CN104374858B - A kind of detection method of sufentanil citrate synthesis material and impurity - Google Patents
A kind of detection method of sufentanil citrate synthesis material and impurity Download PDFInfo
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- CN104374858B CN104374858B CN201410673316.7A CN201410673316A CN104374858B CN 104374858 B CN104374858 B CN 104374858B CN 201410673316 A CN201410673316 A CN 201410673316A CN 104374858 B CN104374858 B CN 104374858B
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Abstract
The present invention provides the detection method of a kind of sufentanil citrate synthesis material and impurity, utilizes gas chromatogram, it is provided that retention time determines dopant species, utilizes area normalization method to determine impurity content.It is specially the mixed solution sample introduction respectively by standard solution and standard solution, each standard of physical solution is carried out chromatography；Again by test sample sample introduction, record chromatogram, the retention time of impurity retention time and standard sample on this chromatogram is compareed, impurity is carried out qualitative, area normalization method is adopted to carry out quantitatively, synthesis material and impurity being carried out qualitative and detection by quantitative to impurity further according to the peak area being respectively arranged with related substance.The method is simple, and the control for sufentanil citrate lmpurities provides good guarantee.
Description
Technical field
The present invention relates to impurity of the drug inspection method, be specifically related to sufentanil citrate synthesis material and intermediate impurities inspection method thereof.
Background technology:
Sufentanil citrate is the derivant of fentanyl citrate (Fentanyl), for opiates powerful analgesics.Sufentanil citrate is a strong mu opioid receptor agonist, to μ-receptor affinity than fentanyl citrate big about 7-10 times.This product analgesia intensity is 75-125 times of morphine, fentanyl citrate 5～10 times.This product is highly lipophilic medicine, rapid-action after intravenous injection, T1/2 π, T1/2 α, T1/2 β respectively 0.73-1.2,13.7-17 and 140-158min.Plasma protein binding rate is 92%, mainly combines with α 1-acidoglycoprotein.Apparent volume of distribution Vd is 1.7L/kg, clearance rate CL is 12.7ml/min/kg, and major part at intrahepatic metabolism, forms N-and removes alkyl and the metabolite of O-demethyl, discharges with urine and bile, with original shape discharge from urine less than 2%.Its metabolite demethyl sufentanil citrate also has pharmacologically active, and titer is about the 1/10 of sufentanil citrate.Sufentanil citrate reduces inhalational anesthetic MAC；EEG amplitude is made to increase, frequency deceleration；Hemodynamics is more more stable than fentanyl citrate, morphine；The stress inhibitory action intubating stimulation is higher；Safety range is more than fentanyl citrate and alfentanil.As narcosis analgesic, sufentanil citrate wide clinical application is in department of cardiac surgery, neurosurgery, big abdominal surgery, department of obstetrics and gynecology etc..The incidence rate of untoward reaction is all low than fentanyl citrate with degree.Although the distribution of sufentanil citrate is longer than alfentanil with the elimination half-life, but observing from the operation being shorter than 6-8 hour, sufentanil citrate is shorter than alfentanil recovery time.
Clinical medicinal for its citrate, i.e. sufentanil citrate, its chemical name is propanamide, N-[4-(methoxymethyl)-1-[2-(2-thienyl) ethyl]-4-piperidinyl]-N-phenyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1), molecular formula is C22H30N2O2S C6H8O7.Molecular weight 578.66, structural formula:Exploitation unit is Janssen (Belgium), and nineteen eighty-three lists in Holland first, and its character is white crystals or crystalline powder.Soluble in water, ethanol, insoluble in chloroform, ether.Sufentanil citrate is used as analgesic.Interior as analgesics holding time of balanced anesthesia.When induction and the maintenance of anesthesia as anesthetis.
The raw material of sufentanil citrate, 2-thiophene ethanol, 2-thienylethyl bromine has been used during synthesis, research finds, when in the 2-thiophene ethanol synthesizing 2-thienylethyl bromine containing impurity 3-thiophene ethanol, 3-thienylethyl bromine will be generated in bromination reaction process, the introducing of 3-thienylethyl bromine may result in introducing impurity in sufentanil citrate synthetic product, thus affecting the quality of Products sufentanil citrate injection.
