Abstract
Mirtazapine is an antidepressant medication used to treat the major depressive disorder in adults. In this study, two different chromatographic methods were developed for the determination of mirtazapine in pharmaceutical products. In the first method, An Extend C18 column (250 × 4.6 mm, 5 μm) was used and the temperature was kept constant at 25 °C. The mobile phase was determined as 0.1% formic acid solution and acetonitrile (80/20, v/v), and isocratic elution was applied. The flow rate of the mobile phase was determined as 1.0 mL min−1 and the injection volume was 20 µL. Detection was performed at 291 nm. using a UV detector. In the second method, ethanol was used as the organic modifier. The only difference between these methods was the organic modifier. All other conditions of the methods were the same. Both chromatographic methods were validated by ICH guidelines for various parameters such as selectivity, linearity, accuracy, precision, detection and quantification limit, and robustness. The determination coefficients of chromatographic methods were greater than 0.999 in the concentration range of 5–30 µg mL−1. of mirtazapine. Later, these chromatographic methods were applied to pharmaceutical formulations. Comparison of the obtained results in terms of means was made using Student's (t) test, and comparisons in terms of standard deviations were made using the Fischer (F) test. It was observed that there was no significant difference between these methods. These two methods were then evaluated using the AGREE-Analytical GREEnness metric software. The chromatographic method using ethanol as an organic modifier has been proposed as an excellent eco-friendly and analyst-friendly alternative for the determination of mirtazapine in pharmaceutical formulations.
Introduction
In today's conditions that directly affect the environment, it is vital to develop more environmentally friendly analytical methodologies. Therefore, the use of environmentally friendly chemicals is becoming more popular in all analytical techniques, including liquid chromatographic methods. When proposing an analytical method for the determination of a particular analyte, it is necessary to justify two main features. The first essential feature is the metrological value of the results of the validation parameters. The second key feature is that the method should be green. Guidelines should be considered when developing more environmentally friendly analytical techniques, as they offer good ideas about green chemicals [1]. Unfortunately, green analytical methods are still insufficient for pharmaceutical analysis.
HPLC is a widely used technology in all areas of quality control analysis of pharmaceutical formulations [2]. HPLC analyses usually use a polar mobile phase with a hydrophobic stationary phase. Mobile phases typically consist of a combination of water (with additions) and organic solvents such as acetonitrile or methanol. These solvents are often used and preferred in HPLC analyses due to their unique chromatographic properties such as complete miscibility with water, low viscosity of aqueous solutions, low UV cut-off wavelength, low chemical reactivity with most sample types, instruments, and columns, and high purity [3, 4]. Although these exceptional chromatographic properties, acetonitrile, and methanol pose some problems in terms of operatör health and ecological effect. Acetonitrile is a volatile, flammable, and toxic chemical. Methanol is biodegradable and less toxic than acetonitrile, but it is classified as a hazardous solvent because of its toxicity and the enormous challenge of waste disposal [5, 6].
Unfortunately, the amount of waste generated during HPLC analysis cannot be ignored. Every day, tons of toxic waste is generated in HPLC instruments. In addition, due to technological advances, the use of HPLC is becoming more widespread and the amount of waste is increasing at the same time. These wastes, which contain large amounts of acetonitrile and methanol, need to be disposed of. This increases the burden of environmental waste disposal in the laboratory and imposes high costs.
The greening of HPLC methods is of great interest among analytical chemists seeking new alternatives to replace polluting analytical methods with cleaner methods. It is now imperative to eliminate the use of hazardous chemicals and develop environmentally and operator-friendly methods without compromising analytical method performance [7].
Ethanol is one of the most environmentally friendly organic solvents and is an ideal solvent for green HPLC methods [8]. It has a lower vapor pressure than acetonitrile and methanol, evaporates less, and consequently causes lower respiration levels. It is also more widely available and cheaper than acetonitrile and methanol. This encourages its use in laboratories with scarce resources, especially in developing countries. Furthermore, since ethanol waste is environmentally friendly, it has cheaper disposal costs than acetonitrile and methanol. From a chromatographic point of view, ethanol has similar properties to acetonitrile and methanol [7]. Similar adsorption and separation mechanisms, similar peak yields, and satisfactory performances were obtained when ethanol was used as an organic modifier instead of acetonitrile and methanol [2]. In the classification of organic solvents, ethanol is in the same group as methanol in terms of selectivity, which means that they have similar dipole moments [9]. In addition, since ethanol has a higher eluotropic power, the same retention time is achieved using a lower proportion of ethanol than methanol in the mobile phase [10].
