Residual Solvents by USP <467>
USP <467> contains limits for residual solvents in pharmaceutical substances along with procedures for measuring residual solvent concentrations. Residual solvent limits are based on their toxicity and hazards. Solvents are ranked into one of three classes: compounds in Class 1 are considered the most toxic/hazardous. Compounds in Class 3 are considered the least toxic/hazardous. The general chapter also contains three procedures for measuring residual solvent concentrations. A list of the solvents in the scope of USP <467> is presented in the Appendix of the general chapter.
The methodology is given in USP <467>. Three (3) procedures each are given for water soluble and water insoluble articles. One of the three procedures must be used according to decision criteria given in the general chapter.
USP <467> relies on Gas Chromatography – Flame Ionization Detection (GC-FID) for analysis. Click here to see more information on GC-FID.
Each of the procedures in USP <467> can be characterized as follows:
- Procedure 1: Analysis of the test solution and comparison to an external standard
- Procedure 2: Analysis of the test solution on a secondary column and comparison to an external standard
- Procedure 3: Quantification of the analyte solvent
LC instruments are externally calibrated with the use of approximately 5 calibration standards. Sample solutions are injected onto the column and are separated based on their relative affinity for the stationary (column) and mobile phases. Components of the analysis solution are detected using one of the available detectors to provide a sample chromatogram. The area under the desired (target) peak(s) is integrated and is compared to the calibration curve to provide the concentration.
Unless otherwise evaluated, the quantitation limit (QL) depends on the concentration of the lowest calibration standard used to calibrate the instrument. Results that read below the QL are reported as less than values, i.e <50 ppm.
Results are reported using the mass of sample originally taken for the analysis. Typical reporting units are ppm, mg/L, or %. Other units may be reported.
The general methodology is suitable for the analysis of regulated samples. The method is considered validated to a reference substance, but not to the sample matrix unless a formal validation is conducted. Click here to see more information on Method Validation.