Abstract
A headspace gas chromatographic method was developed for the determination of residual solvents in linezolid active substances. The solvents include petroleum ether (60–90°C), acetone, tetrahydrofuran, ethyl acetate, methanol, dichloromethane (DCM) and pyridine. The method showed the possibility to detect the tested solvents with a linear determination correlation coefficient (r) greater than 0.9995 except for petroleum ether (0.9980). The limits of detection ranged between 0.12 μg/mL (petroleum ether) and 3.56 μg/mL (DCM), and the limits of quantity ranged between 0.41 μg/mL (petroleum ether) and 11.86 μg/mL (DCM). The method achieved good accuracy (recoveries ranging from 92.8 to 102.5%) and precision for both run-to-run and day-to-day assay (relative standard deviation ranging from 0.4 to 1.3%) for all seven solvents concerned, which were applied in the quality control of three batches of linezolid successfully.
Introduction
The definition of residual solvents is regarded as organic volatile chemicals that are used or produced in the manufacture of drug substances or in the preparation of drug products in pharmaceutical industries (1). Residual solvents that are commonly used in the manufacturing of pharmaceuticals consist of four classes in terms of their level of hazard to humans and the environment (2), which are adopted by Pharmacopoeias (3). The most commonly used solvents include methanol, tetrahydrofuran (THF) and acetone, and the International Conference on Harmonization (ICH) guideline lists methanol, THF as a Class 2 solvent and acetone as a Class 3 solvent (4, 5). Because the residual solvents are not completely removed by practical manufacturing techniques, analytical tasks to determine residual solvents are highly desired. To date, the methods used for the determination of residual solvents in drug substances include thermal desorption (TD) techniques (6), Fourier transform infrared (FTIR) spectrometry (1), high-performance liquid chromatography (HPLC) (7) and gas chromatography (GC) (8, 9). Among them, GC is the most commonly used technique for the analysis of residual solvents, because of its excellent separation ability and low detection limit. Usually, GC is coupled with a flame ionization detector (FID), or an electron-capture detector (ECD), or mass spectrometry (MS) detector, in combination with different sampling techniques, such as dynamic or static headspace techniques. Recently, a number of studies on the analysis of residual solvents in drug substances by GC have been reported. For example, Tian and coworkers presented a GC method to determine triethylamine and dimethyl sulfoxide in a drug substance (ML-189) (10). Quirk and coworkers employed a GC method to determine residual acetone and acetone-related impurities in drug product intermediates (11). Zhong and coworkers used a conventional headspace GC method with contemporary ionic liquid diluents for the determination of trace level genotoxic impurities in small molecule drug substances (12). De Beer and coworkers developed a validated GC–MS method for the determination and quantification of residual solvents in counterfeit tablets and capsules (13). All the examples show that the GC technique is effective for the analysis of residual solvents in drug substances.
Linezolid, a new class of synthetic antibacterial drugs called oxazolidinone derivatives, has been used as antibiotic for the treatment of multidrug-resistant gram-positive bacterial infections (14, 15). It is useful against various antibiotic-resistant isolates of staphylococci, streptococci, enterococci and pneumococci in vitro microbiological studies (16, 17). The early clinical studies have demonstrated that linezolid exhibited a unique mechanism of inhibition of bacterial protein synthesis at the initiation phase of translation (18, 19). The society will need more and more linezolid in the future. However, it is inevitable there exist some residual solvents during the manufacture of linezolid and the determination of its residual solvents must be carried out.
Herein, we will report an approach for the determination of polar residual solvents in linezolid by static headspace gas chromatography, including petroleum ether (60–90°C), acetone, THF, ethyl acetate, methanol, dichloromethane (DCM) and pyridine. The most key step for the successful analysis is the development of a stable, selective, sensitive and precise detection method, which will play an important role in the management of residual solvents in linezolid active substances.
Materials and equipment
Chemicals and reagents
All solvents, such as hexane, acetone, THF, ethyl acetate, methanol, DCM and pyridine (with analytical grade), were obtained from Xilong Chemical Reagents Co. (Guangzhou, China); petroleum ether (60–90°C) with chromatographic pure grade was purchased from Tianjin Institute of Fine Chemical Industry (Tianjin, China); sample solvent dimethyl sulfoxide (DMSO) with optically pure grade was obtained from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China); linezolid was purchased from Wuhan Xinxinjiali Bio-Tech Co., Ltd (Hubei, China).
