A simple and sensitive method for the simultaneous determination of methanol, ethanol, iso propyl alcohol(IPA), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), n-propyl alcohol (n-PA), ethyl acetate (EA), n-butanol, n-propyl acetate (n-PAc), toluene and ortho-xylene by headspace techniques with FID detection is described. An efficient and sensitive method was successfully developed and validated for the determination of above mentioned solvents of varying polarity used as residual solvents from printing ink.
Based on Good Manufacturing Practices, measuring residual solvents is mandatory for the release testing of all active chemical ingredients. The method was validated for repeatability, linearity, limit of detection, limit of quantification and recovery according to the International Conference on Harmonization guidelines. The method validation results indicate that the method is accurate, precise, linear and sensitive for solvents assessed in the printing ink. Excellent results were obtained, within the globally accepted validation reference values, particularly taking into account the low concentration levels investigated.
Key Words: Validation, residual solvents, GC-HS, printing ink, volatiles.
* Corresponding Author: pallavi.gupta24192gmail.com
Abbreviations: Iso propyl alcohol (IPA), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), n-propyl alcohol (n-PA), ethyl acetate (EA), n-butanol, n-propyl acetate (n-PAc),ortho-xylene (xylene).
Residual solvents or organic volatile impurities are a potential toxic risk of pharmaceutical [1] or any other food-related products, whether it is packaging laminates of food as itself, and have been a concern of manufacturers for many years. Moreover, residual solvents can also affect the quality and stability of not only drug substances [2] but also packaging laminates of food as itself.
Thus, acceptable levels of many solvents are included in regulatory guidance documents, in particular in guideline Q3C issued by the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH)[3].
The technique of static headspace gas chromatography has great acceptance in the chemical industry, especially for determination of solvents in printing inks and laminating films. Most chemical industries in the world have this equipment and perform this analysis on a routine basis, but in many of these laboratories, the equipment is exclusively employed to determine solvents, even when this technique can be used to determine many other substances of toxicological interest, such as volatile substances, without major changes to the equipment. We can conclude that these laboratories do not exploit all the possibilities of the technique.
Determination of residual solvents using GC with a flame ionization detector (FID) is the most common technique in the pharmaceutical industry as well as the chemical industry because of its high separation efficiency and sensitivity for volatile organic compounds. The headspace gas chromatography (HS-GC) method has been used for the determination of residual solvents in pharmaceutical compounds [4,5] and also packaging laminates of food.
The determination of volatile substances is one of the most important tests in chemical toxicology. Volatile substances can be defined as those organic compounds whose vapor pressures are greater than or equal to 0.1 mm Hg at 20°C. The determination of volatile substances in polymeric samples has been carried out through titrations, spectrophotometric methods and chromatographic methods. Titrations and spectrophotometric methods are not specific and usually lack sufficient sensitivity, besides not being able to analyze simultaneously all the volatile substances.
In contrast, gas chromatography is qualitative (by the use of retention time) and quantitative (by the use of signal strength), so it is able to analyze simultaneously several volatile substances with the adequate sensitivity and specificity necessary in chemical environments.
The authors have tried to validate a method by using gas chromatography to analyze volatile (%) and residual volatiles. This paper demonstrates a thorough study to establish a validated method for analysis involving volatiles quantitatively and qualitatively.
All gas chromatography experiments were conducted with Perkin Elmer Clarus 500, Headspace Turbo matrix 16 Auto-samplers.
The chromatographic oven temperature program was as follows: the initial temperature of 40°C was held for 8 minutes, 15°C/min to 100°C and 25°C/min up to 250°C and FID Detector temperature set at 260°C. Column used Elite-5 (Cross bond 5% diphenyl-95% dimethyl polysiloxane) length 30 meter, diameter 0.25mm ID, thickness 0.25 micrometer. Nitrogen as carrier gas with 22.8 cm/sec, flow rate of hydrogen was 40ml/min, Air was 400ml/min and sample flow rate was 1ml/min.
Headspace conditions of the oven temperature were set at 90°C and Needle temperatures were 100°C. The pressurization time was 1 min and the Transfer line temperature was 110°C.
A. Material GC-HS analysis was carried out by using analytical grade (AR) solvent with purity of more than 99% such as methanol (99.5%), ethanol (97.5%), IPA (99.7%), n-propyl alcohol (99.7%), MEK (99.5%), EA (99%), n-butanol (99.5%), n-propyl acetate (98%), MIBK (98%), toluene (99.5%), xylene (97%) and HPLC water used as a diluents.
B. Method of preparation of Sample
a) Preparation of Stock solution: 1 g of each solvent weighed accurately and calculated the concentration involved in the analysis shown in Table 1 used as a stock solution.
b) Dilution: – Stock solution was diluted to varying concentrations used for analysis, where varying volume (1ml, 3ml, 5ml) of stock has been taken in GC/HS (20 ml) vial and diluted with 10 ml water varying concentrations shown in Table 1. Water was used as a preferred solvent as a standard, because of its polarity and compatibility with all solvents.
c) Concentration of each solvents: Concentration of all solvents has been calculated as per the standard calculation procedure as shown in Table 1.
Transfer the above prepared diluted three base concentration into GC-HS vials (20 ml) sealed and crimped. Each of the vials contains 10-50 ppm of methanol, 10-50 ppm of ethanol, 10-50 ppm of IPA, 10-50 ppm of n-propyl alcohol and 10-50ppm of other solvents with respect to the sample. The vials have 10ml water containing solvents at different concentrations; the vials are kept at 60°C injector temperature in headspace since a sufficient flow must be maintained through the system to avoid excessive peak broadening.
