Abstract: Objective: To check the illegal production of sildenafil citrate raw materials and the illegal addition of sildenafil citrate in Chinese patent medicines and sexual health medicines. METHODS: A chemical separation method was established to isolate and extract sildenafil from the raw materials, proprietary Chinese medicines and sexual health products containing sildenafil citrate by high performance liquid chromatography , and to use mid-infrared spectrophotometry (bromination). Potassium tablet) for qualitative identification. Results The high performance liquid chromatography method was used to detect 28 batches of raw materials containing sildenafil and 62 batches of Chinese patent medicines of various dosage forms, and the infrared identification was carried out, and sildenafil was detected. Conclusion: This method is specific, fast and simple.
Key words: bulk drug; proprietary Chinese medicine; sildenafil; infrared spectrum; chemical component sildenafil Citrate is invented and produced by Pfizer Pharmaceutical Co., Ltd., is the world's * FDA-approved treatment Oral medication for erectile dysfunction (ED). Since 2000, Viagra (sildenafil) has sales worldwide of more than $800 million, accounting for 90% of erectile dysfunction (ED) drugs. Huge sales and profits have prompted criminals to counterfeit, fake, or illegally join sildenafil in some proprietary Chinese medicines. It has been reported in the literature that thin layer chromatography (TLC), high performance liquid chromatography ( HPLC ) and high performance liquid chromatography- mass spectrometry (LC-MS) are used to identify and quantify sildenafil in Chinese patent medicines. In the absence of LC-MS technology, only the retention time from TLC and HPLC is consistent, and it is not fully certain that sildenafil is contained in the sample. The specificity of the mid-infrared spectrophotometer and infrared spectroscopy makes this technology a powerful drug identification. tool. This paper reports the method of extracting and isolating sildenafil from various health care drugs and proprietary Chinese medicines, and identifying them by infrared spectroscopy.
1 Materials and methods
1.1 Sources of chemical reagents and instruments: Sources of various health products, foods, and counterfeit Pfizer Pharmaceuticals Co., Ltd., collected by law enforcement agencies such as the State Drug Administration, Shanghai Municipal Drug Administration, and Shanghai Municipal Bureau. ) and raw materials, including 28 batches of raw materials, about 62 illegal products. Sildena citrate non-control: Pfizer Pharmaceutical Co., Ltd., batch number: 98068-QCS-7, content 99.8%. All other reagents were of analytical grade.
Instrument: Nicolet AVATAR 360 FT IR mid-infrared analyzer, scanning times 16, resolution 4, measuring range 4000 ~ 400 / cm.
1.2 Method for extracting and separating sildenafil All samples were first separated and identified by HPLC method. When the peak of the retention time of the main peak retention time of sildenafil citrate appeared in the sample, the sample was used as the raw material. According to the infrared spectrophotometry, potassium bromide tablets, the infrared spectrum obtained is compared with the map of sildenafil citrate or sildenafil control. If there is a difference in the infrared spectrum, which may be caused by other acid radicals, the sildenafil salt of other acid radicals is converted into the form of sildenafil according to the method of (1), and then compared with the infrared spectrum of sildenafil. Infrared identification was carried out; 28 batches of raw material samples were tested, and the matching ratios of their infrared spectra and reference maps were all in the range of 94.9% to 98.7%. When the sample is a preparation, sildenafil is obtained by the following separation extraction method according to the liquid chromatogram.
(1) When HPLC detects a sildenafil chromatographic peak or sildenafil chromatographic peak accounted for more than 50% of the total peak area, take the appropriate amount of sample powder, add 3mL of water, shake to disperse, add ammonia test solution (about 5 mL) was made alkaline, 20 mL of chloroform was added, shaken for 5 min, filtered, and the solid was washed with 5 mL of chloroform. The chloroform layer was separated, evaporated to dryness on a water bath, and the residue was washed with diethyl ether. The residue was subjected to infrared spectrophotometry, potassium bromide tableting, and the obtained spectrum was compared with the infrared spectrum prepared by the same method as the sildenafil citrate reference substance. For the 66 batches of the preparation samples, the matching ratios of their infrared spectra to the sildenafil reference maps ranged from 92.9% to 96.7.