Standard solutions
Standard stock solutions of eight solvents were prepared by dissolving accurately weighed reference substances [0.2582 g petroleum ether (60–90°C), 0.5001 g hexane, 0.4978 g acetone, 0.1838 g THF, 0.5040 g ethyl acetate, 0.3925 g methanol, 0.1482 g DCM and 0.0492 g pyridine] in DMSO (50 mL) and stored in dark glass vials at 4°C. The mixture stock solution was prepared by dissolving accurately weighed reference substances [0.2515 g petroleum ether (60–90°C), 0.5023 g acetone, 0.1778 g THF, 0.5147 g ethyl acetate, 0.3741 g methanol, 0.1542 g DCM and 0.0517 g pyridine] in DMSO (50 mL) and stored in dark glass vials at 4°C. Before use, a series of standard work solutions for eight solvents and mixture work solution were freshly prepared in DMSO by further diluting respective standard stock solution and mixture stock solution. For sensitivity experiments, the limits of detection (LOD) and limits of quantitation (LOQ) were estimated at a signal-to-noise ratio of ∼3 : 1 and 10 : 1, respectively.
GC–FID analysis
GC was conducted using the Agilent 7890A gas chromatograph equipped with an FID. The ZB-WAX capillary column (30 m length × 0.53 mm i.d., and 1.0 µm film thickness; Phenomenex Co., USA) and the DB-FFAP capillary column (30 m length × 0.53 mm i.d., and 1.0 µm film thickness; Agilent Co., USA) were used for the quantification of residual solvents. Analysis was performed using an oven programming at an initial temperature of 30°C for 15 min followed by a ramp rate of 10°C/min, 35°C for 10 min followed by 10°C/min ramp rate, 30°C for 5 min followed by 30°C/min ramp rate and finally, a temperature of 220°C with a hold time of 30 min and the total run time is 37 min. The temperature of the injector was set at 90°C with a split ratio of 5 : 1. The detector temperature was maintained at 280°C. Nitrogen (N2, 99.999% purity) was used as carrier gas with a flow rate of 1 mL/min. The injection volume of the sample was 1 mL.
Results
Precision, accuracy and recovery
The validation of the analysis was performed by evaluating precision, accuracy and recovery on quality control samples using the total error approach according to the guidelines, which are the quality standard analytical method validation guidelines of residual solvents (20).
Precision represents an estimate of the variability of measurements and the reproducibility of the test method, which was described as the value of relative standard deviation (RSD) (21). The precision of the proposed method was tested by performing six reduplicate injections and calculating the RSD% of the peak area of the mixture work solution as illustrated in Table I, which are below 0.8% for seven residual solvents.
Table I.
Analytical Results of System Precision Test
| Average peak area (n = 6) |
|||||||
|---|---|---|---|---|---|---|---|
| Petroleum ether | Acetone | THF | Ethyl acetate | Methanol | DCM | Pyridine | |
| 1 | 1464.7 | 464.4 | 213.6 | 360.9 | 58.2 | 30.1 | 11.9 |
| 2 | 1455.6 | 463.6 | 213.2 | 360.7 | 57.9 | 30.1 | 11.9 |
| 3 | 1432.6 | 461.3 | 212.2 | 358.8 | 57.8 | 30.0 | 11.8 |
| 4 | 1438.7 | 460.7 | 211.9 | 358.1 | 57.8 | 30.0 | 11.8 |
| 5 | 1451.0 | 466.6 | 214.6 | 362.9 | 58.4 | 30.5 | 12.0 |
| 6 | 1438.8 | 463.0 | 212.8 | 359.8 | 57.8 | 30.0 | 11.8 |
| Average | 1446.9 | 463.3 | 213.1 | 360.2 | 58.0 | 30.1 | 11.9 |
| RSD% | 0.8 | 0.5 | 0.5 | 0.5 | 0.5 | 0.6 | 0.7 |
The precision was also evaluated with intermediate precision. The intermediate precision of the as-established analytical method was determined by calculating the RSD% of the peak area of the mixture work solution following the same procedure by six reduplicate injections by two analysts on three different days to avoid false-positive results. The data of average peak area and RSDs of seven residual solvents are given in Table II. It can be seen that the RSD% is kept at 0.4–0.8% of run-to-run precision and 0.4–1.3% of day-to-day precision for seven residual solvents. The results indicated that the as-established analytical method has relatively good intermediate precision.