In this study, a HS-GC analytical method was developed and validated for the quantitative determination of the all the solvents methanol, ethanol, IPA, MEK, MIBK, EA, n-butanol, n-propyl acetate and so on. The proposed method uses the standard addition technique with internal standard quantization for determination of eleven solvents. The method was validated as per food safety regulation defined quantitation, linearity, range, precision (system repeatability), recovery and robustness (changes in HS and GC conditions and solution stability) were determined.
Excellent results were obtained, within global validation reference values, particularly taking into account the low concentration levels investigated. The test method was validated and had good Repeatability [Table 2], relative standard deviation RSD and linearity (%) [Table 3 and 4] and linearity [Figure 01, 02 and 03 and Table 4] for the solvents used for the current study.
The recovery was good and justified the preparation of the standard in water without the product as matrix. The linear range and correlation coefficients were determined between 10-50 ppm of each solvent.
The concentration of residual solvents (ppm) determined using the formula for solvent (Equation 1).
The ELITE-5 column, in the 30 m x 0.32 mm I.D. configuration, was chosen because this column has a standard stationary phase, which is recommended by the European and American Pharmacopeias, and has provided baseline of all solvents used in the validation, including the diluent (water). The method showed good peak shape, and the narrow peak width resulted in excellent column efficiency. The blank chromatogram did not show any interference with the solvent peaks.
To carry out this study, three concentrations were prepared for each solvent. All concentrations were prepared in triplicate, by individually weighing of solvents. The experimental results were represented graphically to obtain a calibration curve and carry out the corresponding statistical study (Anova). The method is linear within a wide range for the solvents included in the validation.
The correlation coefficients were all above 0.99 and linear regression showed a positive response throughout the range [Figure 2 and 3; Table 4]. The specified range is normally derived from linearity studies and depends on the intended application of the procedure[6]. In this paper it was characterized as the interval between the lowest (8 ppm) and highest (50 ppm) concentration, which can be determined using a given method, with assumed precision, trueness and linearity. This method determine lowest concentration so it is valid for wide measurement range allows determination with adequate precision of different solvents at higher concentration too. The measurement ranges are shown in the Table 4 with the respective RSD values.
LODs were calculated at S/N ratio of ≥ 3 and LOQs were calculated as at S/N ratio ≥10 and low-residual linearity values. The sensitivity of the method was demonstrated by the low-LOD values and low LOQ obtained for all the solvents analyzed.
The mean recoveries for all the solvents were between 95.0–105.3% and were lower than tabulated [Table 4], so the recoveries and 100% values were not significantly different.
The analytical method proposed for the quality control of all selected solvents methanol, ethanol, iso propyl alcohol, MEK, MIBK, n propyl alcohol, EA, n-butanol, n propyl acetate, toluene and xylene very well complete the validation requirements and precisely fit for various polarity solvents as the method was sensitive, linear, accurate and precise. Excellent results were obtained, within globally accepted validation reference values, particularly taking into account the low concentration levels investigated.
The authors are thankful to Uflex Chemical Division for providing infrastructure and constructive criticism which have helped to accomplish this work.
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Pallavi Gupta, masters in instrumentation, is currently working with Uflex Limited, Noida as chemist (R&D instrumentation). She has research experience of more than two years with the expertise in the area of analysis of and cross-verification quality checks of inks, adhesives, coatings, and multi components coatings by using state-of-the-art instruments like Py- GC-MS, GC-HS, FTIR, UV-spectrophotometer, HPLC, LCMS.
Dr. Ruchi Gupta, masters in industrial chemistry and Ph.D. in chemistry, is currently with Uflex Limited, Noida as manager (R&D), and prior to this, worked as a scientist with Shriram Institute for Industrial Research.
She has research experience of more than 11 years and her areas of interest include inks, adhesives, coatings, nanomaterials, nanophotocatalysts, optical polymers, natural polymers etc. She has published 12 papers in reputed international journals and has published four chapters in national and international handbooks.
Dr. Pinaki Ranjan Samanta has more than two decades of experience in the areas associated to industrial research of coating and testing of FG and RM’s of coating-related materials. He received M. Sc and Ph. D in the field of organic chemistry, also earning his PG diploma in paint technology.
He has published more than 12 papers in national and international journals, and also two patents in his cap in the field of high performance coatings. Since the middle of 1990s, he is an accomplished analytical chemist with years of research. Dr. Pinaki is experienced in the use of several analytical techniques including mass spectrometry (GC-MS, LC-MS), atomic spectrometry (AAS) and chromatography, and is also involved in the project development and research on new technology. Dr. Pinaki’s background includes tenures at reputed organizations like Berger Paints, Shriram Institute for Industrial Research, Moser Baer and Uflex in the area of research and development.
Pradeep Shah is a science graduate and has done B. Tech. chemical technology specialization in paints from Harcourt Butler Technological Institute Kanpur – 1980 batch. He has been selected from the campus by INCOWAX Ltd., now Flint Group India Ltd. He has done post- graduate diploma in business management (PGDBM).
He joined Uflex Group Chemical Division for its ink project in 1991 to start its ink plant with initial capacity of 3,000 tons per annum in Noida. The current capacity is 25,284 ton per annum with two plants located at Noida and Jammu in India. His total experience is more than 37 years.