Mirtazapine is an antidepressant drug used to treat the major depressive disorder in adults. It works by positively affecting the communication between nerve cells in the central nervous system and restoring the chemical balance in the brain [11]. The physicochemical properties of mirtazapine are presented in Table 1 [12].
The physicochemical properties of mirtazapine
 |
Several analytical procedures previously published in the literature were scanned to determine the amount of mirtazapine in bulk and pharmaceutical dosage forms and biological fluids. Spectrophotometric, spectrofluorimetric [13–15], high-performance liquid chromatographic [14, 16–20], capillary electrophoresis [21, 22], liquid chromatographic coupled with tandem mass spectrometry (LC-MS/MS) [23–25], gas chromatographic–mass spectrometric (GC-MS/MS) [26, 27], methods were reported for determination of mirtazapine in bulk and pharmaceutical dosage forms and biological fluids were developed.
Most of these methods are quite complex and require expensive equipment, toxic organic solvents, and special chemicals. The sample preparation stages of these techniques are complex and require long working times and gradient elution. Therefore, the current study aimed to develop and validate an environmentally and analyst-friendly liquid chromatography method in which ethanol is used as a mobile phase organic solvent for mirtazapine quantification in pharmaceutical products by a simple extraction procedure. Ethanol is considered as ecologically alternative to acetonitrile and methanol. This study describes a novel chromatographic method that uses the less hazardous solvent ethanol. This study also shows how easy it is to replace standard mobile phases with less dangerous chemicals and "greener" solvents with satisfactory performance.
Experimental
Instruments
An Agilent HPLC 1260 Infinity system was used for the HPLC analysis. This chromatographic system is equipped with a Chemstation software, ultraviolet detector, degasser, quaternary pump, autosampler, and column oven temperature was 25 ◦C. An Extend C18 (5 μm 250 × 4.6 mm) column (Agilent, USA) was used for analysis. A Mettler Toledo pH meter equipped with a glass electrode was used for pH measurement. Millipore Milli-Q water purification system (Milford, MA, USA) was used for the preparation of ultrapure water.
Reagent and chemicals
All solvents were gradient grades for liquid chromatography. Standard mirtazapine was supplied by Bilim Pharmaceuticals. Chromatography grade acetonitrile (≥99.9%), methanol (≥99.0%), ethanol (≥99%), analytical grade, and formic acid (≥99.0%) were bought from Sigma-Aldrich Chemie GmbH (Istanbul, Turkey). Mirtazapine tablets (Minelza, 30 mg) used in this study were purchased from a local pharmacy (Afyonkarahisar, Turkey). Ultrapure water (18.2 MMΩ cm), which was utilized to make all solutions and the mobile phase, was produced from the Millipore Milli-Q system. The mobile phase was filtered through a membrane filter (0.20 μm) using a vacuum pump and sonicated before analysis.
Pharmaceutical preparations
Stock standard solution (500 μg mL−1) was prepared by dissolving appropriate amounts of the mirtazapine reference standard in formic acid solution (0.1%, in ultrapure water). Standard solutions (5, 10, 15, 20, 25, and 30 μg mL−1) were prepared by diluting with ultrapure water from this stock standard solution.
Ten tablets (Minelza, 30 mg) were weighed precisely, ground into a fine powder using a mortar and pestle, and mixed. Tablet powder containing 25 mg of mirtazapine was precisely weighed into a 50 mL calibrated volumetric flask; about 20 mL of formic acid solution (0.1%, in ultrapure water) was added, and the mixture was sonicated for 10 min to complete the dissolution of mirtazapine; then the mixture was diluted up to the mark with ultrapure water. In order to guarantee that there were no particles present, the final mixture was filtered using a 0.22 μm filter. The sample solution (20 μg mL−1) was prepared by diluting with ultrapure water from this solution and then injected into the column.
Determination of λmax for mirtazapine
Standard solutions in the concentration range of 5–30 μg mL−1 were scanned in a UV spectrophotometer (Shimadzu UV-1800 spectrophotometer) device at a wavelength range of 200–400 nm. The overlapping spectrum of standard solutions is given in Fig. 1.