Table II.
Analytical Results of System Intermediate Precision Test
| Residual solvents | Different analysts | Average peak area (n = 6) |
|||||
|---|---|---|---|---|---|---|---|
| 0 h | RSD (%) | 48 h | RSD (%) | 96 h | RSD (%) | ||
| Petroleum ether | 1 | 1455.6 | 0.8 | 1464.7 | 0.8 | 1409.4 | 1.2 |
| 2 | 1459.9 | 0.8 | 1452.1 | 0.8 | 1415.0 | 1.3 | |
| Acetone | 1 | 464.4 | 0.6 | 467.1 | 0.6 | 471.5 | 0.8 |
| 2 | 466.6 | 0.6 | 468.9 | 0.6 | 469.9 | 0.7 | |
| THF | 1 | 213.2 | 0.5 | 214.7 | 0.6 | 216.7 | 0.8 |
| 2 | 213.6 | 0.5 | 215.3 | 0.6 | 216.1 | 0.7 | |
| Ethyl acetate | 1 | 360.9 | 0.5 | 363.6 | 0.7 | 366.7 | 0.8 |
| 2 | 362.9 | 0.5 | 365.0 | 0.7 | 365.4 | 0.9 | |
| Methanol | 1 | 57.8 | 0.5 | 57.8 | 0.4 | 59.0 | 0.6 |
| 2 | 58.2 | 0.5 | 58.3 | 0.5 | 58.7 | 0.7 | |
| DCM | 1 | 30.1 | 0.5 | 30.3 | 0.5 | 30.6 | 0.5 |
| 2 | 30.0 | 0.4 | 30.4 | 0.5 | 30.5 | 0.5 | |
| Pyridine | 1 | 11.8 | 0.5 | 11.7 | 0.5 | 11.9 | 0.5 |
| 2 | 11.9 | 0.5 | 11.8 | 0.5 | 12.0 | 0.5 | |
The accuracy of the method was assessed with recovery by spiking standard work solution into 100 mg linezolid drug substance. Three spiking concentrations at low level (three preparations), moderate level (six preparations) and high level (three preparations) of seven residual solvents were chosen for the analysis as presented in Table III. The averages recoveries were used as the peak areas of residual solvents in the drug substance. From Table III, it can be seen that at three levels of concentration of standard work solution, the average recoveries of the solvents were from 92.8 to 102.5% and the RSD% was in the range of 3.5–5.2% to show the accuracy of the as-established analytical method.
Table III.
Analytical Results of System Accuracy Test
| Residual solvents | Spiked concentration (μg/mL) |
Average recovery (%) | RSD (%) | ||
|---|---|---|---|---|---|
| Petroleum ether | 17.6 | 263.6 | 878.6 | 92.8 | 4.1 |
| Acetone | 35.1 | 526.4 | 1754.8 | 102.5 | 4.5 |
| THF | 12.4 | 186.3 | 621.1 | 94.6 | 2.4 |
| Ethyl acetate | 36.0 | 539.4 | 1798.1 | 96.8 | 2.7 |
| Methanol | 26.1 | 392.1 | 1307.0 | 102.5 | 3.6 |
| DCM | 10.8 | 161.6 | 538.7 | 101.8 | 5.2 |
| Pyridine | 3.6 | 54.2 | 180.6 | 97.8 | 3.5 |
Linearity of calibration curve, LOD and limits of quantity (LOQ)
Quantitative analysis was conducted using an external standard. For all seven solvents, three calibration standards were prepared in order to evaluate the relationship between the area under the curve and the concentration at seven different levels. The calibration curves were obtained using ordinary least square linear regression, and the linearity was confirmed with the correlation coefficient (r) and a quality coefficient. The r was found to be >0.9995, except for petroleum ether (r> 0.9980). The linearity of the relationship was evaluated for each of the solvents in a broad concentration range as presented in Table IV. From this table, it can be concluded that the calibration curves for all solvents are linear within the chosen standard concentration ranges of 0.41–3088.20 µg/mL. The LOD and LOQ were estimated by yielding a signal-to-noise ratio of three (S/N ≥3) for each solvent was defined as the LOD, and the concentration giving an S/N ≥10 was considered as the LOQ. The LOD and LOQ for the test solvents are presented in Table VI. With the present method, solvent analyses presented LOD and LOQ in the range of 0.12–3.56 and 0.41–11.86 μg/mL, respectively.
