CN109580826A - Anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of E-1-, the detection method of 3- dichloropropylene - Google Patents
Anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of E-1-, the detection method of 3- dichloropropylene Download PDFInfo
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- CN109580826A CN109580826A CN201811612510.9A CN201811612510A CN109580826A CN 109580826 A CN109580826 A CN 109580826A CN 201811612510 A CN201811612510 A CN 201811612510A CN 109580826 A CN109580826 A CN 109580826A
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Abstract
The invention discloses anti-form-1 in a kind of chloro- 6,6- dimethyl -2- heptene -4- alkynes of E-1-, the detection methods of 3- dichloropropylene.It is by (E) -1- chloro- 6, anti-form-1 in 6- dimethyl -2- heptene -4- alkynes, 3- dichloropropylene acceptable limit is determined as≤6ppm, by (E) -1- chloro- 6, direct injected after 6- dimethyl -2- heptene -4- alkynes is dissolved with solvent, using GC-ECD detection method to impurity anti-form-1 in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloropropylene carries out qualitative, quantitative.The experiment proved that, this method has many advantages, such as easy to operate, and specificity is good, sensitive, accurate, can be reliably to (E) -1- chloro- 6, impurity-anti-form-1 in 6- dimethyl -2- heptene -4- alkynes, 3- dichloropropylene require to carry out qualitative and quantitative analysis according to the control of genotoxicity impurity.
Description
Technical field
The present invention relates to impurity --- the anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1-, 3- bis-
The detection method of chloropropene, belongs to pharmaceutical technology field.
Background technique
Terbinafine hydrochloride (Terbinafine hydrochloride), chemical name: (E)-N- (6,6- dimethyl -2- heptan
Alkene-4- alkynes)-N- methyl-1-naphthalene methylamine hydrochloric salt, it is a kind of Allylamines drug with broad-spectrum antifungal activity, it can be special
Ground interferes the early stage biosynthesis of fungi ergosterol, inhibits the squalene epoxidase of fungi with high selectivity, keeps fungi thin
Squalene epoxidation reaction is obstructed in after birth forming process, to have the function that killing or inhibit fungi.Because it has height
Lipophilicity and close epidermis, in addition to external application, also orally available carry out Formulations for systemic administration, is known as killing only without tight in fungi-medicine
The kind of weight liver kidney adverse reaction.Terbinafine column name among standard essential medicines list of WHO, based on cure
One for the treatment of system indispensability drug.
(E) chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of -1- is the key intermediate of synthetic hydrochloric acid Terbinafine, and market is huge
Greatly.The patent document of preparation about chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1- is relatively more, but mostly with anti-form-1,
3- dichloropropylene is chloro- 6, the 6- dimethyl -2- heptene -4- alkynes (such as CN101624328A) of Material synthesis (E) -1-, while trans- -
1,3- dichloropropylene is genotoxicity impurity, therefore the customer requirement of many American-European high-end markets is to chloro- 6, the 6- diformazan of (E) -1-
Anti-form-1 in base -2- heptene -4- alkynes, 3- dichloropropylene carry out Quality Control according to genotoxicity impurity.But through retrieving, pass there is no at present
The anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloropropylene according to genotoxicity impurity Quality Control text
Offer report.
(E) chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of -1-, English name: (E) -1-Chloro-6,6-dimethyl-5-
Hept-2-en-4-ino, molecular formula: C9H13Cl, molecular weight: 156.65, CAS registration numbers: 126764-17-8, structural formula are as follows:
Anti-form-1,3- dichloropropylene, English name: 1,3-Dichloropropene, molecular formula: C3H4Cl2；Molecular weight:
111.00 structural formula is as follows:
Summary of the invention
In view of the above-mentioned problems, the present invention provides the one kind controlled according to genotoxicity Control of Impurities limit (6ppm) for the first time
(E) impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of -1-, the detection method of 3- dichloropropylene.This method uses
GC-ECD detection method determines impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloropropylene
Property, it is quantitative, and carried out methodology validation.The experiment proved that this method has easy to operate, specificity is good, sensitive, accurate etc.
Advantage, can reliably to impurity-anti-form-1 in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloropropylene according to
The control of genotoxicity impurity requires to carry out qualitative and quantitative analysis.
