CN105418377B - A kind of hexylene glycol purifying process of 2 ethyl 1,3 and relevant substance detecting method - Google Patents
A kind of hexylene glycol purifying process of 2 ethyl 1,3 and relevant substance detecting method Download PDFInfo
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- CN105418377B CN105418377B CN201610015628.8A CN201610015628A CN105418377B CN 105418377 B CN105418377 B CN 105418377B CN 201610015628 A CN201610015628 A CN 201610015628A CN 105418377 B CN105418377 B CN 105418377B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
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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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas chromatography
Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of purifying process and its relevant substance detecting method of the hexylene glycol of 2 ethyl 1,3.Purifying process of the present invention is calcium hydride reducing process.The detection method, comprises the following steps：Step 1, prepared by system suitability solution：Impurity 1, impurity 2, the hexylene glycol of 3 and 2 ethyl of impurity 1,3 is taken to be configured to system suitability solution；Step 2, prepared by need testing solution：The hexylene glycol of 2 ethyl 1,3 is taken to be configured to need testing solution；Step 3, the preparation of contrast solution：Need testing solution is taken to be configured to contrast solution；Step 4, system suitability solution, contrast solution and need testing solution are injected into gas chromatograph respectively, obtains chromatogram；Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, the content of each known impurities, unknown impuritie and total impurities in need testing solution is obtained by calculating.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the purifying process of a kind of 2- ethyls -1,3- hexylene glycol and relevant
Substance detecting method.
Background technology
2- ethyls -1,3- hexylene glycol is almost colourless, slightly sticky oily liquids, for boric acid complexing agent, medicine, coating
Vehicle and solvent and cosmetics, pest repellant.《American Pharmacopeia》USP18 is upper to be recorded to it, but afterwards《U.S.'s medicine
Allusion quotation》It there are no and include again, other pharmacopoeia of each country and Chinese Pharmacopoeia do not include this kind yet.
2- ethyls -1,3- hexylene glycol easily introduces some impurity in process of production, so that the quality to final products is produced
Raw influence, especially influences it as the application of injection-grade auxiliary material.
It has been shown that, be readily incorporated during 2- ethyl -1,3- hexylene glycols are produced following several according to current result of study
Plant impurity：
In order to effectively control the generation of above-mentioned several impurity, it is ensured that the quality and security of product, the present invention is provided
A kind of purification process of 2- ethyls -1,3- hexylene glycol, and for detecting the detection method of content of above-mentioned several impurity.
The content of the invention
An object of the present invention is to provide a kind of purification process of 2- ethyls -1,3- hexylene glycols.
By means of the invention it is also possible to effectively ensure the quality of product, the generation of impurity is reduced, the steady of product is improved
It is qualitative.
Specifically, the purifying process of 2- ethyls -1,3- hexylene glycol of the present invention, comprises the following steps：
Step 1：2- ethyls -1,3- hexylene glycol and calcium hydride are taken, it is slow under nitrogen protection to add in reaction bulb, slowly
50 DEG C are warming up to, continues to stir 2 hours to there is no bubble formation, reaction is down to room temperature after terminating,
Step 2：By reacting liquid filtering, after filtering is finished, filtrate sealing preserve,
Step 3：Filter cake used steeps in ethanol and stirred when upper step is filtered, and adds water, and handles without the hydrogenation reacted
Calcium.
Wherein, the addition of the calcium hydride presses quality volume percentage, is 2- ethyl -1,3- hexylene glycol consumptions
1.5%.
It is preferred that, the purifying process of 2- ethyls -1,3- hexylene glycol of the present invention comprises the following steps：
Step 1：2- ethyls -1,3- hexylene glycol and calcium hydride are taken, it is slow under conditions of nitrogen protection to add reaction bulb
In, 50 DEG C are to slowly warm up to, continues to stir 2 hours to there is no bubble formation, reaction is down to room temperature after terminating,
Step 2：Buchner funnel is cleaned up, and is put into drying in drying box, drying is finished, and spreads 2 layers of suitable filter paper,
Action is fast in reacting liquid filtering, filter process, and 2- ethyls -1,3- hexylene glycol easily moisture absorption, suction filtration is finished, and filtrate sealing is protected
Deposit,
Step 3：Filter cake, which is quickly steeped in ethanol, to be stirred, and is added water, is handled without the calcium hydride reacted.