Table IV.
Linear Data of Residual Solvents Analyzed by the Proposed GC Method
| Residual solvents | Regression equation | Linearity range (μg/mL) | r (n = 7) | LOD (μg/mL) | LOQ (μg/mL) |
|---|---|---|---|---|---|
| Petroleum ether | ya = 13.519xb + 234.362 | 0.41–1509.00 | 0.9980 | 0.12 | 0.41 |
| Acetone | y = 4.462x + 9.760 | 1.19–3013.80 | 0.9995 | 0.36 | 1.19 |
| THF | y = 2.050x + 5.389 | 1.47–1066.80 | 0.9995 | 0.44 | 1.47 |
| Ethyl acetate | y = 3.481x + 6.139 | 4.03–3088.20 | 0.9995 | 1.21 | 4.03 |
| Methanol | y = 0.573x− 1.046 | 9.42–2244.60 | 0.9995 | 2.82 | 9.42 |
| DCM | y = 0.289x + 2.758 | 11.86–925.20 | 0.9995 | 3.56 | 11.86 |
| Pyridine | y = 0.114x + 0.285 | 1.97–310.20 | 0.9995 | 0.59 | 1.97 |
ay = peak area.
bx = concentration of the respective solvent.
Table VI.
Chromatographic Behavior of All Residual Solvents on Two Polar Columns
| Residual solvents | Resolution |
Number of plates |
||||||
|---|---|---|---|---|---|---|---|---|
| ZB-WAX | DB-FFAP | ZB-WAX | DB-FFAP | |||||
| Petroleum ether (1) | – | – | – | – | 53,656 | 51,014 | 58,206 | 58,061 |
| Petroleum ether (2) | 2.09 | 1.96 | 2.10 | 2.12 | 47,250 | 46,428 | 47,844 | 49,273 |
| Petroleum ether (3) | 1.41 | 1.41 | 1.43 | 1.43 | 42,728 | 43,629 | 43,387 | 44,222 |
| Petroleum ether 4 (hexane) | 1.11 | 1.13 | 1.13 | 1.15 | 49,546 | 50,269 | 50,251 | 50,900 |
| Petroleum ether (5) | 7.72 | 7.64 | 7.74 | 7.71 | 33,111 | 31,985 | 32,841 | 32,700 |
| Petroleum ether (6) | 6.03 | 5.94 | 5.90 | 5.94 | 26,008 | 25,713 | 24,463 | 25,157 |
| Acetone | 14.40 | 14.39 | 13.22 | 13.43 | 184,252 | 181,002 | 181,210 | 183,890 |
| THF | 10.46 | 10.34 | 10.36 | 10.41 | 117,592 | 114,644 | 115,362 | 116,455 |
| Ethyl acetate | 7.06 | 7.02 | 7.01 | 7.03 | 112,023 | 111,984 | 111,529 | 112,427 |
| Methanol | 4.33 | 4.34 | 4.32 | 4.32 | 126,735 | 126,710 | 124,762 | 125,719 |
| DCM | 8.89 | 8.86 | 8.77 | 8.83 | 102,610 | 101,627 | 99,789 | 101,259 |
| Pyridine | 35.04 | 34.83 | 33.11 | 33.73 | 6,703,298 | 6,443,000 | 6,328,023 | 6,710,732 |
Application
To confirm that the optimized method was suitable for application, the established method was applied in the quality control of three batches of linezolid (100 mg), and only acetone was checked out with the highest residual level of 640 ppm as given in Table V, which did not exceed the limited quantity (ICH acetone ≤5,000 ppm).
Table V.