The quality standard of present sufentanil citrate crude drug adopts State Food and Drug Administration standard YBH06742005 and replacement demand official written reply: Hubei Province B200800188.Standard adopts liquid chromatography for measuring have related substance, be disadvantageous in that magazins' layout poor effect, and be served only for the detection of sufentanil citrate crude drug finished product impurity, it is impossible to from source, control the content of impurity.
State's food medicine prison [2011] No. 430 file distribution of note carry out the notice of drug standard revision about carrying out subsidy from central government finance in 2011, the raising work of 957 drug standards is proposed requirement, wherein just include sufentanil citrate injection.
Improve the work of fentanyl citrate injection quality standard, it is critical only that the quality standard improving fentanyl citrate crude drug.Research finds, will improve the quality standard of sufentanil citrate crude drug, controls sufentanil citrate synthesis material and intermediate impurities content is particularly critical.
Summary of the invention
It is an object of the invention to, the inspection method of a kind of sufentanil citrate synthesis material and intermediate impurities thereof is provided, the method can efficiently control the content of fentanyl citrate synthesis material and intermediate impurities, thus the control for sufentanil citrate lmpurities provides good guarantee.
Sufentanil citrate Material synthesis process is it may happen that following reaction:
Process controls the content of 3-thiophene ethanol and corresponding product 3-thienylethyl bromine in crude drug it can be seen that control it is critical only that of sufentanil citrate raw material impurity from the reactions above.Owing to 2-thiophene ethanol, 3-thiophene ethanol, 2 thienylethyl bromines, the molecular structure of 3-thienylethyl bromine these four material and physicochemical property are all much like, good separating effect to be obtained and be not easy to, it is necessary to
It is optimized to suitable chromatographic condition.
Thering is provided the forming process analyzing above impurity, the main purpose of the present invention is just to provide a kind of method for detecting impurities simple to operate, utilizes gas chromatogram (GC) to carry out checking, specifically includes following steps:
Standard solution is prepared
2-thiophene ethanol solution: take 2-thiophene ethanol reagent, direct injected.
3-thiophene ethanol solution: take 3-thiophene ethanol reagent, direct injected.
2-thienylethyl bromine solutions: take 2-thienylethyl bromine, direct injected.
3-thienylethyl bromine solutions: take 3-thienylethyl bromine, direct injected.
Chromatographic condition
Chromatographic column: CP8770 (100% dimethyl polysiloxane) 30m*0.25mm*1.0um
Carrier gas: nitrogen
Split ratio 1:200
Column pressure: 15psi
Detector: hydrogen flame ionization detector (temperature is 300 DEG C)
Detector sensitivity is: 20
Injector temperature: 250 DEG C
Temperature programming: initial 150 DEG C of column temperature keeps 5min, is then warming up to 250 DEG C with 5.0 DEG C per minute again
Sample size: 1ul.
Mixing contrast solution: take 1ml2-thiophene ethanol, 1ml3-thiophene ethanol, 1ml2-thienylethyl bromine, 1ml3-thienylethyl bromine, to 50ml measuring bottle, adds ethanol dilution to scale, direct injected.
Blank: directly to use ethanol sample introduction.
In mixing contrast solution, the separating degree at main constituent peak should be greater than 1.5.
Take above-mentioned 6 kinds to take 1ul respectively and be directly injected into gas chromatograph.
The key point of the present invention is in that: utilize retention time to determine dopant species, utilizes area normalization method to determine impurity content.
Result is as shown in table 1, and chromatography of gases figure is as shown in Figure 1.
Conclusion: in mixing contrast solution, 4 kinds of separating substances degree are all higher than 1.5, meet regulation.