Wherein, the addition of the calcium hydride presses quality volume percentage, is 2- ethyl -1,3- hexylene glycol consumptions
1.5%.
It is another object of the present invention to provide the detection method of content of 2- ethyl -1,3- hexylene glycols.
The product quality for the 2- ethyl -1,3- hexylene glycols that the detection of the present invention can be used for detecting after above-mentioned purifying process.
Relevant material in present invention application gas chromatography detection 2- ethyl -1,3- hexylene glycols, passes through system suitability
Solution is positioned to known impurities, and known impurity level is calculated with Self-control method, makes the control about material more strict and accurate
Really.
Detection method of content of the present invention, comprises the following steps：
Step 1, prepared by system suitability solution：Impurity 1, impurity 2, impurity 3 and 2- ethyl -1,3- hexylene glycols is taken to be configured to
System suitability solution；
Step 2, prepared by need testing solution：2- ethyl -1,3- hexylene glycols are taken to be configured to need testing solution；
Step 3, the preparation of contrast solution：Need testing solution is taken to be configured to contrast solution；
Step 4, system suitability solution, contrast solution and need testing solution are injected into gas chromatograph respectively, obtains color
Spectrogram；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, supplied by calculating
The content of each known impurities, unknown impuritie and total impurities in test sample solution；
Wherein, the chromatographic condition of the gas-chromatography is as follows：
From the chromatographic column using cyanogen propyl group phenyl-methyl polysiloxane as fixer, or select and cyanogen propyl group phenyl-first
The close chromatographic column of based polysiloxane polarity；Initial column temperature is 65~70 DEG C, is maintained 3 minutes, with 19~20 DEG C per minute of speed
Rate is warming up to 260 DEG C, maintains 16 minutes；Split ratio is 10:1, flow velocity is 2.7ml/min-3ml/min, and injector temperature is 250
DEG C, detector temperature is 275 DEG C.
Following three impurity in 2- ethyl -1,3- hexylene glycols can effectively be detected by above-mentioned detection method：
It is preferred that, detection method of content of the present invention comprises the following steps：
Step 1, prepared by system suitability solution：Weigh 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2, impurity 3 are each suitable
Amount, plus absolute ethyl alcohol are configured to ethyl containing 2- -1,3- hexylene glycols 20mg/ml and impurity 1, impurity 2, each 0.1mg/ml of impurity 3
Solution is used as system suitability solution；
Step 2, prepared by need testing solution：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is configured to concentration and is
20mg/ml solution is used as need testing solution；
Step 3, the preparation of contrast solution：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles, is diluted with water to
Scale, shakes up, and obtains contrast solution；
Step 4, it is accurate respectively to draw said system applicability solution, need testing solution and each 1 μ l of contrast solution, inject gas
Chromatography, obtains chromatogram；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, supplied by calculating
The content of each known impurities, unknown impuritie and total impurities in test sample solution.
Wherein, chromatographic condition：Using (6%) cyanogen propyl group phenyl-(94%) methyl polysiloxane as the chromatographic column of fixer；Just
Beginning column temperature is 70 DEG C, is maintained 3 minutes, and 260 DEG C are warming up to 20 DEG C per minute of speed, is maintained 16 minutes；Split ratio is 10:1,
Flow velocity is 3ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C.
It is preferred that, the model DB624 chromatographic columns of chromatographic column of the present invention, specification is 30m × 0.53mm × 3 μm.