Contents of Residual Solvents in Three Batches of Linezolid (ppm)
| Batch | Petroleum ether | Acetone | THF | Ethyl acetate | Methanol | DCM | Pyridine |
|---|---|---|---|---|---|---|---|
| 1 | – | 638 | – | – | – | – | – |
| 2 | – | 640 | – | – | – | – | – |
| 3 | – | 637 | – | – | – | – | – |
–, No detected.
Discussion
To establish the quality control system of linezolid active substances, a headspace gas chromatographic method should be established and validated for the determination of residual solvents. The most important factor is the selection of capillary columns. Among the solvents petroleum ether (60–90°C), acetone, THF, ethyl acetate, methanol, DCM and pyridine, some of them are polar solvents. The polarity of acetone and pyridine is ∼5.30 (22), so polar capillary columns that can separate the solvents with different polarity should be selected. Herein, two polar capillary columns ZB-WAX (Phenomenex) and DB-FFAP (Agilent) were selected for GC experiments following GC-FID analysis. For the mixture work solution, two reduplicate injections were carried out on two polar capillary columns by the GC method. The resolution and number of plates are listed in Table VI. From the table, it can be seen that two selected polar capillary columns show very good resolution (>4.3) for all residual solvents except for petroleum ether (60–90°C), which is composed of six mixtures, showing lower resolution. Although the resolutions of petroleum ether mixtures are >1, they are also separated by the polar capillary column. It should be mentioned that one ingredient of petroleum ether is hexane (petroleum ether 4), which belongs to Class 2 solvent (ICH), so its content in drug active substances must be detected. If the plates are >5,000, they are suitable for the separation of residual solvents. We consider the resolution of two capillary columns again. ZB-WAX shows better performance than DB-FFAP, especially for acetone and pyridine. Their resolutions range from 14.40 and 35.04 to 13.43 and 33.73, respectively. Therefore, the ZB-WAX polar capillary column was selected for the following GC experiments. Another important factor of the gas chromatographic method is the choice of sample solvents, because the polarity of DMSO is 7.2, which is greater than that of the residual solvents, and DMSO was chosen as the sample solvent.
After the selection of capillary columns and sample solvent, two reduplicate injections of mixture work solution were carried out to see whether all the solvents can be separated by the ZB-WAX polar capillary column completely. The retention time, resolution and numbers of plates are listed in Table VII.
Table VII.
Results of System Suitability Test
| Residual solvents | Retention time (min) |
Resolution |
Number of plates (n) |
|||
|---|---|---|---|---|---|---|
| 1 | 2 | 1 | 2 | 1 | 2 | |
| Petroleum ether (1) | 9.245 | 9.250 | / | / | 55,341 | 56,407 |
| Petroleum ether (2) | 9.602 | 9.598 | 2.13 | 2.10 | 47,071 | 47,792 |
| Petroleum ether(3) | 9.863 | 9.860 | 1.43 | 1.44 | 43,546 | 44,510 |
| Petroleum ether (4)(hexane) | 10.076 | 10.071 | 1.14 | 1.15 | 48,667 | 50,168 |
| Petroleum ether (5) | 11.784 | 11.782 | 7.70 | 7.73 | 32,722 | 32,357 |
| Petroleum ether (6) | 13.582 | 13.590 | 5.88 | 5.82 | 24,120 | 23,019 |
| Acetone | 17.188 | 17.187 | 14.08 | 13.86 | 181,339 | 184,547 |
| THF | 19.212 | 19.211 | 10.46 | 10.45 | 116,477 | 115,008 |
| Ethyl acetate | 20.896 | 20.895 | 7.04 | 7.05 | 109,936 | 111,180 |
| Methanol | 21.986 | 21.984 | 4.37 | 4.37 | 127,367 | 127,345 |
| DCM | 24.462 | 24.463 | 8.91 | 8.87 | 100,445 | 98,636 |
| Pyridine | 30.559 | 30.559 | 30.14 | 33.84 | 6,573,010 | 6,444,761 |
From Table VII, it can be seen that the retention times of six ingredients in petroleum ether (60–90°C) are 9.245, 9.602, 9.863, 10.076, 11.784 and 13.582 min. The retention times of other residual solvents are 17.188, 19.212, 20.896, 21.986, 24.462, 30.559 min all less than the retention time of DMSO (32.993 min). The resolutions of six ingredients in petroleum ether (60–90°C) are >1, and the resolutions of other residual solvents are >4.3. So they can be separated by the GC method on the ZB-WAX polar capillary column.
