CN116465985A - Method for detecting residual solvent in alpha-ribose mesylate by gas chromatography - Google Patents
Method for detecting residual solvent in alpha-ribose mesylate by gas chromatography Download PDFInfo
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- 239000013557 residual solvent Substances 0.000 title claims abstract description 18
- -1 alpha-ribose mesylate Chemical compound 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000004817 gas chromatography Methods 0.000 title claims abstract description 15
- 238000001514 detection method Methods 0.000 claims abstract description 14
- 238000002347 injection Methods 0.000 claims abstract description 13
- 239000007924 injection Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000012159 carrier gas Substances 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000007789 gas Substances 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000523 sample Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011550 stock solution Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 4
- 239000012085 test solution Substances 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000013558 reference substance Substances 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims 2
- 230000014759 maintenance of location Effects 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- 238000007789 sealing Methods 0.000 claims 2
- 238000005303 weighing Methods 0.000 claims 2
- 230000005540 biological transmission Effects 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 239000012488 sample solution Substances 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 2
- 239000010453 quartz Substances 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 abstract 1
- 239000012088 reference solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000012490 blank solution Substances 0.000 description 4
- 238000011067 equilibration Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Description
技术领域technical field
本发明属于化学检测技术领域,特别涉及一种气相色谱法检测α-核糖甲磺酸酯中残留溶剂的方法。The invention belongs to the technical field of chemical detection, in particular to a method for detecting residual solvent in α-ribose mesylate by gas chromatography.
背景技术Background technique
α-核糖甲磺酸酯是盐酸吉西他滨原料药合成中重要的起始物料,盐酸吉西他滨是一种临床应用广泛的抗癌药,其注射剂在许多国家上市,在源头控制好起始物料的质量尤为重要,目前对于α-核糖甲磺酸酯中残留溶剂的检测方法还没有报道,α-核糖甲磺酸酯中有机溶剂残留对产品质量有一定的影响,因此,开发出一种能有效检测α-核糖甲磺酸酯中残留溶剂的检测方法是十分必要的,我们经过长时间研究终于研究出一种能检测出α-核糖甲磺酸酯中残留溶剂的方法,而且此方法操作方便,检测效果较佳。α-Ribose mesylate is an important starting material in the synthesis of gemcitabine hydrochloride raw materials. Gemcitabine hydrochloride is an anticancer drug widely used in clinical practice. Its injections are listed in many countries. It is particularly important to control the quality of starting materials at the source. At present, there is no report on the detection method of residual solvents in α-ribose mesylate. Residual organic solvents in α-ribose mesylate have a certain impact on product quality. Yes, after a long period of research, we have finally developed a method that can detect residual solvents in α-ribose mesylate, and this method is easy to operate and has better detection results.
发明内容Contents of the invention
针对现有技术的不足,本发明的目的在于提供一种气相色谱法检测α-核糖甲磺酸酯中残留溶剂的方法,包括以下步骤:For the deficiencies in the prior art, the object of the present invention is to provide a method for gas chromatography detection of residual solvent in α-ribose mesylate, comprising the following steps:
1)仪器与色谱条件的选择:气相色谱仪;色谱柱为DB-WAX(30m×0.53mm×1.0μm)毛细管色谱柱;采用FID检测器,色谱柱初始温度为35-45℃,保持时间为8-12min,然后以8-12℃/min的升温速率升至80℃,再以35-45℃/min的升温速率升至色谱柱最终温度为250℃,色谱柱最终温度保持时间为2-5min;载气为氮气,所述载气流速为2.5-3.5ml/min,分流比为20:1;进样口温度为190-210℃,检测器温度为240-260℃;进样方式为顶空进样,平衡温度90℃,定量环温度100℃,传输线温度110℃,平衡时间30min;进样体积为1.0mL。1) Selection of instrument and chromatographic conditions: gas chromatograph; the chromatographic column is DB-WAX (30m×0.53mm×1.0μm) capillary column; using FID detector, the initial temperature of the chromatographic column is 35-45°C, the holding time is 8-12min, and then the temperature is raised to 80°C at a rate of 8-12°C/min, and then the final temperature of the column is raised to 250°C at a rate of 35-45°C/min. The time is 2-5min; the carrier gas is nitrogen, the carrier gas flow rate is 2.5-3.5ml/min, the split ratio is 20:1; the inlet temperature is 190-210°C, the detector temperature is 240-260°C; the sampling method is headspace injection, the equilibrium temperature is 90°C, the loop temperature is 100°C, the transfer line temperature is 110°C, and the equilibrium time is 30min; the injection volume is 1.0mL.
