS　2B 5.477 0.52 3.38
7  Nitromethane  NtMe  CLASS　2B 7.025 0.82 2.44
8  cis-1,2 Dchloroethylene  cis-12DCEy  CLASS　2A 7.216 5.05 2.49
9  Tetrahydrofuran  THF  CLASS　2A 7.918 3.12 2.12
10  Chloroform  CRF  CLASS　2B 8.304 1.97 2.67
11  1,1,1-Trichloroethane  111TCEa  CLASS　1 8.728 0.033 2.61
12  Cyclohexane  cycC6  CLASS　2A 8.939 24.1 2.27
13  Carbon tetrachloride  CCl4  CLASS　1 9.24 0.045 1.62
14  Benzene  Bz  CLASS　1 10.018 0.064 2.01
15  1,2-Dimethoxymethane  12DMOEa  CLASS　2B 10.222 0.42 2.74
16  1,2-Dichloroethane  12DCEa  CLASS　1 10.358 0.085 2.30
17  Trichloroethylene  TCEy  CLASS　2B 13.293 0.42 1.56
18  Methylcyclohexane  mecycC6  CLASS　2A 14.509 8.72 1.69
19  1,4-Dioxane  14-D  CLASS　2A 15.501 6.15 2.54
20  Pyridine  Pry  CLASS　2B 21.644 1.67 3.29
21  Toluene  Tol  CLASS　2A 22.354 7.00 1.56
22  n-Butyl methyl ketone  MBK  CLASS　2B 25.172 0.83 1.34
23  Chlorobenzene  ClBz  CLASS　2A 26.884 2.92 1.28
24  Ethylbenzene  EB  CLASS　2A 27.221 1.47 1.41
25  m,p-Xylene  m,p-X  CLASS　2A 27.542 2.48 1.41
26  o-Xylene  o-X  CLASS　2A 28.362 10.3 1.66
27  Tetralin  Sulfln  CLASS　2B 34.516 0.65 1.77

Headspace Analysis System: Environment, Foods, and Chemical Product Analysis

Volatile components in liquids and solids can be analyzed by using headspace analysis. The term headspace refers to the space atop an object. Constituent compounds with particularly low boiling points are found at the top of liquids and solids. With a headspace sampler, a sample sealed in a vial is heated for a set time so that the sample reaches equilibrium with its gas phase. This gas component (headspace) is then introduced to a gas chromatograph for analysis. Headspace samplers are used to qualitatively and quantitatively analyze aromatic components in foods, components with noxious odors in chemical products, and toxic volatile components in environmental waters.