CN104678017A - Method for detecting organic-solvent residues in dabigatran etexilate - Google Patents
Method for detecting organic-solvent residues in dabigatran etexilate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000003960 organic solvent Substances 0.000 title claims abstract description 18
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title abstract description 23
- 229960000288 dabigatran etexilate Drugs 0.000 title abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 150
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 139
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 135
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 99
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000001514 detection method Methods 0.000 claims abstract description 14
- 238000002347 injection Methods 0.000 claims abstract description 8
- 239000007924 injection Substances 0.000 claims abstract description 8
- 238000011067 equilibration Methods 0.000 claims abstract description 7
- 238000010812 external standard method Methods 0.000 claims abstract description 6
- 239000012159 carrier gas Substances 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 60
- 239000013558 reference substance Substances 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 27
- 239000000523 sample Substances 0.000 claims description 20
- 238000012360 testing method Methods 0.000 claims description 20
- 238000011084 recovery Methods 0.000 claims description 13
- 239000011550 stock solution Substances 0.000 claims description 12
- 229960003850 dabigatran Drugs 0.000 claims description 10
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000012417 linear regression Methods 0.000 claims description 3
- 239000012488 sample solution Substances 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims 2
- 238000004364 calculation method Methods 0.000 claims 1
- 238000004817 gas chromatography Methods 0.000 abstract description 6
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 239000007789 gas Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000012088 reference solution Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000011003 system suitability test Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940066336 pradaxa Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000581 reactive spray deposition Methods 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
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Abstract
本发明涉及一种检测达比加群酯中有机溶剂残留的方法，尤其是气相色谱同时检测达比加群酯中乙醇、丙酮、乙酸乙酯、四氢呋喃残留的方法。其中，采用外标法同时检测达比加群酯中4种有机溶剂残留量，色谱条件为：色谱柱Agilent DB-1301（30 m×0.32 mm×0.25 μm），柱温程序升温，起始温度40 ℃，保持6 min，然后温度以50 ℃/min速率升温至180 ℃，保持10 min，进样口温度200 ℃，检测温度250 ℃，载气N2，流量2 ml/min，采用顶空进样法，平衡时间30 min，平衡温度为90 ℃。本法灵敏度高，重复性好，精确度高；适合达比加群酯中有机溶剂残留的检测。The invention relates to a method for detecting residues of organic solvents in dabigatran etexilate, in particular to a method for simultaneously detecting residues of ethanol, acetone, ethyl acetate and tetrahydrofuran in dabigatran etexilate by gas chromatography. Among them, the external standard method was used to simultaneously detect the residues of four organic solvents in dabigatran etexilate. The chromatographic conditions were: chromatographic column Agilent DB-1301 (30 m×0.32 mm×0.25 μm), the column temperature was programmed, and the initial temperature 40 ℃, keep for 6 min, then increase the temperature to 180 ℃ at a rate of 50 ℃/min, keep for 10 min, the injection port temperature is 200 ℃, the detection temperature is 250 ℃, the carrier gas is N 2 , the flow rate is 2 ml/min, using headspace In the sample injection method, the equilibration time was 30 min, and the equilibration temperature was 90 °C. This method has high sensitivity, good repeatability and high precision; it is suitable for the detection of organic solvent residues in dabigatran etexilate.
Description
技术领域technical field
本发明涉及一种检测达比加群酯中有机溶剂残留的方法，尤其是涉及用气相色谱同时检测达比加群酯中乙醇、丙酮、乙酸乙酯、四氢呋喃残留的方法，属于药物分析检测领域。The invention relates to a method for detecting residual organic solvents in dabigatran etexilate, in particular to a method for simultaneously detecting residues of ethanol, acetone, ethyl acetate and tetrahydrofuran in dabigatran etexilate by gas chromatography, belonging to the field of drug analysis and detection .