2)配制溶液,配制下列溶液:2) Prepare the solution and prepare the following solutions:
a.空白溶液(稀释剂):二甲基亚砜;a. blank solution (diluent): dimethyl sulfoxide;
b.对照品溶液:称取丙酮0.5g、二氯甲烷0.06g、四氢呋喃0.072g、乙酸乙酯0.5g、甲苯0.089g、乙醚0.5g、乙腈0.041g、二氟溴乙酸乙酯0.1g,置50ml量瓶中,用稀释剂稀释至刻度,摇匀,作为储备液;移取储备液2.0ml,置100ml量瓶中,用稀释剂稀释至刻度,摇匀,再精密量取5.0ml置20ml顶空瓶中,加盖密封。C.供试品溶液:取α-核糖甲磺酸酯0.2g,置20ml顶空瓶中,加5.0ml稀释剂溶解,加盖密封,摇匀,即得,平行配2份。b. Reference substance solution: Weigh 0.5g of acetone, 0.06g of dichloromethane, 0.072g of tetrahydrofuran, 0.5g of ethyl acetate, 0.089g of toluene, 0.5g of diethyl ether, 0.041g of acetonitrile, and 0.1g of ethyl difluorobromoacetate, put them in a 50ml measuring bottle, dilute to the mark with a diluent, shake well, and use it as a stock solution; pipette 2.0ml of the stock solution and put it in a 100ml measuring bottle , dilute to the mark with a diluent, shake well, then accurately measure 5.0ml, place it in a 20ml headspace bottle, and seal it with a cap. C. The test solution: take 0.2g of α-ribose mesylate, put it in a 20ml headspace bottle, add 5.0ml of diluent to dissolve, seal it with a cap, shake well, and prepare 2 parts in parallel.
按下述序列表进样:Inject samples according to the following sequence table:
α-核糖甲磺酸酯供试品溶液中各个溶剂按加外标法以峰面积计算。Each solvent in the α-ribose mesylate solution of the test product is calculated by the peak area by adding an external standard method.
优选地,本发明所述气相色谱分析选定的色谱条件如下:Preferably, the selected chromatographic conditions for gas chromatography analysis of the present invention are as follows:
采用FID检测器;Using FID detector;
色谱柱:DB-WAX(30m×0.53mm×1.0μm)毛细管色谱柱;Chromatographic column: DB-WAX (30m×0.53mm×1.0μm) capillary column;
程序升温:起始温度为40℃,维持10分钟,以每分钟10℃升温至80℃,再以每分钟40℃升温至250℃维持3分钟。Programmed temperature rise: the initial temperature is 40°C, maintained for 10 minutes, raised to 80°C at a rate of 10°C per minute, and then raised to 250°C at a rate of 40°C per minute and maintained for 3 minutes.
载气:氮气,流速为3.0mL/min,分流比:20:1;Carrier gas: nitrogen, flow rate 3.0mL/min, split ratio: 20:1;
进样口温度:200℃;Injection port temperature: 200°C;
检测器(FID)温度:250℃;Detector (FID) temperature: 250°C;
进样方式:顶空进样,平衡温度90℃,定量环温度100℃,传输线温度110℃,平衡时间30min;Sampling method: headspace sampling, equilibration temperature 90°C, quantitative loop temperature 100°C, transfer line temperature 110°C, equilibration time 30min;
进样体积:1.0ml。Injection volume: 1.0ml.