(2) When the sample contains a large amount of traditional Chinese medicine and the sildenafil chromatographic peak detected by HPLC accounts for less than 50% of the total peak area, the sample powder can be taken when the above method cannot be separated and extracted to obtain the higher purity sildenafil. Appropriate amount, placed in a centrifuge tube, add 2mL of methanol, solubilized by ultrasound, centrifuged. The supernatant was taken as the test solution; another 10 mg of sildenafil citrate reference substance was added, and 1 mL of methanol was dissolved to prepare a reference solution. According to the thin layer chromatography method, 300-400 μL of each of the above two solutions was taken up, and the strips were spotted on a 20 cm×20 cm GF254 thin layer plate, and developed with a n-hexane-ethanol ammonia aqueous solution (30:70:1) as a developing agent. At the UV 254nm lamp inspection, the spot of the sample which is consistent with the Rf value of the sildenafil citrate reference substance and the spot of the sildenafil citrate reference substance were simultaneously taken out, placed in a test tube, 2 mL of methanol was added, and ultrasonication was performed for 5 min. Centrifugation. The supernatant was evaporated to dryness in a water bath, and the residue was washed with a small amount of diethyl ether. According to the infrared spectrophotometry, the potassium bromide tablet was obtained, and the obtained spectrum was compared with the infrared spectrum prepared by the same method as the sildenafil citrate reference substance. Six batches of samples were tested and their match rates with the reference map were 89.2% to 94.8%.
2 Discussion In the infrared spectrum of the sample and the control, the absorption peak reflecting the structural characteristics of sildenafil can be found: amide group (-CONH-) 3100.1 / cm, 1 689.0 / cm (amide I band). 1531.5/cm (amide II band), 1290.1/cm (amide III band). 749.3/cm; sulfonamide group (RSO2N-) 1172.5 /cm. The sulfone group (SO2) was 1330.7/cm. Unsaturated ether bond (one (COC) 1248.5 / / cm. 1067.7 / cm; benzene ring skeleton (C == C) and carbon and nitrogen bonds (C == N). 1 581.1 / cm, 1599.9 / cm; 1489.8 / cm 1464.8/cm; benzene ring carbon-hydrogen bond (-C--H): 789.8 /cm, 688.8/cm, 3100/cm; nitrogen methyl (N--CH3) 1390.9/cm; methyl and methylene ( C--H) 2973.9 to 2795.9/cm, 1455.6 /cm, 1370.5/cm, etc., thereby confirming that the raw material sample and the preparation sample contain sildenafil in the infrared spectrum of the sample and the control, due to the addition of citric acid To reflect some of the fine absorption peaks of sildenafil, but by comparing the infrared spectrum of the sample with the control map, it can be confirmed that the raw material sample is sildenafil citrate instead of sildenafil, which is determined by HPLC. The basis for the calculation is provided. Then, such a sample is converted into the form of sildenafil citrate by the method of (1). The infrared spectrum consistent with the figure can be obtained, sildenafil The structural characteristic peaks are fully apparent.
In the infrared spectrum of the sample and control. Due to the solvent and silica gel, they are different from the figure, but the infrared spectrum of the sample obtained under the same conditions is consistent with the control map. And reflect the amide group (--CONH-) 3311.2 / cm, 1689.7 / cm (amide I band). 1531.0/cm (amide II band). 1290.0/cm (amide III band). 745.3/cm: sulfone group (SO2) 1330.9/cm; unsaturated ether bond (C-(COC) 1247.4/cm, 1066.4/cm; benzene ring skeleton (C=C) and carbon-nitrogen bond (C--N) 1581.1/cm, 1600.6/cm; 1489.2/cm, 1465.0/cm; benzene ring carbon-hydrogen bond (==C-H): 790.8 /cm, 689.0/cm, 3100/cm; methyl and methylene (C- -H) 29ll. 7 to 2795.4/cm, 1457.2/cm, etc., thereby confirming the sildenafil contained in the preparation sample.