背景技术Background technique
达比加群酯(dabigatran etexilate)，商品名为Pradaxa，是由德国勃林格殷格翰公司开发的具有多种特点的新型抗凝血药物，达比加群酯是达比加群的前体药物，在体内转化为有活性的达比加群，后者通过直接抑制凝血酶而发挥抗凝血效应。达比加群酯可用于膝关节和髋关节置换术后深静脉血栓栓塞预防、深静脉血栓栓塞治疗、心房颤动、冠脉事件的二级预防，具有固定剂量给药以及无需实验室监测等多项优势。Dabigatran etexilate (dabigatran etexilate), trade name Pradaxa, is a novel anticoagulant drug with multiple characteristics developed by Boehringer Ingelheim of Germany, and dabigatran etexilate is the prodrug of dabigatran , which is converted into active dabigatran in vivo, which exerts anticoagulant effect by directly inhibiting thrombin. Dabigatran etexilate can be used for the prevention of deep vein thromboembolism after knee and hip replacement, the treatment of deep vein thromboembolism, atrial fibrillation, and the secondary prevention of coronary events. It has many advantages such as fixed dose administration and no laboratory monitoring. advantage.
药品中的残留溶剂是指在原料药、制剂生产中所使用却没有完全除去的有机溶剂。如果药品中含有的残留有机溶剂浓度高于安全值，患者服用后会对人体产生危害。人用药物注册技术要求国际协调会(ICH)的指导原则中，将药品生产中常用的溶剂按照危害程度分为4类，并规定了每种溶剂的限值。我国2010年版药典也规定了“在生产过程中与贮藏期间控制质量应检查的项目”中，需要对有害有机溶剂限度进行检查，对乙醇、丙酮、乙酸乙酯、四氢呋喃限度要求分别为不高于0.5％，0.5％，0.5％，0.072％。Residual solvents in pharmaceuticals refer to organic solvents used in the production of raw materials and preparations but not completely removed. If the concentration of residual organic solvents contained in the medicine is higher than the safe value, it will cause harm to the human body after the patient takes it. In the guiding principles of the International Council for Harmonization (ICH) of Technical Requirements for Registration of Drugs for Human Use, the solvents commonly used in drug production are divided into 4 categories according to the degree of hazard, and the limit value of each solvent is specified. my country's 2010 edition of the Pharmacopoeia also stipulates that in the "items that should be inspected for quality control during the production process and storage period", it is necessary to check the limits of harmful organic solvents, and the limits for ethanol, acetone, ethyl acetate, and tetrahydrofuran are not higher than 0.5%, 0.5%, 0.5%, 0.072%.
本发明针对达比加群酯中，由合成工艺引入的乙醇、丙酮、乙酸乙酯、四氢呋喃4种有机溶剂残留，利用气相色谱法，并选择在合适的色谱条件下同时检测这四种有机溶剂的含量。The present invention is aimed at dabigatran etexilate, four kinds of organic solvent residues of ethanol, acetone, ethyl acetate and tetrahydrofuran introduced by the synthesis process, utilize gas chromatography, and select to detect these four kinds of organic solvents simultaneously under suitable chromatographic conditions content.
发明内容Contents of the invention
本发明所要解决的技术问题是，提供一种检测达比加群酯中有机溶剂残留的方法，利用气相色谱法简便、快速、准确的同时检测出存在于达比加群酯中的乙醇、丙酮、乙酸乙酯、四氢呋喃4种有机溶剂残留量。The technical problem to be solved by this invention is to provide a method for detecting residual organic solvents in dabigatran etexilate, and to detect ethanol and acetone present in dabigatran etexilate in a simple, fast and accurate manner by gas chromatography. , ethyl acetate, tetrahydrofuran 4 kinds of organic solvent residues.
本发明通过下列技术方案解决上述技术问题。The present invention solves the above-mentioned technical problems through the following technical solutions.