The overlaid spectrum of mirtazapine standard solutions in the 5–30 μg mL−1 concentration range
Citation: Acta Chromatographica 36, 3; 10.1556/1326.2023.01155
Chromatographic conditions
In the first method, An Extend C18 column (250 × 4.6 mm, 5 μm) was used and the temperature was kept constant at 25 °C. The mobile phase was determined as 0.1% formic acid solution and acetonitrile (80/20, v/v), and isocratic elution was applied. The flow rate of the mobile phase was determined as 1.0 mL min−1 and the injection volume was 20 µL. Detection was performed at 291 nm. using a UV detector. In the second method, ethanol was used as the organic modifier. The only difference between these methods was the organic modifier. All other conditions of the methods were the same.
Method validation
Both chromatographic methods were validated by ICH guidelines for various parameters such as linearity, specificity, precision, accuracy, detection limit (LOD), quantification limit (LOQ), and robustness was investigated on these considerations, a specific concentration range (5–30 μg mL−1) was chosen for the validation procedure [28, 29].
Selectivity
Standard, sample, and mobile phase solutions were injected into the chromatographic system to evaluate the selectivity of the chromatographic methods. Chromatograms were compared and it was examined whether there were interference peaks in the retention time region of the mirtazapine peak.
System suitability
Mirtazapine standard solution (20 μg mL−1) was injected into the chromatographic system six times at short regular time intervals. Peak area, retention time, tailing factor, and theoretical plate number values were recorded from chromatograms. The RSD% values of peak areas and retention times were calculated for six injections. The relative standard deviation was calculated for the peak area and the retention time.
Linearity
The linearity of the methods was evaluated by regression analysis. The standard stock solution was prepared by dissolving 5 mg of the mirtazapine reference standard in 25 mL formic acid solution (0.1%, ultra-pure water). This solution was diluted with ultra-pure water to obtain standard solutions of 5, 10, 15, 20, 25, and 30 μg mL−1. 20 µL of each standard solution was injected into the colon in triplicate and the chromatograms were recorded. Then, a calibration curve was created by plotting the peak areas of mirtazapine against their respective concentrations. Linear regression analysis was used to evaluate the linearity of the chromatographic methods.
The limit of detection (LOD) and limit of quantification (LOQ)
LOD and LOQ of the methods were calculated from equation 1: LOD: 3.3 σ/S and equation 2: LOQ: 10 σ/S. Where: σ is the standard deviation of the response and S is the slope of the calibration curve.
Precision
The repeatability and reproducibility of the methods were evaluated by performing intraday and interday precision tests. In the intraday precision test, six different concentrations of standard mirtazapine were analyzed in triplicate on the same day, while in the interday precision test, the same standard mirtazapine solutions were analyzed with the same procedure in triplicate on three different days. Statistical analyses were performed using the RSD % values of each test.
Accuracy
The accuracy of the methods was checked by recovery studies performed by the standard method of adding mirtazapine to the sample solution. The recovery test was performed at three different levels of the sample solution: 75%, 100%, and 125%, respectively.
Robustness
Within the scope of robustness studies for chromatographic methods, the effects of small changes deliberately made from optimum values in the flow rate of the mobile phase, the wavelength of the detector, and mobile phase composition on the analysis results were investigated.
Stability of the standard solution
The stability of the standard solution was evaluated by storing it at different conditions including; laboratory conditions (25 °C) for 12, 24, 36, and 48 h, and refrigerator temperature (4 °C) for 10 days. The solutions were injected into the HPLC system at the end of each storage period, the recovery values were computed, and the results were compared with freshly generated solutions. The stability investigation was carried out with an analytical solution at the concentration of 20 μg mL−1.
Evaluation of greenness of chromatographic methods
The proposed chromatographic methods were evaluated using the Analytical Greens (AGREE) evaluation program. AGREE is a metric system for evaluating the environmentalism of analytical procedures based on the principles of significance. AGREE is an easy-to-apply program with user-friendly software, which has been expanded by incorporating 12 basic principles in greenery assessment, allowing flexible working by allowing weight assignment, and an easily interpretable color pictogram output showing strong and weak points. The Analytical Greens score is the weighted average of the benchmark scores. It is shown in the middle of the graph, rounded to two decimals, and its value ranges from 0.0 (lowest score) to 1.0 (excellent score). The chart is a visual representation of the score itself, criterion scores, and criterion weights [30, 31].