The TLC spot separated by the method (2) can also be replaced by chloroform instead of methanol as the solvent. The infrared light spectrum of the sample obtained by the same method is consistent with the infrared spectrum of the reference substance, and the matching ratio of the control map of Fig. 1 is 89.0. %the above.
references
[1] Zhang Qiming, Yin Hua, Huang Haiwei, et al. To examine the method of illegally adding sildenafil in Chinese medicine [J]. Journal of Pharmaceutical Analysis. 2002.22(4). 315
[2] National Drug Administration Standard (Trial) WJ-104(X-305)-99.1999
Key words: bulk drug; proprietary Chinese medicine; sildenafil; infrared spectrum; chemical component sildenafil Citrate is invented and produced by Pfizer Pharmaceutical Co., Ltd., is the world's * FDA-approved treatment Oral medication for erectile dysfunction (ED). Since 2000, Viagra (sildenafil) has sales worldwide of more than $800 million, accounting for 90% of erectile dysfunction (ED) drugs. Huge sales and profits have prompted criminals to counterfeit, fake, or illegally join sildenafil in some proprietary Chinese medicines. It has been reported in the literature that thin layer chromatography (TLC), high performance liquid chromatography ( HPLC ) and high performance liquid chromatography- mass spectrometry (LC-MS) are used to identify and quantify sildenafil in Chinese patent medicines. In the absence of LC-MS technology, only the retention time from TLC and HPLC is consistent, and it is not fully certain that sildenafil is contained in the sample. The specificity of the mid-infrared spectrophotometer and infrared spectroscopy makes this technology a powerful drug identification. tool. This paper reports the method of extracting and isolating sildenafil from various health care drugs and proprietary Chinese medicines, and identifying them by infrared spectroscopy.
1 Materials and methods
1.1 Sources of chemical reagents and instruments: Sources of various health products, foods, and counterfeit Pfizer Pharmaceuticals Co., Ltd., collected by law enforcement agencies such as the State Drug Administration, Shanghai Municipal Drug Administration, and Shanghai Municipal Bureau. ) and raw materials, including 28 batches of raw materials, about 62 illegal products. Sildena citrate non-control: Pfizer Pharmaceutical Co., Ltd., batch number: 98068-QCS-7, content 99.8%. All other reagents were of analytical grade.
Instrument: Nicolet AVATAR 360 FT IR mid-infrared analyzer, scanning times 16, resolution 4, measuring range 4000 ~ 400 / cm.
1.2 Method for extracting and separating sildenafil All samples were first separated and identified by HPLC method. When the peak of the retention time of the main peak retention time of sildenafil citrate appeared in the sample, the sample was used as the raw material. According to the infrared spectrophotometry, potassium bromide tablets, the infrared spectrum obtained is compared with the map of sildenafil citrate or sildenafil control. If there is a difference in the infrared spectrum, which may be caused by other acid radicals, the sildenafil salt of other acid radicals is converted into the form of sildenafil according to the method of (1), and then compared with the infrared spectrum of sildenafil. Infrared identification was carried out; 28 batches of raw material samples were tested, and the matching ratios of their infrared spectra and reference maps were all in the range of 94.9% to 98.7%. When the sample is a preparation, sildenafil is obtained by the following separation extraction method according to the liquid chromatogram.
(1) When HPLC detects a sildenafil chromatographic peak or sildenafil chromatographic peak accounted for more than 50% of the total peak area, take the appropriate amount of sample powder, add 3mL of water, shake to disperse, add ammonia test solution (about 5 mL) was made alkaline, 20 mL of chloroform was added, shaken for 5 min, filtered, and the solid was washed with 5 mL of chloroform. The chloroform layer was separated, evaporated to dryness on a water bath, and the residue was washed with diethyl ether. The residue was subjected to infrared spectrophotometry, potassium bromide tableting, and the obtained spectrum was compared with the infrared spectrum prepared by the same method as the sildenafil citrate reference substance. For the 66 batches of the preparation samples, the matching ratios of their infrared spectra to the sildenafil reference maps ranged from 92.9% to 96.7.