The technical scheme is that impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1-, 3-
The detection method of dichloropropylene, characterized in that by (E) -1- chloro- 6, anti-form-1 in 6- dimethyl -2- heptene -4- alkynes, 3- dichloro
Propylene acceptable limit is determined as≤6ppm, and by (E) -1- chloro- 6,6- dimethyl -2- heptene -4- alkynes is direct after being dissolved with solvent
Sample introduction, using GC-ECD detection method to impurity anti-form-1 in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloro third
Alkene carries out qualitative, quantitative.
Wherein, chromatographic condition are as follows:
Chromatographic column: 6% cyanogen propyl phenyl, 94% dimethyl polysiloxane column DB-624 (30m × 0.53mm, 3.0 μm)；Column
Temperature: 80 ± 5 DEG C of 2 ± 1min of holding are warming up to 220 ± 10 DEG C of 10 ± 2min of holding with the rate of 10 ± 2 DEG C/min；Injection port temperature
Degree: 250 ± 10 DEG C；Carrier gas: nitrogen；Flow velocity: 10 ± 1ml/min；Split ratio: 3~8:1；Sample volume: 1 μ l.
Detector: electron capture detector (ECD)；Detector temperature: 300 ± 20 DEG C.
It is preferred that chromatographic condition is as follows:
Chromatographic column: 6% cyanogen propyl phenyl, 94% dimethyl polysiloxane column DB-624 (30m × 0.53mm, 3.0 μm)；Column
Temperature: 80 DEG C of holding 2min are warming up to 220 DEG C of holding 10min with the rate of 10 DEG C/min；Injector temperature: 250 DEG C；Carrier gas: nitrogen
Gas；Flow velocity: 10ml/min；Split ratio: 5:1；Sample volume: 1 μ l.
Detector: electron capture detector (ECD)；Detector temperature: 300 DEG C.
Further, the solvent of dissolution chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1- is methanol.
Further, the present invention is using external standard method to anti-form-1 in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3-
Dichloropropylene is quantified.
Further, under testing conditions of the invention, anti-form-1, the RT at 3- dichloropropylene peak is 3.1 ± 0.1min,
(E) RT at the chloro- 6,6- dimethyl -2- heptene -4- alkynes peak -1- is 8.3 ± 0.1min.
As preferred embodiment of the invention, detection method is specific as follows:
1) contrast solution: weighing anti-form-1, and 3- dichloropropylene reference substance uses methanol dilution to concentration for 0.1-0.5 μ g/
Ml (preferably 0.3 ± 0.01 μ g/ml)；
2) test solution: weighing chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, use methanol dilution to concentration for
10-60mg/ml (preferably 50 ± 1mg/ml)；
3) above-mentioned 1 μ l of solution is taken respectively, injects gas chromatograph, records chromatogram, peak area is calculated, based on following formula
Calculate anti-form-1 in this product, the content of 3- dichloropropylene.
Specific calculation formula:
In formula: A sample: anti-form-1 in test solution, the peak area of 3- dichloropropylene；
A pairs: anti-form-1 in contrast solution, the peak area of 3- dichloropropylene；
C sample: the concentration of this product, mg/ml in test solution；
C pairs: anti-form-1 in contrast solution, the concentration of 3- dichloropropylene, mg/ml.
Advantage of the invention is:
1, the chloro- 6,6- dimethyl -2- heptene -4- alkynes of (E) -1- is the key intermediate of terbinafine HCl synthesis.Trans--
1,3- dichloropropylene is the raw material for synthesizing chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, while anti-form-1,3- dichloropropylene
For genotoxicity impurity.The present invention establishes impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- for the first time
Dichloropropylene according to genotoxicity impurity Quality Control limit gas-chromatography detection method, convenient for the quality to terbinafine HCl into
(we order its control limit for≤6ppm), to improve the drug safety of terbinafine hydrochloride for row control.
2, good separating effect
The present invention establishes impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloro third for the first time
The detection method of alkene GC-ECD, and method is optimized.As can be seen from Figure 2: anti-form-1,3- dichloropropylene peak RT are
3.132min；The chloro- 6,6- dimethyl -2- heptene -4- alkynes peak RT of (E) -1- is 8.318min as can be seen from Figure 3；It can be with from Fig. 4
Find out, anti-form-1, the separating degree between 3- dichloropropylene and adjacent peak minimum 6.3, theoretical cam curve 13549, separation effect
Fruit is good.