Results and discussion
Determination of the wavelength
Standard solutions prepared using ultrapure water were scanned in a spectrophotometer device in the 200–400 nm wavelength range. The maximum absorption wavelength of mirtazapine was determined as 291 nm (Fig. 1).
Selectivity
Standard, sample, and mobile phase solutions were injected into the chromatographic system to evaluate the selectivity of chromatographic methods. The three chromatograms were compared and examined for interfering peak(s) around the analyte peak for both chromatographic methods. No peak interfering with the mirtazapine retention time was observed in all chromatograms.
System suitability test
The primary parameters were determined for a standard solution at a concentration of 20 μg mL−1 to evaluate the suitability of the system, The determined values are listed in Table 2. Mirtazapine had perfect peak symmetry. In addition, Mirtazapine has consistently shown low variability in peak areas and retention times. The correlation coefficient of the calibration curve in this study is 0.99994, indicating that the method is suitable for samples with simple or highly complex matrices. Thus, it can be concluded that the developed methods are suitable for mirtazapine analysis.
The results of the system suitability tests
| System suitability parameters | Method I | Method II |
| Asymmetry factor | 0.830 | 0.794 |
| R.S.D. % (for peak areas of mirtazapine) | 0.244 | 0.268 |
| R.S.D. % (for retention times of mirtazapine) | 0.087 | 0.109 |
| Tailing factor | 1.170 | 1.197 |
| Teoric plate number | 6,719 | 4,044 |
Linearity
Three replicate standard solutions were prepared from mirtazapine stock standard solution (500 μg mL−1) by diluting with ultrapure water so that the final mirtazapine concentration was 5, 10, 15, 20, 25, and 30 μg mL−1. These standard solutions were injected into the chromatographic system and the peak areas and retention times of the analyte were recorded. Average peak areas were calculated for each concentration level. A calibration graph was drawn with the peak area values versus the concentration of the standard solution versus the peak area. Linearity data of chromatographic methods were evaluated by regression analysis. The regression equation, slope, and intercept were calculated using linear regression analysis based on the least squares method. The results of the linearity studies are presented in Table 3. The calibration graphs of chromatographic methods (5–30 μg mL−1) are presented in Fig. 2. The calibration curve showed a good linear relation over the concentration range of 5–30 μg mL−1.
Regression data for chromatographic methods
| Parameter | Method I | Method II |
| Concentration range [μg mL−1] [n = 6] | 5–30 | 5–30 |
| Regression equation (y = ax + b) | ||
| Slope (a) | 13.389 | 13.433 |
| Intercept (b) | 10.889 | 15.182 |
| Correlation coefficient | 0.99994 | 0.99990 |
| Retention time [min.] | 3.724 | 4.042 |
| Detection limit [μg mL−1] | 0.20 | 0.50 |
| Quantification limit [μg mL−1] | 0.70 | 1.60 |
| Recovery % [n = 3] | 99.87–100.52 | 99.26–100.48 |
The overlaid chromatogram of mirtazapine at concentrations of 5–30 μg mL−1 (A: Method I, B: Method II)
Citation: Acta Chromatographica 36, 3; 10.1556/1326.2023.01155
Precision
The results of intra-day and inter-day precision analyses are summarized in Table 4. As a result of both tests, it was determined that the RSD values were less than 1.0%. This result shows reasonable repeatability for the developed methods.
Precision results of these chromatographic methods
| Method | Concentration μg mL−1 | Intra-day precision | Inter-day precision |
| (RSD, %) | |||
| Method I | 5 | 0.524 | 0.507 |
| 10 | 0.489 | 0.375 | |
| 15 | 0.385 | 0.363 | |
| 20 | 0.318 | 0.331 | |
| 25 | 0.286 | 0.318 | |
| 30 | 0.227 | 0.258 | |
| Method II | 5 | 0.638 | 0.626 |
| 10 | 0.606 | 0.492 | |
| 15 | 0.502 | 0.480 | |
| 20 | 0.435 | 0.448 | |
| 25 | 0.371 | 0.435 | |
| 30 | 0.107 | 0.375 | |
Accuracy
The accuracy of the chromatographic methods was determined by spiking three different amounts of mirtazapine standard into the sample solution. Standard was added to the sample solution (20 mg mL−1) at 75%, 100%, and 125% of the mirtazapine content. The solutions obtained were injected into the chromatographic system. The % recovery values of the added standard amount were calculated. Triplicate tests were performed for each concentration. The recovery percentages ranged between 99.00% and 99.84% in method I and between 98.53% and 99.88 in method II. It was observed that the relative standard deviation values were a maximum of 0.330 in method I and a maximum of 0.445 in method II. The results of the recovery studies are presented in Table 5.