(2) When the sample contains a large amount of traditional Chinese medicine and the sildenafil chromatographic peak detected by HPLC accounts for less than 50% of the total peak area, the sample powder can be taken when the above method cannot be separated and extracted to obtain the higher purity sildenafil. Appropriate amount, placed in a centrifuge tube, add 2mL of methanol, solubilized by ultrasound, centrifuged. The supernatant was taken as the test solution; another 10 mg of sildenafil citrate reference substance was added, and 1 mL of methanol was dissolved to prepare a reference solution. According to the thin layer chromatography method, 300-400 μL of each of the above two solutions was taken up, and the strips were spotted on a 20 cm×20 cm GF254 thin layer plate, and developed with a n-hexane-ethanol ammonia aqueous solution (30:70:1) as a developing agent. At the UV 254nm lamp inspection, the spot of the sample which is consistent with the Rf value of the sildenafil citrate reference substance and the spot of the sildenafil citrate reference substance were simultaneously taken out, placed in a test tube, 2 mL of methanol was added, and ultrasonication was performed for 5 min. Centrifugation. The supernatant was evaporated to dryness in a water bath, and the residue was washed with a small amount of diethyl ether. According to the infrared spectrophotometry, the potassium bromide tablet was obtained, and the obtained spectrum was compared with the infrared spectrum prepared by the same method as the sildenafil citrate reference substance. Six batches of samples were tested and their match rates with the reference map were 89.2% to 94.8%.
2 Discussion In the infrared spectrum of the sample and the control, the absorption peak reflecting the structural characteristics of sildenafil can be found: amide group (-CONH-) 3100.1 / cm, 1 689.0 / cm (amide I band). 1531.5/cm (amide II band), 1290.1/cm (amide III band). 749.3/cm; sulfonamide group (RSO2N-) 1172.5 /cm. The sulfone group (SO2) was 1330.7/cm. Unsaturated ether bond (one (COC) 1248.5 / / cm. 1067.7 / cm; benzene ring skeleton (C == C) and carbon and nitrogen bonds (C == N). 1 581.1 / cm, 1599.9 / cm; 1489.8 / cm 1464.8/cm; benzene ring carbon-hydrogen bond (-C--H): 789.8 /cm, 688.8/cm, 3100/cm; nitrogen methyl (N--CH3) 1390.9/cm; methyl and methylene ( C--H) 2973.9 to 2795.9/cm, 1455.6 /cm, 1370.5/cm, etc., thereby confirming that the raw material sample and the preparation sample contain sildenafil in the infrared spectrum of the sample and the control, due to the addition of citric acid To reflect some of the fine absorption peaks of sildenafil, but by comparing the infrared spectrum of the sample with the control map, it can be confirmed that the raw material sample is sildenafil citrate instead of sildenafil, which is determined by HPLC. The basis for the calculation is provided. Then, such a sample is converted into the form of sildenafil citrate by the method of (1). The infrared spectrum consistent with the figure can be obtained, sildenafil The structural characteristic peaks are fully apparent.
In the infrared spectrum of the sample and control. Due to the solvent and silica gel, they are different from the figure, but the infrared spectrum of the sample obtained under the same conditions is consistent with the control map. And reflect the amide group (--CONH-) 3311.2 / cm, 1689.7 / cm (amide I band). 1531.0/cm (amide II band). 1290.0/cm (amide III band). 745.3/cm: sulfone group (SO2) 1330.9/cm; unsaturated ether bond (C-(COC) 1247.4/cm, 1066.4/cm; benzene ring skeleton (C=C) and carbon-nitrogen bond (C--N) 1581.1/cm, 1600.6/cm; 1489.2/cm, 1465.0/cm; benzene ring carbon-hydrogen bond (==C-H): 790.8 /cm, 689.0/cm, 3100/cm; methyl and methylene (C- -H) 29ll. 7 to 2795.4/cm, 1457.2/cm, etc., thereby confirming the sildenafil contained in the preparation sample.
The TLC spot separated by the method (2) can also be replaced by chloroform instead of methanol as the solvent. The infrared light spectrum of the sample obtained by the same method is consistent with the infrared spectrum of the reference substance, and the matching ratio of the control map of Fig. 1 is 89.0. %the above.
references
[1] Zhang Qiming, Yin Hua, Huang Haiwei, et al. To examine the method of illegally adding sildenafil in Chinese medicine [J]. Journal of Pharmaceutical Analysis. 2002.22(4). 315
[2] National Drug Administration Standard (Trial) WJ-104(X-305)-99.1999
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Specification:
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