3, easy to operate, specificity is good, sensitive, accurate
The experiment proved that this method has, easy to operate, specificity is good, (detection is limited to 0.1ppm, quantitative limit to high sensitivity
For 0.3ppm), the advantages that accurate (rate of recovery 94.5%~115.4%) is measured, it can be reliably to chloro- 6, the 6- diformazan of (E) -1-
Impurity anti-form-1 in base -2- heptene -4- alkynes, it is qualitative fixed that the content of 3- dichloropropylene is carried out according to genotoxicity impurity Quality Control limit
Amount analysis.
Detailed description of the invention
Fig. 1 is blank solution chromatogram；
Fig. 2 is system suitability solution chromatogram, anti-form-1 in figure, 3- dichloropropylene RT=3.132；
Fig. 3 is specificity test solution chromatogram；
Fig. 4 is specificity mixed solution chromatogram.
Fig. 5 is linear standard curve
Specific embodiment
Embodiment 1
1 instrument and material
1.1 instruments: TRACE1300 gas chromatograph (match is silent to fly)；
1.2 reagents: methanol (chromatographic grade).
2 methods and result
2.1 chromatographic condition
Chromatographic column: 6% cyanogen propyl phenyl, 94% dimethyl polysiloxane column DB-624 (30m × 0.53mm, 3.0 μm)；Column
Temperature: 80 DEG C of holding 2min are warming up to 220 DEG C of holding 10min with the rate of 10 DEG C/min；Injector temperature: 250 DEG C；Carrier gas: high
Pure nitrogen gas；Flow velocity: 10ml/min；Split ratio: 5:1；Sample volume: 1 μ l；
Detector: electron capture detector (ECD)；Detector temperature: 300 DEG C.
2.2 solution are prepared
Blank solution: methanol.
Contrast solution: weighing anti-form-1, and 3- dichloropropylene reference substance 30.5mg is set in 100ml measuring bottle, adds methanol dilution extremely
Scale shakes up；Precision measures 1ml, sets in 100ml measuring bottle, adds methanol dilution to scale, shake up as solution A；It is accurate again to measure
1ml is set in 10ml measuring bottle, is added methanol dilution to scale, is shaken up.
Test solution: taking chloro- 6, the 6- dimethyl -2- heptene -4- alkynes test sample 504.2mg of (E) -1-, accurately weighed, sets
In 10ml measuring bottle, adds methanol to dissolve and be diluted to scale, shake up.
2.3 detection
It is accurate respectively to measure above-mentioned 1 μ l of solution, gas chromatograph is injected, chromatogram is recorded, calculates peak area.By external standard method
Calculate anti-form-1 in this product, the content of 3- dichloropropylene.
Calculation formula:
In formula: ASample: anti-form-1 in test solution, the peak area of 3- dichloropropylene；
AIt is right: anti-form-1 in contrast solution, the peak area of 3- dichloropropylene；
CSample: the concentration of this product, mg/ml in test solution；
CIt is right: anti-form-1 in contrast solution, the concentration of 3- dichloropropylene, mg/ml.
3. methodology validation
3.1 specificities and system suitability
Take test sample 501.1mg, it is accurately weighed, set in 10ml measuring bottle, solubilization liquid A1ml, then plus methanol dissolve and be diluted to
Scale shakes up, and mixed solution is made.
It is accurate respectively to measure blank solution, 1 μ l of contrast solution, test solution and mixed solution, gas chromatograph is injected,
Chromatogram is recorded, peak area, number of theoretical plate and separating degree are calculated, as a result shown in table 1 and Fig. 1-4.Wherein, contrast solution continuously into
It sample 6 times, as system suitability, calculates retention time, peak area and calculates RSD, as a result as shown in table 2 and figure 2.
1 specificity test data of table
2 system suitability data of table
3.2 quantitative limits and detection limit
Anti-form-1 is weighed, 3- dichloropropylene reference substance about 30.5mg sets in 100ml measuring bottle, adds methanol dilution to scale, shake
It is even；Precision measures 1ml, sets in 100ml measuring bottle, adds methanol dilution to scale, shake up；It is accurate again to measure 1ml, set 10ml measuring bottle
In, add methanol dilution to scale, shakes up, reference substance stock solution is made.Noise is calculated into 1 needle of blank solution, and as baseline
Than.
