A New Method for Fast Residual Solvents Analysis and Untargeted Unknown Identification Faster Sample Throughput and Shorter GC Runtimes Using GC-VUV and Static Headspace

Jul 17 2017 Comments 0

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Volatile organic compounds are used in pharmaceutical manufacturing during the production of drug substances, pharmaceutical additives, and drug products. Known also as residual solvents, they account for 50-90% of mass in typical pharmaceutical operations and represent most of the process toxicity. These organic solvents can contaminate the drug product during its packaging, storage, and transportation. Testing for the presence of these solvents in Active Pharmaceutical Ingredients (API) is critical for patient safety and commonly follows Unites States Pharmacopeia (USP) Method <467> guidelines, or more broadly, International Council for Harmonization (ICH) Guideline Q3C(R6).

USP Method <467> recommends a 60-minute gas chromatography (GC) runtime for residual solvent analysis [1]. Class 1 and 2 solvents are additionally suggested to be analysed separately. VUV Analytics recently published an application note describing how the spectral deconvolution capabilities of VUV spectroscopy allow GC runtimes to be shortened from 60 minutes to 10 minutes or less [2]. Solvent classes can also be combined into individual analyses for increased sample throughput.

GC-VUV spectral data is inherently three dimensional (time, absorbance, wavelength) and specific to compound chemical structure. Most compounds absorb strongly in the VUV region (120 – 240 nm) of the UV spectrum measured by VUV detection. Photons in this wavelength range are capable of producing electronic transitions in virtually all chemical bonds, especially in ground state to excited state transitions such as σ→σ* and π→π*. The result is spectral signatures that are specific to each compound and can be readily identified by the VUV library [3]. This characteristic of VUV spectroscopy lends itself to intentional chromatographic compression due to the ability to deconvolve overlapping spectral responses.

A GC-VUV method that utilises static headspace sampling was developed for the analysis of all residual solvent classes (Class 1 – 3), as well as other solvents of interest. Significant gains in analysis productivity can be realised by decreasing total GC runtimes by greater than 5X. This capability is demonstrated here by condensing the runtime used in Class 3 residual solvent analysis. The GC-VUV method is also especially adept at identifying untargeted unknown analytes in pharmaceutical samples. An example is provided where an unexpected compound was detected in an over-the-counter hangover relief medication.



GC-VUV analysis was completed with the following setup:

Detector: VUV Analytics VGA-100 

Static Headspace Sampler: Gerstel MPS2

Gas Chromatograph: Agilent 6890 

Column: Restek 30m x 0.25mm x 1.40µm Rxi- 624Sil MS 

Experimental conditions for the gas chromatograph, static headspace sampler, and detector are provided below.

Gas Chromatograph

An Agilent 6890 gas chromatograph was used with its injection port set to 250°C. A helium carrier gas flow rate of 4 mL/min was used throughout the experiment. The oven profile for the residual solvent analysis began at 35°C (held for 1 min), followed by an increase to 245°C at a rate of 30°C/min. A split ratio of 2.5 was utilised to help maximise sensitivity. A total GC runtime of 8 minutes was programmed for each sample analysed.

Static Headspace Sampler

A Gerstel Multi-Purpose Sampler (MPS) was used to provide optimal temperature and injection setting automation and the most efficient delivery of residual solvent samples to the GC. The syringe temperature was held constant at 90°C. An incubation temperature of 80°C was set to best volatilise residual solvents while not going above the boiling point of water. The incubation time was set to 10 min to closely match the GC run time of 8 min. An injection volume of 250 µL was selected to ensure good peak shape. The agitator was 250 rpm (10 sec on, 1 sec off), and an injection speed of 200 µL/sec was used for sample introduction. 

VUV Detector

A VGA-100 gas chromatography detector manufactured by VUV Analytics was used in this experiment. The transfer line & flow cell temperatures were set at 275°C. The makeup gas pressure used was approximately 0.36 psi. An acquisition range of 120 to 240 nm was selected with an acquisition speed of 4.5 spectra/sec.

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Chromatography Today - June 2017 Volume 10 Issue 2

June 2017

In this issue: FUNDAMENTAL ASPECTS Development and Comparison of Quantitative Methods Using Orthogonal Chromatographic Techniques for the Analysis of Potential Mutagenic Impurities Develop...

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