Accuracy data of chromatographic methods
| Compound | Amount spiked μg mL−1 | Amount found μg mL−1 | Mean recovery % ± SD | RSD, % |
| Method I | 15 | 14.85 | 99.00 ± 0.327 | 0.330 |
| 20 | 19.93 | 99.65 ± 0.217 | 0.218 | |
| 25 | 24.96 | 99.84 ± 0.113 | 0.113 | |
| Method II | 15 | 14.78 | 98.53 ± 0.438 | 0.445 |
| 20 | 19.83 | 99.15 ± 0.288 | 0.290 | |
| 25 | 24.97 | 99.88 ± 0.156 | 0.156 |
Robustness
Within the scope of testing the robustness of the method developed for the quantitative analysis of mirtazapine, the study showing the effects of small deviations from the most appropriate (optimal) values for the method parameters on the result was carried out at a concentration level of 20 μg mL−1. According to the findings, the largest relative standard deviation value was calculated as 0.39% (Table 6).
The results of robustness tests for chromatographic analysis methods (n = 3)
| Method | Parameters | Values | Average recovery % | R.S.D. % |
| Method I | Normal conditions | 100.16 | 0.27 | |
| The low flow rate of the mobile phase | 0.90 mL min−1 | 99.84 | 0.34 | |
| The high flow rate of the mobile phase | 1.10 mL min−1 | 99.69 | 0.38 | |
| High detection wavelength | 293 nm. | 99.87 | 0.20 | |
| Low detection wavelength | 289 nm. | 99.92 | 0.30 | |
| High acetonitrile content in the mobile phase | 22% | 99.89 | 0.23 | |
| Low acetonitrile content in the mobile phase | 18% | 99.76 | 0.26 | |
| Method II | Normal conditions | 99.95 | 0.33 | |
| The low flow rate of the mobile phase | 0.90 mL min−1 | 99.52 | 0.35 | |
| The high flow rate of the mobile phase | 1.10 mL min−1 | 99.49 | 0.39 | |
| High detection wavelength | 293 nm. | 99.67 | 0.31 | |
| Low detection wavelength | 289 nm. | 99.48 | 0.42 | |
| The high ethanol content in the mobile phase | 22% | 99.59 | 0.37 | |
| The low ethanol content in the mobile phase | 18% | 99.31 | 0.35 | |
Application of the chromatographic method to pharmaceutical formulations
Six tablets (Minelza, 30 mg), were analyzed by developed chromatographic methods. The results obtained by both chromatographic methods and the mean, standard deviation, and relative standard deviation values calculated over 6 replications are given in Table 7. A comparison of the results obtained with both chromatographic methods in terms of means was made using Student's (t) test, and comparisons in terms of standard deviations were made using the Fischer (F) test. When the results in the table were examined, it is clear that there was no important difference between the two chromatographic methods in terms of accuracy and precision. t and F values calculated for 6 trials were lower than the values reported in the relevant tables.
Statistical evaluation of analysis results of mirtazapine tablets (Minelza, 30 mg)
| Sample | Method I | Method II | ||
| mg/tablet | % | mg/tablet | % | |
| 1 | 29.77 | 99.43 | 30.26 | 100.84 |
| 2 | 29.62 | 98.93 | 29.93 | 99.74 |
| 3 | 30.02 | 100.27 | 30.13 | 100.41 |
| 4 | 29.99 | 100.17 | 29.98 | 99.91 |
| 5 | 29.93 | 99.97 | 30.00 | 99.98 |
| 6 | 30.31 | 101.24 | 29.74 | 99.11 |
| Average | 29.94 | 100.00 | 30.007 | 100.00 |
| SD | 0.24 | 0.79 | 0.18 | 0.59 |
| RSD % | 0.79 | 0.79 | 0.59 | 0.59 |
| tvalue/t(95, 4) | 0.1218/2.7764 | |||
| Fvalue/F(95, 4) | 3.0270/6.3882 | |||
Stability of the standard solution
No stability-related problems were observed when the standard solution was kept under different conditions. The standard solution was able to stay stable at laboratory conditions (25 °C) for 48 h and at refrigerator temperature (4 °C) for 10 days without degradation. The stability of the standard solution was expressed as the average recovery %, which was determined to be in the range of 99.66–99.95%. The fact that the stability study results are within acceptable limits (±2%) indicates that the standard solution can be evaluated under normal laboratory conditions without significant loss. Stability conditions and recovery values are presented in Table 8.