Figure 1 shows typical chromatogram of all standard work solutions (a–h) and mixture work solution (i) in DMSO(j). It can be seen that there are no interfering peaks at the retention times, and all the selected solvents can be detected without interference with each other by GC as shown in Figure 1.
Figure 1.
Chromatogram of standard work solutions (a–h) and mixture work solution (i) (a: petroleum ether 1 (1–5); b: hexane 1 (4); c: acetone 2; d: THF 3; e: ethyl acetate 4; f: methanol 5; g: DCM 6; h: pyridine 7; i: mixture work solution; j: DMSO). This figure is available in black and white in print and in color at JCS online.
After the establishment of the gas chromatographic method, the validation of method should be carried out for the determination of residual solvents, including precision, accuracy and recovery studies, and accompanying with linearity of the calibration curve, LOD and LOQ. On the basis of experimental data, the method achieved good accuracy (recoveries ranging from 92.8 to 102.5%) and precision (RSD ranging from 0.4 to 1.3%) for all seven solvents concerned, which was applied successfully in the quality control of three batches of linezolid.
Conclusion
In summary, a headspace gas chromatographic method was established and validated for the determination of seven residual solvents in linezolid. The established method shows high sensitivity, good accuracy and linearity, which was applied successfully in the quality control of three batches of linezolid.
Acknowledgments
We acknowledge the financial supports from the National Science and Technology Support Program of China (2013BAI03B01), the National Natural Science Foundation of China (61301038 and 61271119) and the Natural Science Foundation of Guangxi Province (2015GXNSFBA139041).
References
- 1.Liu Y., Hu C.Q.; Establishment of a knowledge base for identification of residual solvents in pharmaceuticals; Analytica Chimica Acta, (2006); 575: 246–254. [DOI] [PubMed] [Google Scholar]
- 2.Camarasu C.C.; Headspace SPME method development for the analysis of volatile polar residual solvents by GC–MS; Journal of Pharmaceutical and Biomedical Analysis, (2000); 23: 197–210. [DOI] [PubMed] [Google Scholar]
- 3.The United States Pharmacopeial Convention Inc. Organic volatile impurities. In The United States Pharmacopoeia, 35th edn Chemical Tests/<467>, The United States Pharmacopeial Convention Inc., Rochville, MD, (2013). [Google Scholar]
- 4.ICH Guideline for Industry, Topic Q3C (R4) Impurities, Guideline for Residual Solvents.
- 5.Guo T., Shi Y., Zheng L., Feng F., Zheng F., Liu W.; Rapid and simultaneous determination of sulfonate ester genotoxic impurities in drug substance by liquid chromatography coupled to tandem mass spectrometry: comparison of different ionization modes; Journal of Chromatography A, (2014); 1355: 73–79. [DOI] [PubMed] [Google Scholar]
- 6.Urakami K., Saito Y., Fujiwara Y., Watanabe C., Umemoto K., Godo M. et al. ; Determination of residual solvents in bulk pharmaceuticals by thermal desorption/gas chromatography/mass spectrometry; Chemical & Pharmaceutical Bulletin, (2000); 48: 1894–1897. [DOI] [PubMed] [Google Scholar]
- 7.Jimenez J.J., Bernal J.L., del Nozal M.J., Novo M., Higes M., Llorente J.; Determination of rotenone residues in raw honey by solid-phase extraction and high-performance liquid chromatography; Journal of Chromatography A, (2000); 871: 67–73. [DOI] [PubMed] [Google Scholar]
- 8.Huang X.H., Zhao X.H., Lu X.T., Tian H.P., Xu A.J., Liu Y. et al. ; Simultaneous determination of 50 residual pesticides in Flos Chrysanthemi using accelerated solvent extraction and gas chromatography; Journal of Chromatography B, (2014); 967: 1–7. [DOI] [PubMed] [Google Scholar]