Impurity content is smaller, not easily passs through chromatographic peak and carries out qualitative to impurity, so each test substance is carried out qualitative determination by the main peak retention time that the present invention is determined by each test substance standard substance.Above-mentioned four kinds of material main peak retention times are decided to be T respectively1、T2、T3、T4.By area normalization method, each material is carried out quantitatively.Standard specifies: 3-thiophene ethanol impurity content must not be higher than 0.1%, and 3-thienylethyl bromine impurity content must not be higher than 0.05%.
Figure of description
Fig. 1 is 2-thiophene ethanol, 3-thiophene ethanol, 2-thienylethyl bromine, the chromatography of gases figure of mixture in 3-thienylethyl bromine 4.
Fig. 2 is 140801 batches of test sample 2-thiophene ethanol gas chromatograms.
Fig. 3 is 140801 batches of test samples gas chromatograms of 2-thienylethyl bromine after bromination reaction.
Fig. 4 is 140802 batches of test sample 2-thiophene ethanol gas chromatograms.
Fig. 5 is 140802 batches of test samples gas chromatograms of 2-thienylethyl bromine after bromination reaction.
Fig. 6 is 140901 batches of test sample 2-thiophene ethanol gas chromatograms.
Fig. 7 is 140901 batches of test samples gas chromatograms of 2-thienylethyl bromine after bromination reaction.
Detailed description of the invention
Embodiment 1
The 2-thiophene ethanol taking 140801 batches is appropriate, as test sample, and then direct injected, record chromatogram.Impurity retention time on chromatogram and reference substance impurity retention time are compareed, impurity is carried out qualitative.Adopt area normalization method that impurity is carried out quantitatively further according to the peak area being respectively arranged with related substance.3-thiophene ethanol impurity in 2-thiophene ethanol raw material can be carried out qualitative and quantitative by the present invention, thus controlling the quality of sufentanil citrate synthesis material 2-thiophene ethanol.Testing result is shown in accompanying drawing 2, and it detects data such as table 2.
2-thiophene ethanol test sample vapor detection data in 2.140801 batches of table
The 2-thiophene ethanol taking above-mentioned 140801 batches is appropriate by the intermediate 2-thienylethyl bromine after bromination reaction, as test sample, direct injected, records chromatogram.Testing result is shown in accompanying drawing 3, and it detects data such as table 3.
The vapor detection data of the intermediate 2-thienylethyl bromine intermediate in 3.140801 batches of table
Embodiment 2
The 2-thiophene ethanol taking 140802 batches is appropriate, as test sample, and then direct injected, record chromatogram.Impurity retention time on chromatogram and reference substance impurity retention time are compareed, impurity is carried out qualitative.Adopt area normalization method that impurity is carried out quantitatively further according to the peak area being respectively arranged with related substance.3-thiophene ethanol impurity in 2-thiophene ethanol raw material can be carried out qualitative and quantitative by the present invention, thus controlling the quality of sufentanil citrate synthesis material 2-thiophene ethanol.Testing result is shown in accompanying drawing 4, and it detects data such as table 4.
2-thiophene ethanol test sample vapor detection data in 4.140802 batches of table
The 2-thiophene ethanol taking above-mentioned 140802 batches is appropriate by the intermediate 2-thienylethyl bromine after bromination reaction, as test sample, direct injected, records chromatogram.Testing result is shown in accompanying drawing 5, and it detects data such as table 5.
The vapor detection data of the intermediate 2-thienylethyl bromine intermediate in 5.140802 batches of table
Embodiment 3
The 2-thiophene ethanol taking 140901 batches is appropriate, as test sample, and then direct injected, record chromatogram.Impurity retention time on chromatogram and reference substance impurity retention time are compareed, impurity is carried out qualitative.Adopt area normalization method that impurity is carried out quantitatively further according to the peak area being respectively arranged with related substance.3-thiophene ethanol impurity in 2-thiophene ethanol raw material can be carried out qualitative and quantitative by the present invention, thus controlling the quality of sufentanil citrate synthesis material 2-thiophene ethanol.Testing result is shown in accompanying drawing 6, and it detects data such as table 6.
