Introduction

Residual solvents are typically introduced during the production of active pharmaceutical ingredients (APIs), excipients, or drug products, and are not completely removed during purification. They are one of three major impurity classes in pharmaceuticals, alongside organic and inorganic impurities. Solvents play essential roles in synthesis, influencing drug properties such as crystallinity, purity, and solubility. However, residual solvents provide no therapeutic benefit and should be removed to the greatest extent possible.

The International Council for Harmonisation (ICH) classifies residual solvents into three categories based on human and environmental toxicity. Prior to 2008, the United States Pharmacopeia (USP) only specified limits for chloroform, dioxane, methylene chloride, and trichloroethylene. To align with ICH guidelines, USP revised General Chapter <467>, effective July 1, 2008. This chapter now includes comprehensive lists of Class I, II, and III solvents, specifying their limits and the processes for identification, confirmation, and quantification (referred to as Procedures A, B, and C, respectively). This chapter applies to any substance that is or contains a solvent, as well as to all manufacturers of excipients, drug substances, and drug products.

USP <467> recommends the use of headspace sampling coupled with gas chromatography equipped with a flame ionization detector (GC-FID) for residual solvent analysis. The chapter outlines three testing procedures: screening (Procedure A), confirmation (Procedure B), and quantification (Procedure C). If the solvents used in the manufacturing process are known, only quantification (Procedure C) is required. If the solvents are unknown, all three procedures must be performed. If only Class III solvents are used in the manufacturing process, a loss-on-drying method may be sufficient. However, if Class II solvents are present, chromatographic methods are recommended.

Experimental

Analyses were performed using a PerkinElmer Clarus 600 GC equipped with an FID detector and a TurboMatrix HS-40 headspace sampler. The TurboMatrix HS-40 is a pressure-balanced headspace sampler that calculates sample collection volume based on the volume of sample vapor flowing into the analytical column at a known flow rate over a defined time period. Compared to other headspace techniques, the TurboMatrix HS provides a simpler and more inert flow path, resulting in more accurate results. This technology eliminates the need for gas valves or other moving parts, reduces sample contact with hot metal surfaces, and minimizes maintenance of moving components. The TurboMatrix HS features a multi-position heating oven with overlapping temperature control. This overlapping heating function automatically optimizes the start of heating, allowing sample analysis to begin immediately once the GC oven is ready, thereby improving sample throughput.

The rapid cooling rate of the Clarus 600 GC allows for fast turnaround times between runs, which is particularly beneficial for analyses requiring initial oven temperatures near ambient.

Discussion

In this application, optimized chromatographic methods and run times were developed to analyze solvents listed in USP <467>. Each solvent was completely resolved on both G16 and G43 columns. In addition to separation on different columns, the use of different diluents for analyzing Class I, II, and III residual solvents was investigated. The choice of diluent is critical during method development. Factors to consider include the solubility of the material and analytes, boiling points, and the solvents used during the manufacturing process. Analyte response varies with different diluents; therefore, selecting the appropriate diluent is essential to achieve optimal response and resolution. Some solvents, particularly when water is used as the diluent, show excellent response. However, for some analytes, such as polar compounds, organic diluents may be more suitable.

Procedures A and B – Identification and Confirmation of Residual Solvents in Materials

Procedure A is used to identify residual solvents in pharmaceutical substances. In this procedure, all solvents are first analyzed using a G43 column under the specified conditions. Figures 1, 2, and 3 show the results obtained with different diluents.
Figures 1:Use water as diluent and analyze Class I residual solvents with G43 column.

Figures 2:Use 1,3-Dimethyl-2-imidazolidinone as diluent and analyze Class II residual solvents with G43 column

Figures 3:Use N-methylpyrrolidone as diluent and analyze Class III residual solvents with G43 column

Procedure C – Quantification

After identification and confirmation through Procedures A and B, residual solvents in pharmaceutical substances are quantified. Separation conditions are optimized specifically for the compounds of interest.

Conclusion

This study successfully demonstrated the identification, confirmation, and quantification of all Class I, II, and III residual solvents. All analyte groups were resolved while maintaining analytical efficiency. Additionally, different diluents were tested on both G43 and G16 columns for analyzing all typical residual solvents. The selection of diluents was based on the solubility of the test samples and the boiling points of less volatile solvents. The combined selectivity of different columns enabled the separation of all Class I, II, and III solvents.

Ready to optimize your headspace GC analysis?

Product List：Headspace Vial
Request a Quote：Contact Us
Technical Support ：jkus@jk-sci.com

Related articles：

• The Complete Guide to USP <467> Residual Solvent Testing: Headspace Vial Selection and Usage
• Headspace Vials for GC & GC-MS Applications: High-Quality 20 mL Vials for Residual Solvent Analysis
• Headspace Gas Chromatography: A Comprehensive Overview
• Best Vials for Pharmaceutical QC Headspace Analysis
  
• Minimize Background Noise in USP <467> Residual Solvent Testing | Best Practices