- 9.Zacca J.J., Groberio T.S., Maldaner A.O., Vieira M.L., Braga J.W.B.; Correlation of cocaine hydrochloride samples seized in Brazil based on determination of residual solvents: an innovative chemometric method for determination of linkage thresholds; Analytical Chemistry, (2013); 85: 2457–2464. [DOI] [PubMed] [Google Scholar]
- 10.Tian J.Z., Chen G.R., He Z.F.; Overcoming matrix effects: GC method development for the determination of triethylamine and dimethyl sulfoxide in a drug substance; Journal of Chromatographic Science, (2014); 52: 36–41. [DOI] [PubMed] [Google Scholar]
- 11.Quirk E., Doggett A., Bretnall A.; Determination of residual acetone and acetone related impurities in drug product intermediates prepared as Spray Dried Dispersions (SDD) using gas chromatography with headspace autosampling (GCHS); Journal of Pharmaceutical and Biomedical Analysis, (2014); 96: 37–44. [DOI] [PubMed] [Google Scholar]
- 12.Ho T.D., Yehl P.M., Chetwyn N.P., Wang J., Anderson J.L., Zhong Q.Q.; Determination of trace level genotoxic impurities in small molecule drug substances using conventional headspace gas chromatography with contemporary ionic liquid diluents and electron capture detection; Journal of Chromatography A, (2014); 1361: 217–228. [DOI] [PubMed] [Google Scholar]
- 13.Deconinck E., Canfyn M., Sacre P.Y., Baudewyns S., Courselle P., De Beer J.O.; A validated GC–MS method for the determination and quantification of residual solvents in counterfeit tablets and capsules; Journal of Pharmaceutical and Biomedical Analysis, (2012); 70: 64–70. [DOI] [PubMed] [Google Scholar]
- 14.Ehrlich M., Trittler R., Daschner F.D., Kummerer K.; A new and rapid method for monitoring the new oxazolidinone antibiotic linezolid in serum and urine by high performance liquid chromatography-integrated sample preparation; Journal of Chromatography B, (2001); 755: 373–377. [DOI] [PubMed] [Google Scholar]
- 15.Buerger C., Joukhadar C., Muller M., Kloft C.; Development of a liquid chromatography method for the determination of linezolid and its application to in vitro and human microdialysis samples; Journal of Chromatography B, (2003); 796: 155–164. [DOI] [PubMed] [Google Scholar]
- 16.Peng G.W., Stryd R.P., Murata S., Igarashi M., Chiba K., Aoyama H. et al. ; Determination of linezolid in plasma by reversed-phase high-performance liquid chromatography; Journal of Pharmaceutical and Biomedical Analysis, (1999); 20: 65–73. [DOI] [PubMed] [Google Scholar]
- 17.Moussa B.A., Mahrouse M.A., Hassan M.A., Fawzy M.G.; Spectrofluorimetric determination of gemifloxacin mesylate and linezolid in pharmaceutical formulations: application of quinone-based fluorophores and enhanced native fluorescence; Acta Pharmaceutica, (2014); 64: 15–28. [DOI] [PubMed] [Google Scholar]
- 18.Borner K., Borner E., Lode H.; Determination of linezolid in human serum and urine by high-performance liquid chromatography; International Journal of Antimicrobial Agents, (2001); 18: 253–258. [DOI] [PubMed] [Google Scholar]
- 19.Saviano A.M., Madruga R.O.G., Lourenco F.R.; Measurement uncertainty of a UPLC stability indicating method for determination of linezolid in dosage forms; Measurement, (2015); 59: 1–8. [Google Scholar]
- 20.Feinberg M.; Validation of analytical methods based on accuracy profiles; Journal of Chromatography A, (2007); 1158: 174–183. [DOI] [PubMed] [Google Scholar]
- 21.De Backer B., Debrus B., Lebrun P., Theunis L., Dubois N., Decock L. et al. ; Innovative development and validation of an HPLC/DAD method for the qualitative and quantitative determination of major cannabinoids in cannabis plant material; Journal of Chromatography B, (2009); 877: 4115–4124. [DOI] [PubMed] [Google Scholar]
- 22.Oliveri I.P., Malandrino G., Di Bella S.; Self-assembled nanostructures of amphiphilic zinc(II) salophen complexes: role of the solvent on their structure and morphology; Dalton Transactions, (2014); 43: 10208–10214. [DOI] [PubMed] [Google Scholar]