本发明的有益效果如下:The beneficial effects of the present invention are as follows:
本发明能有效可以有效分离α-核糖甲磺酸酯中残留溶剂并能定量检测其含量,残留溶剂为乙醚、丙酮、四氢呋喃、乙酸乙酯、二氯甲烷、乙腈、甲苯、二氟溴乙酸乙酯中的一种或二种以上,该方法操作简便,专属性强,灵敏度、准确度高,从而确保α-核糖甲磺酸酯质量可控,目前对于α-核糖甲磺酸酯中多种残留溶剂的检测方法还没有报道,本发明可为α-核糖甲磺酸酯中残留溶剂检测提供一种可靠的检测方法,适于全面推广和应用。The present invention can effectively separate the residual solvent in α-ribose mesylate and quantitatively detect its content. The residual solvent is ether, acetone, tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, toluene, and ethyl difluorobromoacetate. The detection of residual solvents in ribose mesylate provides a reliable detection method, which is suitable for general promotion and application.
附图说明Description of drawings
图1为空白溶液色谱图;Fig. 1 is blank solution chromatogram;
图2为对照品溶液色谱图;Fig. 2 is reference substance solution chromatogram;
图3为供试品溶液色谱图;Fig. 3 is need testing solution chromatogram;
图4为各溶剂线性测试结果图;Fig. 4 is each solvent linearity test result figure;
图5为准确度溶液色谱图。Fig. 5 is the accuracy solution chromatogram.
具体实施方式Detailed ways
本发明将结合实施例(附图)对上述内容作进一步补充说明,但不应该理解为本发明范围仅限于以下实例。The present invention will further supplement the above content with reference to the embodiments (accompanying drawings), but it should not be understood that the scope of the present invention is limited to the following examples.
以下实施例中采用的仪器和色谱条件如下:The instrument and chromatographic conditions adopted in the following examples are as follows:
气相色谱仪为Agilent7890A,采用FID检测器,柱初始温度为35-45℃,保持时间为8-12min,然后以8-12℃/min的升温速率升至80℃,再以35-45℃/min的升温速率升至柱最终温度为250℃,柱最终温度保持时间为2-5min;载气为氮气,优选的,所述载气流速为2.5-3.5ml/min,分流比为20:1;进样口温度为190-210℃,检测器温度为240-260℃;进样方式为顶空进样,平衡温度90℃,定量环温度100℃,传输线温度110℃,平衡时间30min;进样体积为1.0mL。The gas chromatograph is Agilent7890A, using FID detector, the initial temperature of the column is 35-45°C, the holding time is 8-12min, then it is raised to 80°C at a heating rate of 8-12°C/min, and then the final temperature of the column is raised to 250°C at a heating rate of 35-45°C/min, and the holding time of the final temperature of the column is 2-5min; the carrier gas is nitrogen. The flow ratio is 20:1; the inlet temperature is 190-210°C, the detector temperature is 240-260°C; the injection method is headspace injection, the equilibrium temperature is 90°C, the quantitative loop temperature is 100°C, the transfer line temperature is 110°C, and the equilibration time is 30 minutes; the injection volume is 1.0mL.
实施例1Example 1
专属性考察,如图1~图2,图5所示:Specificity investigation, as shown in Figure 1-2 and Figure 5:
精密量取空白溶液,对照品溶液、各杂质定位溶液各1.0mL,注入气色谱仪,记录色谱图。各杂质定位及分离度实验结果显示,空白无干扰,其他溶剂对样品测定无干扰,其相邻溶剂之间最小分离度为2.60,本分析条件专属性良好,测试结果如下:Precisely measure 1.0 mL of the blank solution, the reference solution, and each impurity positioning solution, inject them into the gas chromatograph, and record the chromatograms. The results of the impurity location and resolution experiments show that the blank has no interference, and other solvents have no interference to the sample determination, and the minimum resolution between adjacent solvents is 2.60. The specificity of the analysis conditions is good, and the test results are as follows:
实施例2Example 2
灵敏度试验考察结果:Sensitivity test investigation results:
定量限(LOQ)结果如下:The limit of quantitation (LOQ) results are as follows:
检测限(LOD)结果如下:The limit of detection (LOD) results are as follows:
各溶剂的定量限、检测限测定结果显示:各个溶剂检测灵敏度高(远高于限度标准值),方法灵敏度符合要求。The determination results of quantification limit and detection limit of each solvent show that each solvent has high detection sensitivity (far higher than the limit standard value), and the sensitivity of the method meets the requirements.
