Residual solvents are volatile organic compounds employed in the synthesis of complex drug products, including nanomedicines, as well as in the manufacturing of active pharmaceuticals ingredients (APIs), excipients and finished dosage forms [1] [2] . Choosing the right solvent for synthesizing a drug substance or excipient can improve the yield and influence characteristics like crystal form, purity, and solubility. Thus, the solvent can be a crucial component in the synthesis process and might not be entirely eliminated during manufacturing. Since residual solvents offer no therapeutic benefit, they should be removed as much as possible to meet safety-based limits, ingredient and product specifications, good manufacturing practices, and other quality-based requirements [2] .

The primary method for analyzing residual solvents is gas chromatography, utilizing various sample introduction techniques, such as static or dynamic headspace analysis, solid phase microextraction, or direct injection of the analyte into the GC [3] [4] .

There are several studies available for the detection of residual solvents in pharmaceuticals products by GC [3] - [5] . Most studies cover four to five solvents for identification by a single method. This method covers most solvents commonly used in the pharmaceutical manufacturing. It is possible to identify and quantify nine solvents in a single method in the shortest possible time.

The sample is adsorbed onto the stationary phase of the column and then separated by the carrier gas flowing through the column, based on polarity. The carrier gas will be an inert gas, such as helium or nitrogen with more than 99.99% purity. Liquid samples are vaporized prior to being injected into the carrier stream. Substances that have greater interaction with the stationary phase remain in the column longer and are thus separated from those with less interaction. Therefore, compounds eluted from the column at different times, based on their polarity, are detected by detectors, resulting in an enhanced signal. Different compounds have varying retention times (RT) based on their polarity. The response of GC detectors is proportional to the concentration of the analyte in the sample introduced. Various types of detectors used include flame ionization detectors (FID), thermal conductivity detectors (TCD), electron capture detectors (ECD), nitrogen-phosphorus detectors (NPD), and mass detectors (in both single and triple quadruple modes) [5] .

The aim of this study is to develop a cost-effective gas chromatographic method for identification and quantification of some commonly used solvents—methanol, acetone, IPA, methylene chloride, ethyl acetate, THF, benzene, toluene and pyridine—in pharmaceutical product manufacturing. This method will facilitate the identification and quantification of multiple solvents in a single gas chromatographic procedure. This simple method will help to rapid release of drug substances and products and is easy to maintain good documentation practices (GDP) contemporaneously. All analytical methods should be validated as per pharmacopeia or ICH guidelines before use [6] .

All the chemicals used in this study are reagent grade. GC analysis is very sensitive to detection, so GC grade chemicals and standards should be used for analysis. Some unknown peaks were observed in the chromatograms. However, no other peaks were detected at the retention times of methanol, acetone, IPA, methylene chloride, ethyl acetate, THF, benzene, toluene, and pyridine in the blank solution. Therefore, no interference was found from the blank with the targeted peaks indicating that the method is specific for the respective solvents. From the precision study, it was observed that this method gives reproducible results. The %RSD found from the six replicate injections is less than 10.0. The recovery results of sample solutions were satisfactory and the recovery was between 80.0% and 120.0%.

To develop a simple, cost-effective GC method for the identification and quantification of nine residual solvents, this study was conducted. According to pharmacopeia and ICH guidelines, residual solvents are divided into 3 categories: class 1, class 2, and class 3. Class 1 solvents should be avoided, class 2 solvents should be limited, and class 3 solvents are less toxic and pose lower risk to human health. If only class 3 solvents are used in manufacturing process, a loss on drying (LOD) test with a 0.5% limit would be acceptable. If multiple category solvents are used in manufacturing process, they should be identified and quantified within the specified limits as per guidelines. This method was developed considering these three categories of solvents. Pharmaceutical manufacturing companies, quality control scientists, and researchers will benefit from this method. Additionally, it can serve as study material for students learning about method development through headspace gas chromatography. This method can be employed to quantify residual solvents—methanol, acetone, IPA, methylene chloride, ethyl acetate, THF, benzene, toluene, and pyridine—in drug substances and drug products. The developed method is precise, specific, and accurate, and should be validated according to ICH guidelines before being used to release the commercial products.

This research proposal and plan was initiated by Sreekanta Nath Dalal and the amount of publication fees were provided by Sreekanta Nath Dalal.

This research was designed and performed by Sreekanta Nath Dalal. The co-author reviewed the content, data presentation, and overall layout of the study.

The current research does not include any studies involving animal or human subjects conducted by any of the authors.