一种检测达比加群酯中有机溶剂残留的方法，用气相色谱同时检测达比加群酯中乙醇、丙酮、乙酸乙酯、四氢呋喃4种有机溶剂残留量，其步骤具体如下。A method for detecting residual organic solvents in dabigatran etexilate, using gas chromatography to simultaneously detect residual amounts of four organic solvents in dabigatran etexilate, ethanol, acetone, ethyl acetate, tetrahydrofuran, the steps are as follows.
1.色谱条件1. Chromatographic conditions
色谱柱：Agilent DB-1301(30m×0.32mm×0.25μm)；柱温：程序升温，起始温度为40℃，保持6min，然后温度以50℃/min速率升温至180℃，保持10min；进样口温度：200℃；检测温度：250℃；载气：N2，流量2ml/min；进样方式：顶空进样法；平衡时间：30min；平衡温度：90℃。Chromatographic column: Agilent DB-1301 (30m×0.32mm×0.25μm); column temperature: programmed temperature rise, the initial temperature is 40°C, keep for 6min, then the temperature is raised to 180°C at a rate of 50°C/min, and keep for 10min; Sample port temperature: 200°C; detection temperature: 250°C; carrier gas: N 2 , flow rate: 2ml/min; sampling method: headspace sampling method; equilibration time: 30min; equilibration temperature: 90°C.
2.样品测定，采用外标法，其具体步骤如下。2. The sample is determined by using the external standard method, and the specific steps are as follows.
(1)系统适用性试验(1) System suitability test
取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液和四者的混合对照品溶液，分别进样，绘制图谱。Take ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution and the mixed reference substance solution of the four, inject samples respectively, and draw a spectrum.
(2)精密度试验(2) Precision test
分别取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品贮备液置入同一量瓶，N,N-二甲基甲酰胺稀释后，连续进样6次，记录各对照品峰面积的相对标准偏差RSD。Take ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance stock solution respectively into the same measuring bottle, after dilution with N,N-dimethylformamide, inject the sample continuously for 6 times, record the relative standard deviation RSD of the peak area of each reference substance .
(3)线性试验(3) Linearity test
分别取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液，等比例稀释后，进样，以乙醇、丙酮、乙酸乙酯、四氢呋喃对照品的峰面积为纵坐标，以四者浓度为横坐标建立线性回归曲线。Take the ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution respectively, after diluting in equal proportions, inject the sample, take the peak area of the ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance as the ordinate, and take the concentration of the four as the abscissa to establish Linear regression curve.
(4)回收率试验(4) Recovery test
取达比加群酯适量，精密称量，分别加入乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液作为回收率样品溶液，进样，记录色谱图，计算回收率。Take an appropriate amount of dabigatran etexilate, accurately weigh, add ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution respectively as the recovery rate sample solution, inject a sample, record the chromatogram, and calculate the recovery rate.
回收率％＝(测得量-样品量)/加入量×100％Recovery%=(measured amount-sample amount)/added amount×100%
(5)检测限及定量限试验(5) Detection limit and quantitative limit test
依次分别用N,N-二甲基甲酰胺稀释乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液，以信噪比S/N＝3计算检测限，以信噪比S/N＝10计算定量限。Dilute ethanol, acetone, ethyl acetate, and tetrahydrofuran reference solution with N,N-dimethylformamide in turn, calculate the detection limit with the signal-to-noise ratio S/N=3, and calculate the quantification with the signal-to-noise ratio S/N=10 limit.
(6)样品检验(6) Sample inspection
取达比加群酯适量，精密称量，加N,N-二甲基甲酰胺溶解制成供试品溶液，乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液和供试品溶液分别进样，记录色谱图，按外标法以峰面积计算达比加群酯中乙醇、丙酮、乙酸乙酯、四氢呋喃的含量。Get appropriate amount of dabigatran etexilate, accurately weigh, add N,N-dimethylformamide to dissolve and make the test solution, ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution and the test solution are respectively injected , record chromatogram, calculate the content of ethanol, acetone, ethyl acetate, tetrahydrofuran in dabigatran etexilate with peak area by external standard method.
