Residual solvents in pharmaceuticals are volatile organic compounds used or created during the manufacture of drugs and pharmaceutical additives. Manufactures are forced by regulation to ensure pharmaceuticals are free from toxicologically significant levels of volatile organic compounds. Typically, headspace gas chromatography is employed (GC) for this task, and often together with identification and quantification using mass spectrometry (GC-MS).
Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process.
In 1988, the United States Pharmacopoeia (USP) provided control limits and testing criteria for seven organic volatile impurities (OVIs) under official monograph USP <467> Residual Solvents. The compounds were chosen based on relative toxicity and only applied to drug substances and some excipients. They have since extended the compound list in General Chapter <467> Residual Solvents, and harmonized their efforts by aligning limits with the International Council for Harmonization (ICH) guidelines ICH Q3C Guideline for Residual Solvents.
Allowable limits or Permitted Daily Exposure (PDE) for residual solvents are defined in ICH Q3C. The PDE is based on the toxicity of the solvent. Solvents are defined into three class:
|Class||PDE (mg/day)||Solvent Concentration Limit (ppm)|
ICH Q3C and USP <467> are harmonized in their approach with a salient exception: whereas ICH Q3C applies only to new drug products, USP <467> applies the same requirements to all new and existing drug products.
To meet low levels in regulated analytical protocols, many modern methods employ valve and loop style headspace auto-samplers, gas chromatographs with flame ionization or mass spectrometric detection and compliant chromatography data software.
For more information on these technologies, please visit our Volatile Organic Impurities section of web content.
A key stage in many pharmaceutical processes is the complete or partial removal of a solvent or solvents from a product or intermediate. This drying process can occur in a variety of process vessels, including vacuum dryers, tray dryers and rotary dryers. Many API drying processes involve the removal of two or more solvents from a potential list of over thirty compounds. This requires complex chemometric modelling to turn the spectroscopic data into process friendly concentration data. Gas analysis by MS offers significant advantages of simplicity in both sampling and data manipulation for the solvent drying application.
Water is the most common solvent to dissolve a drug formulation in for residual solvent deteremination; however many drug APIs or formulations are insoluble in water. Consequently headspace grade solvents are required. Here we evaluate five different solvents for headspace GC analysis. The solvents are water, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and 1-methyl-2-pyrrolidinone (NMP).
This application note describes the use of the new Thermo Scientific TriPlus 500 Headspace autosampler, which is based on Valve-and-Loop technology, for the analysis of residual solvents in accordance with USP method <467>. Discover the benefits of direct column connection and highly precise pneumatic control in delivering the best analytical performance, combined with this autosampler's routine grade robustness.
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|Application Note||Generating Reliable Quantitative Solvent Drying Process Data in the Pharmaceutical Industry||Process Analytical||2014|
|Application Note||Routine-grade Residual Solvents According to USP 467||Gas Chromatography||2018|
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|Article||Detecting impurities in drugs by Orbitrap MS||Gas Chromatography Mass Spectrometry||2016|
|Blog||Doctor, Doctor My Pills Smell of Residual Solvents||Gas Chromatography||2015|
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|Case Study||Sanofi evaluates and recommends new "flexible and user friendly" GC system||Gas Chromatography||2012|
|Case Study||Case Study SGS on Enhanced Productivity and Reliability in Pharmaceutical Laboratories||Pharmaceutical||2019|
|Poster||Analysis of residual solvents using GC/FID with headspace and a cyanopropylphenyl polysiloxane phase||Chemistries and Consumables||2010|
|Poster Note||Headspace Grade Solvents for Trace Level Analyte Detection||Chemistries and Consumables||2016|
|Technical Note||Simplified, Cost-Effective Headspace GC Method for Residual Solvents Analysis in Pharmaceutical Products||Gas Chromatography||2019|
|Technical Note||Routine-Grade Quantitative Performance of TriPlus 500 HS Coupled to TRACE 1310 GC-FID||Gas Chromatography||2018|
|Webinar||Pharmaceutical Impurity Profiling: Simple, Confident Analysis with New GC-MS Technology (AstraZeneca)||Gas Chromatography Mass Spectrometry||2015|