CN103728403A - Method for detecting relevant substance in hydrochloric acid remifentanil active ingredient - Google Patents
Method for detecting relevant substance in hydrochloric acid remifentanil active ingredient Download PDFInfo
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- CN103728403A CN103728403A CN201310386314.5A CN201310386314A CN103728403A CN 103728403 A CN103728403 A CN 103728403A CN 201310386314 A CN201310386314 A CN 201310386314A CN 103728403 A CN103728403 A CN 103728403A
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Abstract
The invention provides a relevant substance detection method which is high in sensitivity and short in detection time. Through the adoption the method, the content of relevant substances can be rapidly and accurately detected, and the separation degree between impurity peak and main peak is greater than or equal to 1.5. The method specifically comprises the steps of confirming the relevant substances and confirming the chromatographic condition, wherein the chromatographic condition is that the octadecyl silane bonded silica gel (3mu m) chromatographic column is 0.1m*4.6mm, the concentration of a mobile phase A sal volatile solution is 5g/l, tetrahydrofuran-water (10:90) is used as a solvent, and acetonitrile is used as a mobile phase B.
Description
Background technology
Remifentanil (1-piperidines propionic acid, 4-(methoxyl-carbonyl)-4-((1-oxopropyl) phenylamino (phenylamino))-, methyl esters; CAS 132875-61-7) be synthetic opioid.It has molecular formula C
20h
28n
2o
5, and there is following structural formula:
The salt of modal Remifentanil is remifentanil hydrochloride (CAS 132539-07-2)
N-phenyl-N-(4-piperidyl) acid amides, as Remifentanil, and their preparation is at first at United States Patent (USP) 5,019, in 583 (its content is all quoted as a reference at this), describes.United States Patent (USP) 5,466,700 (its content is all quoted as a reference at this) have been described at United States Patent (USP) 5,019, and that describes in 583 opioidly causes and keeps anaesthetizing and the purposes of associated with conscious sedation.
Remifentanil is commercially available parenteral solution or transfusion, and brand name is
(GlaxoSmithKline), it has market outlook widely.Owing to there being certain impurity in finished product, bring certain impact to its clinical practice.Simultaneously; because the detection method of related substance in remifentanil hydrochloride bulk drug is not embodied in Chinese Pharmacopoeia; a but standard of the promulgation of State Food and Drug Administration in 2009; WS1-(X-008)-2009Z (Ye Shiwo company drafts); its detection sensitivity is poor; cannot reach and the good baseline separation of impurity; impurity component and content are all indefinite; can not clearly show the concrete content of each related substance, the related substance impurity that it contains is conventionally hydrolysate, de-benzyl thing, acetylate etc. such as.The present invention is directed to the deficiencies in the prior art; through long-term practical studies; determine a kind of highly sensitive, related substance detection method that detection time is short; it can detect the content of hydrolysate, de-benzyl thing, acetylate fast; and can make related substance and active component reach baseline separation; for the active component further separating, purifying obtains high-quality provides reliable foundation, also provide a kind of highly sensitive, related substance detection method that detection time is short simultaneously.
Summary of the invention
The invention provides a kind of highly sensitive, related substance detection method that detection time is short.It can determine the content of each related substance fast and accurately, and between each impurity peaks and major component peak, degree of separation all >=1.5.It specifically includes determining of determining of related substance and chromatographic condition.
Chromatographic condition:
Octadecylsilane chemically bonded silica (3um) chromatographic column, 0.1m × 4.6mm.
Mobile phase A sal volatile 5g/l, solvent is tetrahydrofuran-water (10:90).
Mobile phase B acetonitrile.
With acetonitrile balance pillar at least 30 minutes, then use initial eluent composition balance pillar at least 5 minutes.
Flow rate of mobile phase is 1.5ml/min.
Detect wavelength: 220nm.
Column temperature: 35 ℃.
Input mode: auto injection
Detecting device: UV-detector
Sample size: 10ul
Type of elution: gradient elution
System suitability:
Get contrast solution 10 μ l, injection liquid chromatography, records chromatogram.In chromatogram, the tailing factor at major component peak should be not more than 1.5, repeats sample introduction 6 times, and RSD should be not more than 2.0%, and number of theoretical plate calculates and should be not less than 2000 by Remifentanil peak.
Assay method:
Need testing solution preparation: get the about 0.1g of this product, add methyl alcohol 10ml and make to dissolve, obtain.Precision measures the each 10 μ l of need testing solution, and injection liquid chromatography, records chromatogram respectively.
Wherein definite method of related substance is as follows:
1. impurity location
1.1 experimental apparatus
DX205-DU electronic balance
Waters?e2495HPLC(VWD)
The preparation of 1.2 contrast solutions:
The preparation of contrast solution: each concentration is below calculated according to base.
