Reliable determination of residual solvents Analytical challenges with pharmaceuticals, extracts, food and raw materials

Residual solvents are produced in numerous manufacturing processes, such as extraction, purification and synthesis, and they are also subject to strict regulatory requirements. Reliable determination of these substances therefore constitutes a central component of quality control in the pharmaceutical, food technology, and cosmetics industries.

However, the analysis of residual solvents poses particular challenges in complex product matrices, such as plant extracts, high-fat foods or pharmaceutical formulations.

Typical analytical challenges

In practice, the determination of residual solvents can be hampered by a number of different factors:

• complex matrices, such as botanical extracts, oils, or pastes
• a broad spectrum of possible solvents
• very low regulatory limits
• solvents with similar retention times
• different regulatory requirements in different industries

As far as manufacturers are concerned, this often means that standard methods cannot be applied to every product matrix without being modified. Meticulous method selection and optimization are therefore crucial in order to obtain reliable results.

Why determination of residual solvents is so important

Residual solvents can have different effects on different products. They may have toxicological relevance, affect stability or alter sensory properties according to the respective substance and concentration. At the same time, they are subject to binding limits, such as those imposed by ICH Guideline Q3C or laid down in food legislation.

Chemical analysis therefore fulfils several functions: ensuring compliance with regulatory limits, supporting quality assurance during production and providing indications of any deviations in the process.

Regulatory principles

The requirements to be met in the pharmaceutical sector are particularly stringent. ICH Guideline Q3C assigns solvents to three classes, according to their respective toxicological risk, and defines permissible limit values. Furthermore, pharmacopoeias, such as Ph. Eur. or USP, define methodological stipulations for the determination of residual solvents. Analytical methods must also be validated in accordance with the requirements of ICH Q2(R2).

Clearly defined stipulations also exist in the food sector, in the form of European regulations on extraction solvents or maximum levels defined for certain solvents, for instance. Raw materials and reference substances are frequently evaluated on the basis of product-specific specifications.

Analytical methods

Headspace GC (HS-GC)

Headspace gas chromatography has become established as the standard procedure for the determination of residual solvents. It not only enables sensitive analysis with relatively little sample preparation work, but is also suitable for solid, liquid, and pasty matrices.

Flame ionization detectors (FID) or mass spectrometers (MS) are frequently used as detectors. MS detection is particularly useful for complex matrices or for confirming identity.

Direct injection (GC-DI)

Alternatively, direct injection can also be used in gas chromatography if solvents are only moderately volatile, for example, or headspace technology is unsuitable. However, this method leads to increased matrix loading of the system.

Validation and verification

Complete method validation is required for pharmaceutical applications. The assessment evaluates various properties, including specificity, linearity, accuracy, precision, limits of quantification and robustness.

Method verification is necessary when pharmacopoeia methods are adopted or validated methods are transferred to new matrices. The purpose of this is to obtain evidence to prove that the method also works reliably for the product matrix concerned.

Practical solutions

A number of different strategies are frequently used to meet analytical challenges. They include product-specific methods for problematic matrices, optimization of headspace parameters and use of MS detection for better identification of individual solvents.

It may also be necessary to adopt matrix-adapted calibration strategies. Multimethods that offer an efficient means of covering a broad spectrum of solvents are also being used to an increasing extent.

Conclusion

Determination of residual solvents is an integral element of quality control in many industries. Complex product matrices, diverging regulatory requirements, and a broad range of possible solvents place high demands on chemical analysis.

Headspace GC has become established as a reliable standard method, but there are certain sample matrices that require adapted or specialised sample preparation routines and alternative measurement techniques. Appropriate method selection and meticulous validation or verification are crucial in order to obtain reliable results.