The detection method of content of the present invention is obtained after lot of experiments, and experimentation is as follows：
1st, system suitability
Weigh 2- ethyls -1,3- hexylene glycol and impurity 1, impurity 2, impurity 3 are each appropriate, plus absolute ethyl alcohol is configured to second containing 2-
Base -1,3- hexylene glycol 20mg/ml and impurity 1, impurity 2, each 0.1mg/ml of impurity 3 solution enter as system suitability solution
Sample is determined.
The system suitability result of table 1
| Material title | Concentration (mg/ml) | Retention time (min) | Relative retention time | Separating degree |
| Impurity 1 | 0.1 | 12.509 | 1.09 | 10.29 |
| Impurity 2 | 0.1 | 12.659 | 1.10 | 1.74 |
| Impurity 3 | 0.1 | 12.935 | 1.12 | 3.15 |
| 2- ethyl -1,3- hexylene glycols | 20 | 11.493 | 1.00 | 7.20 |
The system suitability result of table 2
The result from upper table we can see that：Separating degree between each chromatographic peak meets regulation, peak area relative standard
Deviation meets regulation.
2nd, specificity is tested
2.1 interference and location test
Need testing solution, each dirt solution, blank solvent difference sample introduction are taken respectively, and each impurity can reach completely with main peak
Separation, and blank solvent not interference measurement.
2.2 destructive test
The method in this product according to the form below is taken to carry out acid, alkali, high temperature and illumination destructive test, with above-mentioned chromatographic condition inspection
Catabolite.
The degradation experiment table of table 3
As seen from the figure, 2- ethyls -1,3- hexylene glycol has good stability in ethanol.
3rd, test limit quantitative limit is verified
Under this experiment condition, impurity reference substance solution is diluted into sample detection, calculated with signal to noise ratio S/N=10, impurity
1st, the quantitative limit of impurity 2, impurity 3 and 2- ethyl -1,3- hexylene glycols is 10 μ g/ml, and chromatogram is shown in accompanying drawing；With signal to noise ratio S/N
=3 calculate, and impurity 1, impurity 2, the detection of impurity 3 and 2- ethyl -1,3- hexylene glycols are limited to 3.3 μ g/ml.
4th, linear verification
Impurity 1, impurity 2, impurity 3,2- ethyl -1,3- hexylene glycols reference substance are weighed respectively appropriate, dissolved with absolute ethyl alcohol
And the solution for being made that every 1ml about impure 1, impurity 2, impurity 3,2- ethyls -1,3- hexylene glycol are 1.0mg is diluted, it is used as control
Storing solution, respectively precision measure control storing solution be placed in right amount in measuring bottle, scale is diluted with water to, with obtained 6 parts of solution concentrations
It is followed successively by impurity 1, impurity 2, impurity 3, the μ g/ of 2- ethyls -1,3- hexylene glycols each 0.04,0.06,0.08,0.10,0.12,0.15
ml.Each μ l of strength solution 1 are taken, are operated by primary colors spectral condition, measurement result is shown in Table 4.
Table 4 linear relationship result of the test table (n=7, concentration：μg/ml)
Make regression straight line to concentration (C) with peak area (A), 2- ethyl -1,3- hexylene glycol linear equations are：Y=
555128x-366.2, R2=0.9997；The linear equation of impurity 1 is y=530341x-593.39, R2=0.9999；Impurity 2 is linear
Equation is：Y=515997x-587.16, R2=0.9998；The linear equation of impurity 3 is y=540149x+11.174, R2=
0.9995.Therefore, impurity 1, impurity 2, impurity 3,2- ethyl -1,3- hexylene glycol concentration have good linear between respective concentration
Relation.Warp sexual intercourse slope ratio is calculated, the impurity peaks correction factor f values of impurity 1 be 1.05, the impurity peaks of impurity 2 correction because
Sub- f values are 1.08, and the impurity peaks correction factor f values of impurity 3 are 1.03, therefore can be using the Self-control method for being not added with correction factor.
5th, precision is verified
5.1 it is repeated
Met the requirements by configuring 6 sample solutions and being tested come the precision of substantive approach.It the results are shown in Table 5.