实施例3Example 3
线性考察,如图4所示:Linear investigation, as shown in Figure 4:
以峰面积对浓度作图,乙醚在浓度40.664μg/mL-304.980μg/mL范围内,丙酮在浓度40.120μg/mL-300.900μg/mL范围内,四氢呋喃在浓度5.928μg/mL-44.460μg/mL范围内,乙酸乙酯在浓度40.160μg/mL-301.200μg/mL范围内,二氯甲烷在浓度5.128μg/mL-38.460μg/mL范围内,乙腈在浓度3.232μg/mL-24.240μg/mL范围内,甲苯在浓度7.016μg/mL-52.620μg/mL范围内,二氟溴乙酸乙酯在浓度8.792μg/mL-65.940μg/mL范围内,样品浓度与峰面积成线性关系,线性良好,具体结果如下:The peak area is plotted against the concentration, the concentration of ether is in the range of 40.664μg/mL-304.980μg/mL, the concentration of acetone is in the range of 40.120μg/mL-300.900μg/mL, the concentration of tetrahydrofuran is in the range of 5.928μg/mL-44.460μg/mL, and the concentration of ethyl acetate is in the range of 40.160μg/mL-301.200μg In the range of 5.128μg/mL-38.460μg/mL for dichloromethane, in the range of 3.232μg/mL-24.240μg/mL for acetonitrile, in the range of 7.016μg/mL-52.620μg/mL for toluene, in the range of 8.792μg/mL-65.940μg/mL for ethyl difluorobromoacetate, the sample concentration and The peak area has a linear relationship, and the linearity is good. The specific results are as follows:
实施例4Example 4
准确度考察,色谱图如图5所示:Accuracy inspection, the chromatogram is shown in Figure 5:
分别按乙醚、丙酮、四氢呋喃、乙酸乙酯、二氯甲烷、乙腈、甲苯、二氟溴乙酸乙酯的限度浓度50%、100%、150%加样配制回收率溶液,每组浓度平行配制3份,同时配制一份供试品溶液和一份对照品溶液,按照上述色谱条件测定,计算回收率。各溶剂回收率均在90%-110%范围内,结果见下表:Respectively add samples to prepare recovery rate solutions according to the limit concentrations of ether, acetone, tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, toluene, and ethyl difluorobromoacetate at 50%, 100%, and 150%. Prepare 3 parts in parallel for each group of concentrations, prepare a part of the test solution and a part of the reference solution at the same time, measure according to the above-mentioned chromatographic conditions, and calculate the recovery rate. Each solvent recovery rate is in the range of 90%-110%, the results are shown in the following table:
实施例5Example 5
耐用性考察,分别更换色谱柱、改变初始柱温(40±1℃)、载气流速(3.0±0.1ml/min)、进样口温度(200±2℃)、升温速率(±1℃/min),对对照品溶液中各溶剂峰面积的RSD及各溶剂出峰的最小分离度结果进行比较,考察其耐用性。改变色谱条件参数,对照品溶液中各溶剂6针峰面积最大RSD为6.7%,小于10%;系统适用性溶液的分离度均大于1.5,说明该方法耐用性良好。结果见下表:To inspect the durability, replace the chromatographic column, change the initial column temperature (40±1°C), carrier gas flow rate (3.0±0.1ml/min), injection port temperature (200±2°C), and heating rate (±1°C/min), compare the RSD of the peak area of each solvent in the reference solution and the minimum resolution of each solvent’s peak separation, and investigate its durability. Changing the parameters of the chromatographic conditions, the maximum RSD of the 6-pin peak area of each solvent in the reference solution was 6.7%, which was less than 10%. The results are shown in the table below:
以上所述仅是本发明的优选实施方式,应当指出,本技术领域人员应当明了,在不脱离本发明原理的前提下,还可以作出若干改进,这些改进也应视为本发明的保护范围,不应视为对本发明的具体限制。The above is only a preferred embodiment of the present invention. It should be pointed out that those skilled in the art should understand that some improvements can be made without departing from the principles of the present invention.
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