本发明的优点在于：The advantages of the present invention are:
(1)采用气相色谱法同时检测乙醇、丙酮、乙酸乙酯、四氢呋喃含量，灵敏度高，重复性好，精密度高。(1) The content of ethanol, acetone, ethyl acetate and tetrahydrofuran is detected simultaneously by gas chromatography, which has high sensitivity, good repeatability and high precision.
(2)本发明方法适合达比加群酯中乙醇、丙酮、乙酸乙酯、四氢呋喃残留的检测。(2) The inventive method is suitable for the detection of ethanol, acetone, ethyl acetate, tetrahydrofuran residues in dabigatran etexilate.
附图说明Description of drawings
图1乙醇系统适应性试验气相色谱图(1.乙醇；2.N,N-二甲基甲酰胺)Figure 1 Gas chromatogram of ethanol system adaptability test (1. Ethanol; 2. N,N-dimethylformamide)
图2丙酮系统适应性试验气相色谱图(1.丙酮；2.N,N-二甲基甲酰胺)Figure 2 Gas chromatogram of acetone system adaptability test (1. Acetone; 2. N,N-dimethylformamide)
图3乙酸乙酯系统适应性试验气相色谱图(1.乙酸乙酯；2.N,N-二甲基甲酰胺)Figure 3 Ethyl acetate system adaptability test gas chromatogram (1. Ethyl acetate; 2. N, N-dimethylformamide)
图4四氢呋喃系统适应性试验气相色谱图(1.四氢呋喃；2.N,N-二甲基甲酰胺)Figure 4 The gas chromatogram of tetrahydrofuran system adaptability test (1. tetrahydrofuran; 2. N,N-dimethylformamide)
图5乙醇、丙酮、乙酸乙酯、四氢呋喃混合系统适应性试验气相色谱图(1.乙醇；2.丙酮；3.乙酸乙酯；4.四氢呋喃；5.N,N-二甲基甲酰胺)Figure 5 Gas chromatogram of ethanol, acetone, ethyl acetate, tetrahydrofuran mixed system adaptability test (1. Ethanol; 2. Acetone; 3. Ethyl acetate; 4. Tetrahydrofuran; 5. N,N-dimethylformamide)
具体实施方式Detailed ways
实施例Example
1.仪器与试药1. Instruments and reagents
仪器：Agilent6890气相色谱仪，检测器FID；Agilent色谱工作站；试药：所用试剂均为色谱纯。Instrument: Agilent6890 gas chromatograph, detector FID; Agilent chromatographic workstation; reagents: all reagents used are chromatographically pure.
2.色谱条件2. Chromatographic conditions
色谱柱：Agilent DB-1301(30m×0.32mm×0.25μm)；柱温：程序升温，起始温度为40℃，保持6min，然后温度以50℃/min速率升温至180℃，保持10min；进样口温度：200℃；检测温度：250℃；载气：N2，流量2ml/min；进样方式：顶空进样法；平衡时间：30min；平衡温度：90℃。Chromatographic column: Agilent DB-1301 (30m×0.32mm×0.25μm); column temperature: programmed temperature rise, the initial temperature is 40°C, keep for 6min, then the temperature is raised to 180°C at a rate of 50°C/min, and keep for 10min; Sample port temperature: 200°C; detection temperature: 250°C; carrier gas: N 2 , flow rate: 2ml/min; sampling method: headspace sampling method; equilibration time: 30min; equilibration temperature: 90°C.