Stability results at different conditions (n = 3)
| Storage conditions | Average recovery % | |
| Room temperature (25 °C) | 12 h | 99.66 |
| 24 h | 99.72 | |
| 36 h | 99.74 | |
| 48 h | 99.83 | |
| Refrigerator temperature (4 °C) | 10 days | 99.95 |
Greenness assessment of chromatographic methods
The greenness evaluation pictograms of the chromatographic methods have been presented in Fig. 3. While the score of the chromatographic method I (using acetonitrile in the mobile phase) is 0.67, the score of the chromatographic method II (using ethanol in the mobile phase) is 0.76. In the AGREE pictogram of the chromatographic method I, the scores corresponding to the GAC principles 1, 7, 8, 10, and 11 are quite low, while the performance for principles 2, 4, and 6 is excellent (Fig. 3A). In the AGREE pictogram of the chromatographic method II, the scores for the GAC 1 and 7 principles are quite low, while the performance for principles 2, 4, 6, 10, and 11 are excellent (Fig. 3C). It can be said that both chromatographic methods are green, but the second chromatographic method (using ethanol in the mobile phase) is greener than the other method.
A: AGREE pictogram of the chromatographic method I, B: corresponding color scale for reference, C: AGREE pictogram of the chromatographic method II
Citation: Acta Chromatographica 36, 3; 10.1556/1326.2023.01155
Discussion
This study aims to evaluate the chromatographic behavior of mirtazapine using an environment and operator-friendly mobile phase. Contrary to conventional chromatographic components, the use of ethanol in the mobile phase has brought an alternative perspective to environmentally friendly analyses. The greenness of the analytical methods is evaluated from the sample preparation stage to the detection stage. We didn't use any toxic solvent in the extraction stage of the analytical method we developed. was needed by using any toxic solvent. The sample preparation step was carried out with ultrapure water and was quite simple.
Chromatographic analyses were performed using ethanol that is safe for the environment and analyst health. An important result of this study is that it produces non-toxic waste. Mirtazapine was selectively analyzed with high sensitivity, accuracy, linearity, repeatability, and robustness by the chromatographic method we developed. The detection and quantification limits of the developed chromatographic method were quite low. Additionally, the system suitability parameters showed that the chromatographic performance was not lacking. The purpose of this study was achieved by meeting all the needs of the validation process without compromising the quality of the chromatographic performance. As the HPLC technique is widely used in the pharmaceutical industry, This greening effort is very important to minimize toxicity during the analysis stage.
The results of our study showed that ethanol and water-based mobile phases can be successfully applied in pharmaceutical analysis. Such chromatographic analyses will encourage analysts who want to develop more environmentally friendly analysis methods in their laboratories. When our chromatographic method was compared with other reported methods, detection and quantification limits values, and improved greening aspects are better. The findings showed that the green quantification of mirtazapine in pharmaceutical products was performed without losing chromatographic quality thanks to the reduced hazardous effects.
Conclusions
Developing environmentally friendly methods to prevent environmental pollution, reducing energy consumption and waste management has become even more critical for the future of humanity in a world where clean water resources are rapidly decreasing and air pollution is a significant problem, the effects of global warming and climate change are more evident. It is thought that the method developed with this thought can be considered an environmentally friendly alternative to the methods currently used in the quantification of apixaban in pharmaceutical products in the pharmaceutical industry. The developed liquid chromatographic method includes safe and economical organic solvents such as ethanol for the determination of apixaban in pharmaceutical products. The greenness profile score of the developed method was found to be higher than the published chromatographic methods for the determination of mirtazapine. No method for the quantitative determination of mirtazapine without the use of toxic solvents was found in the reviewed scientific journals. Therefore, the proposed method can be considered an advantageous and innovative method in the application of green analytical chemistry, being an alternative ecologically safe and correct to be used in routine quality control analysis.
Acknowledgment
The authors thank Bilim Pharmaceuticals for providing the pure mirrtazapine reference standard and supporting this study.
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