Remifentanil hydrochloride contrast solution: get remifentanil hydrochloride (C20H28N205HCl) (lot number: RF111103) 0.10060g, dissolve and be diluted to 10ml with methyl alcohol, shake up, concentration is 10.06mg/ml.
Free carboxy acid's contrast solution: getting free carboxy acid (C19H22N2O2) (lot number: RFYL120502) 0.01973g, dissolve and be diluted to 20ml with methyl alcohol, shake up, is storing solution; Measure 0.5ml again, be diluted to 25ml, shake up, concentration is 19.73ug/ml.
Acetylate contrast solution: get acetylate oxalates (C19H26N2O5C2H2O4) (lot number: 080902) 0.02018g, dissolve and be diluted to 20ml with methyl alcohol, shake up, be storing solution; Measure 0.5ml again, be diluted to 25ml, shake up, concentration is 20.18ug/ml.
Hydrolysate contrast solution: get hydrolysate hydrochloride (C18H24N2O5HCl) (lot number: 081102) 0.02006g, dissolve and be diluted to 20ml with methyl alcohol, shake up, be storing solution; Measure 0.5ml again, be diluted to 25ml, shake up, concentration is 20.06ug/ml.
De-benzyl thing contrast solution: get de-benzyl thing oxalates (C15H20N2O3C2H2O4) (lot number: 081101) 0.01992g, dissolve and be diluted to 20ml with methyl alcohol, shake up, be storing solution; Measure 0.5ml again, be diluted to 25ml, shake up, concentration is 19.92ug/ml.
Carboxylate contrast solution: getting carboxylate (C20H24N2O2) (lot number: RFZH120601) 0.02088g, dissolve and be diluted to 20ml with methyl alcohol, shake up, is storing solution; Measure 0.5ml again, be diluted to 25ml, shake up, concentration is 20.88ug/ml.
Propionyl compound contrast solution: getting propionyl compound oxalates (C23H28N2O3C2H2O4) (lot number: RFBX120601) 0.01999g, dissolve and be diluted to 20ml with methyl alcohol, shake up, is storing solution; Measure 0.5ml again, be diluted to 25ml, shake up, concentration is 19.99ug/ml.
Mixed solution: get remifentanil hydrochloride (C20H28N205HCl) (lot number: RF111103) 0.10051g, add respectively above-mentioned each impurity storing solution 0.2ml, dissolve and be diluted to 10ml with methyl alcohol, shake up twice inserting needle.
Method: according to chromatographic condition and method, get above-mentioned mixed solution 10 μ l injection liquid chromatographies, record chromatogram, check from mixed solution chromatogram between each peak and can separate, calculate its degree of separation.
1.3 measurement results:
Get contrast solution 10 μ l injection liquid chromatographies separately, record chromatogram, each known impurities is positioned, result is as following table 1.
Table 1
From the above results, can find out; remifentanil hydrochloride has in the peak chromatogram of hydrolysate in independent sample introduction; except main peak; the peak area of hydrolysate must not be greater than main peak area (0.15%) in contrast solution collection of illustrative plates; the peak area of acetylate must not be greater than main peak area (0.15%) in contrast solution collection of illustrative plates; other impurity peak area must not be greater than 2/3 (0.1%) of main peak area in contrast collection of illustrative plates, and its each impurity peak area sum must not be greater than 20/3 (1.0%) of main peak area in contrast solution collection of illustrative plates.Ignoring in corresponding blank solution peak, less than the peak of 0.01 times of contrast solution main peak area, also ignores.The relative retention time of two impurity: acetylate: 0.80, hydrolysate: 0.30.
Accompanying drawing explanation
Fig. 1 remifentanil hydrochloride contrast solution chromatogram;
Fig. 2 free carboxy acid contrast solution chromatogram;
Fig. 3 acetylate contrast solution chromatogram;
Fig. 4 hydrolysate contrast solution chromatogram;
Fig. 5 takes off benzyl thing contrast solution chromatogram;
Fig. 6 carboxylate contrast solution chromatogram;
Fig. 7 propionyl compound contrast solution chromatogram;
Fig. 8 mixed solution 1 chromatogram;
Fig. 9 mixed solution 2 chromatograms;
Figure 10 embodiment 1 chromatogram;
Figure 11 embodiment 2 chromatograms;
Figure 12 embodiment 3 chromatograms;
Embodiment
Embodiment 1:
Get 120801 crowdes of about 0.1g of remifentanil hydrochloride raw material, adding methyl alcohol 10ml makes to dissolve, as need testing solution, sample introduction 10 μ l, chromatographic condition is with reference to a standard of the promulgation of State Food and Drug Administration in 2009, and chromatographic column is octadecylsilane chemically bonded silica (3um) chromatographic column, 0.1m × 4.6mm, detection wavelength is 220nm, obtains chromatogram.