2-thiophene ethanol test sample vapor detection data in 6.140901 batches of table
The 2-thiophene ethanol taking above-mentioned 140901 batches is appropriate by the intermediate 2-thienylethyl bromine after bromination reaction, as test sample, direct injected, records chromatogram.Testing result is shown in accompanying drawing 7, and it detects data such as table 7.
The vapor detection data of the intermediate 2-thienylethyl bromine intermediate in 7.140901 batches of table
Claims (3)
1. the detection method of a sufentanil citrate synthesis material and impurity, it is characterised in that adopt gas chromatogram to detect, comprise the steps:
2-thiophene ethanol reagent: take 2-thiophene ethanol reagent, direct injected；
3-thiophene ethanol reagent: take 3-thiophene ethanol reagent, direct injected；
2-thienylethyl bromide reagent: take 2-thienylethyl bromide reagent, direct injected；
3-thienylethyl bromide reagent: take 3-thienylethyl bromide reagent, direct injected；Gas chromatographic detection is carried out as standard substance；
The condition of gas chromatogram
Chromatographic column: CP8770,100% dimethyl polysiloxane, 30m*0.25mm*1.0 μm；
Carrier gas: nitrogen；
Split ratio 1:200；
Column pressure: 15psi；
Detector: hydrogen flame ionization detector, detector temperature is 300 DEG C；
Detector sensitivity is: 20；
Injector temperature: 250 DEG C；
Temperature programming: initial 150 DEG C of column temperature keeps 5min, is then warming up to 250 DEG C with 5.0 DEG C per minute again；
Sample size: 1 μ L；
Mixing contrast solution
Taking 1mL2-thiophene ethanol, 1mL3-thiophene ethanol, 1mL2-thienylethyl bromine, 1mL3-thienylethyl bromine to 50mL measuring bottle, ethanol dilution is to scale, direct injected, and blank group directly uses ethanol sample introduction；
Take test sample, direct injected, record chromatogram, impurity retention time on this chromatogram and reference substance impurity retention time are compareed, impurity is carried out qualitative, area normalization method is adopted to carry out quantitatively, synthesis material and impurity being carried out qualitative and detection by quantitative to impurity further according to the peak area being respectively arranged with related substance.
2. detection method according to claim 1, it is characterised in that: described impurity is 3-thiophene ethanol and 3-thienylethyl bromine.
3. detection method according to claim 1, it is characterised in that: in mixing contrast solution, the separating degree that gas chromatogram separates is more than 1.5.
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| CN101084250A (en) * | 2004-12-21 | 2007-12-05 | 三井化学株式会社 | Modified phenolic resin, epoxy resin composition containing the same, and prepreg containing the composition |
| CN102060753A (en) * | 2010-12-29 | 2011-05-18 | 宜昌人福药业有限责任公司 | Refining method of 4-phenylaminopiperidine analgesic |
| CN103483310A (en) * | 2013-10-16 | 2014-01-01 | 连云港宏业化工有限公司 | Synthesis method of 2-thiopheneethanol |
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| IL108459A0 (en) * | 1993-02-05 | 1994-04-12 | Opjohn Company | 4-Hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl [B] pyran-2-ones useful for treating infections due to hiv and other retroviruses |
| US20090137822A1 (en) * | 2005-05-16 | 2009-05-28 | Akio Matsushita | Process for preparing 3-substituted thiophene |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101084250A (en) * | 2004-12-21 | 2007-12-05 | 三井化学株式会社 | Modified phenolic resin, epoxy resin composition containing the same, and prepreg containing the composition |
| CN102060753A (en) * | 2010-12-29 | 2011-05-18 | 宜昌人福药业有限责任公司 | Refining method of 4-phenylaminopiperidine analgesic |
| CN103483310A (en) * | 2013-10-16 | 2014-01-01 | 连云港宏业化工有限公司 | Synthesis method of 2-thiopheneethanol |
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| 2-噻吩乙醇的合成及工艺改进;郑志满 等;《广州化工》;20111231;第39卷(第4期);87-88、151页 * |
| 枸橼酸舒芬太尼有关物质HPLC分析方法的忧化;徐华丽 等;《中国药品标准》;20131231;第14卷(第2期);122-125页 * |
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