3.溶液配制3. Solution preparation
精密称取乙醇、丙酮、乙酸乙酯、四氢呋喃各500mg、500mg、500mg、72mg，加N,N-二甲基甲酰胺溶解于100ml量瓶，制成浓度为每1ml中分别含乙醇5mg、丙酮5mg、乙酸乙酯5mg、四氢呋喃0.72mg溶液，作为乙醇、丙酮、乙酸乙酯、四氢呋喃的对照品贮备液。Accurately weigh 500mg, 500mg, 500mg, and 72mg of ethanol, acetone, ethyl acetate, and tetrahydrofuran, add N,N-dimethylformamide and dissolve them in a 100ml measuring bottle to make a concentration of 5mg of ethanol and 5mg of acetone in 1ml. 5mg, ethyl acetate 5mg, tetrahydrofuran 0.72mg solution, as the reference substance stock solution of ethanol, acetone, ethyl acetate, tetrahydrofuran.
精密量取上述贮备液10ml置入100ml量瓶，加N,N-二甲基甲酰胺至刻度，摇匀，制成浓度为每1ml中分别含乙醇0.5mg、丙酮0.5mg、乙酸乙酯0.5mg、四氢呋喃0.072mg溶液，作为乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液。Precisely measure 10ml of the above-mentioned stock solution and put it into a 100ml measuring bottle, add N,N-dimethylformamide to the mark, shake well, and make a concentration of 0.5mg of ethanol, 0.5mg of acetone, and 0.5mg of ethyl acetate in each 1ml. mg, tetrahydrofuran 0.072mg solution, as ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution.
取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品贮备液各10ml，混合均匀制成四者的混合对照品溶液。Take 10ml each of ethanol, acetone, ethyl acetate, and tetrahydrofuran reference substance stock solutions, and mix them evenly to make a mixed reference substance solution of the four.
4.样品测定4. Sample determination
(1)系统适用性试验(1) System suitability test
精密量取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品溶液、混合对照品溶液，各取5ml，顶空进样。Precisely measure ethanol, acetone, ethyl acetate, tetrahydrofuran reference solution, mixed reference solution, each take 5ml, headspace injection.
在上述色谱条件下各组分可以得到较好的分离，各组分保留时间及分离度见表1，系统适用性图谱见附图1～5。Under the above-mentioned chromatographic conditions, each component can be better separated. The retention time and resolution of each component are shown in Table 1, and the system suitability diagram is shown in Figures 1-5.
表1各组分保留时间及分离度测定结果Table 1 Retention time of each component and determination result of resolution
(2)精密度试验(2) Precision test
精密量取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品贮备液各10ml置入同一100ml量瓶，加N,N-二甲基甲酰胺至刻度，摇匀，取5ml顶空进样。连续进样6针，记算各对照品峰面积的RSD见表2。结果表明，RSD均在5％以内。Precisely measure 10ml each of ethanol, acetone, ethyl acetate, and tetrahydrofuran reference substance stock solution into the same 100ml measuring bottle, add N,N-dimethylformamide to the mark, shake well, and take 5ml headspace injection. Inject 6 needles continuously, and record the RSD of the peak area of each reference substance in Table 2. The results showed that the RSDs were all within 5%.
表2精密度试验数据结果(n＝6)Table 2 Precision test data results (n=6)
(3)线性试验(3) Linearity test
精密量取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品贮备液，分别取5ml，7.5ml，12.5ml，15ml置入100mL量瓶，加N,N-二甲基甲酰胺至刻度，摇匀，作为一系列线性试验溶液。顶空进样，每个溶液连续进样2次。以对照品峰面积为纵坐标，乙醇、丙酮、乙酸乙酯、四氢呋喃对照品浓度为横坐标建立线性回归线。测定结果见表3。Accurately measure ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance stock solution, respectively take 5ml, 7.5ml, 12.5ml, 15ml into a 100mL measuring bottle, add N,N-dimethylformamide to the mark, shake well, As a series of linear test solutions. For headspace injection, each solution was injected twice consecutively. A linear regression line was established with the peak area of the reference substance as the ordinate, and the concentrations of the reference substances of ethanol, acetone, ethyl acetate, and tetrahydrofuran as the abscissa. The measurement results are shown in Table 3.