Quantitative limit: taking above-mentioned reference substance stock solution, gradually diluted with blank solution, and record signal-to-noise ratio is 10:1 or so Shi Rong
The concentration of liquid is quantitative limit concentration, and the ratio relative to theoretical sample concentration is quantitative limit.
Detection limit: taking above-mentioned reference substance stock solution, gradually diluted with blank solution, when record signal-to-noise ratio is 3:1 or so
The concentration of solution is to detect limit concentration, and the ratio relative to theoretical sample concentration is detection limit.Repeat sample introduction three times.
Quantitative limit, detection limit test data and result see the table below 3-4:
3 quantitative limit data of table
The detection limit data of table 4
3.3 linear
Take under 3.2 control stock solution (concentration: 0.01525 μ g/ml), be diluted to 30% respectively with methanol, 60%,
100% and 120% anti-form-1,3- dichloropropylene solution；Separately quantitative limit solution is prepared according to 3.2.
It is accurate respectively to measure above-mentioned 1 μ l of solution, gas chromatograph is injected, chromatogram is recorded, calculates peak area.Each concentration
It repeats sample introduction 3 times, statistics control peak area does regression curve to corresponding average peak area with sample concentration, calculates regression equation
And corresponding linear regression coeffficient (linear standard curve is shown in Fig. 5).Verification result are as follows: linearly dependent coefficient 0.999；Its intercept
Absolute value is 0.0018, is the 4.0% of 100% concentration area.
3.4 precision
Anti-form-1 is weighed, 3- dichloropropylene reference substance 29.6mg is set in 100ml measuring bottle, adds methanol dilution to scale；It is accurate
1ml is measured, is set in 100ml measuring bottle, is added methanol dilution to scale, shake up as solution A；It is accurate again to measure 10ml, set 100ml measuring bottle
In, add methanol dilution to scale, shakes up, as control.Test sample about 0.5g separately is taken, it is accurately weighed, it sets in 10ml measuring bottle, is added
Methanol dissolves and is diluted to scale, parallel to prepare 6 parts.It is accurate respectively to measure above-mentioned 1 μ l of solution, inject gas chromatograph, record
Chromatogram, control continuously into 6 needles, calculate peak area, verify its repeatability, as a result as figure 5 illustrates；Six parts of test solutions respectively into
Sample calculates peak area and calculates anti-form-1 in test solution, 3- dichloropropylene content, verification result such as the following table 6.
5 repetitive test contrasting data of table
6 Precision test result of table
3.5 accuracy
Take test sample about 0.5g, it is accurately weighed, set in 10ml measuring bottle, be separately added into solution A 0.1ml under precision item,
1.0ml, 2.0ml add methanol to dissolve and are diluted to scale, shake up, be equivalent to contrast solution 10%, 100%, 200% is made
Recovery test solution.It is accurate respectively to measure above-mentioned 1 μ l of solution, gas chromatograph is injected, chromatogram is recorded, calculates peak face
Product.Verification result are as follows: the rate of recovery 94.5%~115.4%, RSD is up to 1.4%.
4 discuss
Anti-form-1,3- dichloropropylene are genotoxicity impurity, we order its control limit for≤6ppm.It establishes herein
The detection method of GC-ECD, and method is optimized and has carried out methodology validation.This method has easy to operate, exclusive
Property good, high sensitivity (detection is limited to 0.1ppm, is quantitatively limited to 0.3ppm), measure accurate (rate of recovery 94.5%~115.4%)
The advantages that, can to impurity anti-form-1 in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-, the content of 3- dichloropropylene according to
Genotoxicity impurity Quality Control limit carries out qualitative and quantitative analysis.
Embodiment 2: the detection of actual sample
Chloro- 6, the 6- dimethyl -2- heptene -4- alkynes sample of three crowdes of (E) -1- is taken, according to 2.1,2.2 and 2.3 preparation in example 1
Contrast solution and test solution simultaneously measure in accordance with the law, as a result as follows:
7 sample detection result of table
| Lot number | 180803LQ | 180804LQ | 180805LQ |
| WSample(mg) | 505.6 | 501.6 | 508.6 |
| Peak area | 0.0225 | 0.0098 | 0.0199 |
| Content ppm | 3.0 | 1.3 | 2.7 |
。
Claims (9)
1. impurity anti-form-1 in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of one kind (E) -1-, the detection method of 3- dichloropropylene,
It is characterized in, by (E) -1- chloro- 6, direct injected after 6- dimethyl -2- heptene -4- alkynes is dissolved with solvent, using the detection side GC-ECD
To impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of (E) -1-, 3- dichloropropylene carries out qualitative, quantitative method.
2. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as described in claim 1,3- dichloro
The detection method of propylene, characterized in that by (E) -1- chloro- 6, anti-form-1 in 6- dimethyl -2- heptene -4- alkynes, 3- dichloropropylene
Acceptable limit is determined as≤6ppm.
3. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as described in claim 1,3- dichloro
The detection method of propylene, characterized in that use 6% cyanogen propyl phenyl, 94% dimethyl polysiloxane column DB-624 for chromatographic column.
4. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as claimed in claim 3,3- dichloro
The detection method of propylene, characterized in that
Chromatographic condition are as follows:
Chromatographic column: 6% cyanogen propyl phenyl, 94% dimethyl polysiloxane column DB-624；Column temperature: 80 ± 5 DEG C of 2 ± 1min of holding, with
The rate of 10 ± 2 DEG C/min is warming up to 220 ± 10 DEG C of 10 ± 2min of holding；Injector temperature: 250 ± 10 DEG C；Carrier gas: nitrogen；
Flow velocity: 10 ± 1ml/min；Split ratio: 3~8:1；
Detector: electron capture detector ECD；Detector temperature: 300 ± 20 DEG C.
5. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as claimed in claim 4,3- dichloro
The detection method of propylene, characterized in that
The chromatographic condition is as follows:
Chromatographic column: 6% cyanogen propyl phenyl 94% dimethyl polysiloxane column DB-624,30m × 0.53mm, 3.0 μm；Column temperature: 80
DEG C keep 2min, 220 DEG C of holding 10min are warming up to the rate of 10 DEG C/min；Injector temperature: 250 DEG C；Carrier gas: nitrogen；Stream
Speed: 10ml/min；Split ratio: 5:1；Sample volume: 1 μ l；
Detector: electron capture detector ECD；Detector temperature: 300 DEG C.
6. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as claimed in claim 5,3- dichloro
The detection method of propylene, characterized in that the anti-form-1, the RT at 3- dichloropropylene peak are 3.1 ± 0.1min, (E) -1- chloro- 6,
The RT at 6- dimethyl -2- heptene -4- alkynes peak is 8.3 ± 0.1min.
7. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as described in claim 1,3- dichloro
The detection method of propylene, characterized in that the solvent of dissolution chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1- is methanol.
8. impurity anti-form-1 in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as described in claim 1,3- dichloro
The detection method of propylene, characterized in that described to use external standard method to anti-in chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1-
Formula -1,3- dichloropropylene is quantified.
9. impurity in the chloro- 6,6- dimethyl -2- heptene -4- alkynes of one kind (E) -1- as described in any one of claim 1-8
Anti-form-1, the detection method of 3- dichloropropylene, characterized in that its detection method is specific as follows:
1) reference substance solution: weighing anti-form-1, and 3- dichloropropylene reference substance uses methanol dilution to concentration for 0.1-0.5 μ g/
ml；
2) test solution: chloro- 6, the 6- dimethyl -2- heptene -4- alkynes of (E) -1- is weighed, uses methanol dilution to concentration for 10-
60mg/ml；
3) reference substance solution and each 1 μ l of test solution are taken respectively, injects gas chromatograph, records chromatogram, calculate peak area,
Anti-form-1 in this product according to the following formula, the content of 3- dichloropropylene；
Specific calculation formula:
In formula: A sample: anti-form-1 in test solution, the peak area of 3- dichloropropylene；
A pairs: anti-form-1 in contrast solution, the peak area of 3- dichloropropylene；
C sample: the concentration of this product, mg/ml in test solution；
C pairs: anti-form-1 in contrast solution, the concentration of 3- dichloropropylene, mg/ml.
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| CN110208433A (en) * | 2019-07-09 | 2019-09-06 | 南京卡文迪许生物工程技术有限公司 | The detection method of residual chlorine propen compounds in a kind of drug |
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