Embodiment 2
Get 120802 crowdes of about 0.1g of remifentanil hydrochloride raw material, adding methyl alcohol 10ml makes to dissolve, as need testing solution, sample introduction 10 μ l, chromatographic condition is with reference to a standard of the promulgation of State Food and Drug Administration in 2009, and chromatographic column is octadecylsilane chemically bonded silica (3um) chromatographic column, 0.1m × 4.6mm, detection wavelength is 220nm, obtains chromatogram.
Embodiment 3
Get 121101 crowdes of about 0.1g of remifentanil hydrochloride raw material, adding methyl alcohol 10ml makes to dissolve, as need testing solution, sample introduction 10 μ l, chromatographic condition is with reference to a standard of the promulgation of State Food and Drug Administration in 2009, and chromatographic column is octadecylsilane chemically bonded silica (3um) chromatographic column, 0.1m × 4.6mm, detection wavelength is 220nm, obtains chromatogram.
From chromatogram 1-9, adopt detection method of the present invention, can separate fast each impurity, and can determine particular type and the content of an impurity, and with reference to Figure 10-12 of the promulgation drug standards of State Food and Drug Administration in 2009, can find out and all related substanceses do not detected, and baseline separation is bad, therefore detection method of the present invention, for the purity that improves remifentanil hydrochloride, is better applied to clinical application significant.
Claims (4)
1. a detection method for remifentanil hydrochloride related substance, is characterized in that: mobile phase is, mobile phase A: sal volatile 5g/l, solvent is the mixed solution of tetrahydrofuran-water (10:90) and Mobile phase B acetonitrile, adopts gradient elution.
2. the method for claim 1, is characterized in that: detection wavelength is 220nm.
3. the method for claim 1, is characterized in that: mobile phase is linear elution 0-15 minute, and mobile phase A volume is 95 → 55, Mobile phase B volume be 5 → 45,15-20 minute for mobile phase A volume is 55, Mobile phase B volume is 45.
4. the method for claim 1, is characterized in that: related substance is one or more in free carboxy acid (C19H22N2O2), hydrolysate hydrochloride (C18H24N2O5HCl), acetylate oxalates (C19H26N2O5C2H2O4), de-benzyl thing oxalates (C15H20N2O3C2H2O4), carboxylate (C20H24N2O2), propionyl compound oxalates (C23H28N2O3C2H2O4).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111487336A (en) * | 2020-04-13 | 2020-08-04 | 司法鉴定科学研究院 | Method for analyzing 37 fentanyl novel psychoactive substances in hair |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5019583A (en) * | 1989-02-15 | 1991-05-28 | Glaxo Inc. | N-phenyl-N-(4-piperidinyl)amides useful as analgesics |
| WO2002094234A1 (en) * | 2001-05-24 | 2002-11-28 | Alexza Molecular Delivery Corporation | Delivery of opioids through an inhalation route |
| CN101398414A (en) * | 2008-10-15 | 2009-04-01 | 上海市公安局刑事侦查总队 | Method for qualitatively screening 242 kinds of compounds by liquid phase chromatography-mass spectra at the same times |
-
2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5019583A (en) * | 1989-02-15 | 1991-05-28 | Glaxo Inc. | N-phenyl-N-(4-piperidinyl)amides useful as analgesics |
| WO2002094234A1 (en) * | 2001-05-24 | 2002-11-28 | Alexza Molecular Delivery Corporation | Delivery of opioids through an inhalation route |
| CN101398414A (en) * | 2008-10-15 | 2009-04-01 | 上海市公安局刑事侦查总队 | Method for qualitatively screening 242 kinds of compounds by liquid phase chromatography-mass spectra at the same times |
Non-Patent Citations (3)
| Title |
|---|
| 张兴安 等: "瑞芬太尼群体药代、药效学研究进展", 《实用医学杂志》, vol. 23, no. 2, 28 February 2007 (2007-02-28), pages 291 - 294 * |
| 毕小玲 等: "盐酸瑞芬太尼的合成", 《中国药物化学杂志》, vol. 12, no. 6, 31 December 2002 (2002-12-31), pages 354 - 355 * |
| 袁琴 等: "盐酸瑞芬太尼合成过程中两种中间体含量的测定", 《广州化工》, vol. 38, no. 8, 31 August 2010 (2010-08-31), pages 186 - 188 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111487336A (en) * | 2020-04-13 | 2020-08-04 | 司法鉴定科学研究院 | Method for analyzing 37 fentanyl novel psychoactive substances in hair |
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