表3线性试验测定结果Table 3 linear test results
(4)回收率试验(4) Recovery test
精密称量达比加群酯500mg共9份，分别加入乙醇、丙酮、乙酸乙酯、四氢呋喃对照品贮备液8、10、12ml置入100ml量瓶，加N,N-二甲基甲酰胺至刻度，摇匀，作为回收率样品溶液，取5ml顶空进样。记录色谱图，由测得量和加入量计算回收率。可接受的回收率应在90％～110％(100％±10％)。测定结果见表4。Accurately weigh 500 mg of dabigatran etexilate in 9 parts, add ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance stock solution 8, 10, 12 ml respectively into a 100 ml measuring bottle, add N,N-dimethylformamide to Scale, shake well, as the recovery rate sample solution, take 5ml headspace injection. Record the chromatogram, and calculate the recovery rate from the measured amount and the added amount. The acceptable recovery rate should be between 90% and 110% (100%±10%). The measurement results are shown in Table 4.
回收率％＝(测得量-样品量)/加入量×100％Recovery%=(measured amount-sample amount)/added amount×100%
表4回收率试验测定结果Table 4 recovery rate test measurement result
(5)检测限及定量限试验(5) Detection limit and quantitative limit test
以信噪比S/N＝3计算检测限，以信噪比S/N＝10计算定量限，依次分别用N,N-二甲基甲酰胺稀释乙醇、丙酮、乙酸乙酯、四氢呋喃的对照品贮备液。取5ml顶空进样。记录色谱图，检测限及定量限测定结果见表5。Calculate the limit of detection based on signal-to-noise ratio S/N=3, calculate the limit of quantification based on signal-to-noise ratio S/N=10, and dilute ethanol, acetone, ethyl acetate, and tetrahydrofuran with N,N-dimethylformamide in sequence. stock solution. Take 5ml headspace injection. Record the chromatograms, and see Table 5 for the results of detection limits and quantitation limits.
表5乙醇、丙酮、乙酸乙酯、四氢呋喃检测限、定量限结果Table 5 Ethanol, acetone, ethyl acetate, tetrahydrofuran limit of detection, limit of quantitation results
(6)样品检验结果(6) Sample inspection results
取达比加群酯，精密称定，加N,N-二甲基甲酰胺溶解并制成每1ml中含100mg溶液，作为供试品溶液。精密吸取乙醇、丙酮、乙酸乙酯、四氢呋喃对照品贮备液各10ml，加N,N-二甲基甲酰胺定容至100ml量瓶，作为对照品溶液。精密吸取供试品和对照品溶液各5ml，顶空进样，记录色谱图，按外标法以峰面积计算，含乙醇不得过0.5％、丙酮不得过0.5％、乙酸乙酯不得过0.5％、四氢呋喃不得过0.072％。Take dabigatran etexilate, accurately weighed, add N,N-dimethylformamide to dissolve and make a solution containing 100mg per 1ml, as the test solution. Precisely draw 10ml each of ethanol, acetone, ethyl acetate, and tetrahydrofuran reference substance stock solutions, add N,N-dimethylformamide to a 100ml measuring bottle, and use it as the reference substance solution. Accurately draw 5ml each of the test product and the reference solution, inject the headspace sample, record the chromatogram, calculate the peak area according to the external standard method, and contain no more than 0.5% ethanol, no more than 0.5% acetone, and no more than 0.5% ethyl acetate , Tetrahydrofuran shall not exceed 0.072%.
照上述方法检测样品的残留溶剂，乙醇0％、丙酮0.03％、乙酸乙酯0％、四氢呋喃0％。Detect the residual solvent of the sample according to the above method, ethanol 0%, acetone 0.03%, ethyl acetate 0%, tetrahydrofuran 0%.
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