Table 5 is about material Precision test result
| Sample introduction sequence | Impurity 1 (%) | Impurity 2 (%) | Impurity 3 (%) | Total miscellaneous (%) |
| 1 | 0.12 | 0.67 | 0.15 | 0.94 |
| 2 | 0.11 | 0.65 | 0.15 | 0.91 |
| 3 | 0.12 | 0.66 | 0.16 | 0.94 |
| 4 | 0.12 | 0.65 | 0.16 | 0.93 |
| 5 | 0.11 | 0.67 | 0.16 | 0.94 |
| 6 | 0.12 | 0.67 | 0.16 | 0.95 |
| RSD (%) | 4.43 | 1.48 | 3.30 | 1.47 |
Test result indicates that, repeatability is good.
5.3 Intermediate precision
To investigate influence of the random fluctuation factor to precision, another analyst builds on different high resolution gas chromatography instrument
Erection system, is prepared 6 sample solutions and is detected, the good Intermediate precision of this method is confirmed with this again.
Table 6 is about material Intermediate precision result of the test
| Sample introduction sequence | Impurity 1 (%) | Impurity 2 (%) | Impurity 3 (%) | Total miscellaneous (%) |
| 1 | 0.12 | 0.67 | 0.15 | 0.94 |
| 2 | 0.11 | 0.65 | 0.15 | 0.91 |
| 3 | 0.12 | 0.66 | 0.16 | 0.94 |
| 4 | 0.12 | 0.65 | 0.16 | 0.93 |
| 5 | 0.11 | 0.67 | 0.16 | 0.94 |
| 6 | 0.12 | 0.67 | 0.16 | 0.95 |
| 7 | 0.12 | 0.66 | 0.15 | 0.93 |
| 8 | 0.12 | 0.66 | 0.15 | 0.93 |
| 9 | 0.11 | 0.66 | 0.15 | 0.92 |
| 10 | 0.12 | 0.65 | 0.14 | 0.91 |
| 11 | 0.12 | 0.67 | 0.14 | 0.93 |
| 12 | 0.12 | 0.67 | 0.15 | 0.94 |
| RSD (%) | 3.85 | 1.26 | 4.73 | 1.33 |
Test result indicates that, Intermediate precision is good.
6th, stability of solution
Need testing solution is taken, different time sample introductions is determined under above-mentioned chromatographic condition, the results are shown in Table 7.
The sample solution stability test result of table 7
Impurity 1, impurity 2, impurity 3 and the change of 2- ethyl -1,3- hexylene glycols peak area are smaller in 10 hours, illustrate sample
In each impurity it is good in 10 hours internal stabilities.
7th, the degree of accuracy
By added in need testing solution index 50%, 100%, 150% 3 each impurity of various concentrations measure back
Yield, has the good degree of accuracy with substantive approach.
Take every 1ml containing about impurity 1, impurity 2, the concentration of impurity 3 for 1mg reference substance solution as impurity storing solution.Prepare 9
Part need testing solution, is separately added into each 3 parts of 2.5ml, 5.0ml, 7.5ml impurity storing solution, is diluted with water to scale, takes 1 μ l to note
Enter chromatograph, determined by above-mentioned chromatographic condition, calculate the rate of recovery, the results are shown in Table 8.As a result show, high, medium and low three kinds of concentration
The rate of recovery meets regulation.
Table 8 is about substance recovery measurement result
Recovery test shows：Accurately and reliably, error is in allowed limits for this method.
8th, durability
Take need testing solution respectively in different pH value mobile phases, different wave length, different in flow rate, different mobile phase ratios, no
With sample introduction under the conditions of chromatographic column and different column temperatures, record separating degree, post are imitated and calculate content.It the results are shown in Table organic in 9, mobile phase
Phase Proportion change influences smaller to result, and other condition changes, substantially without influence, show that system robustness is good to result.
Table 9 is about substance-measuring serviceability test measurement result
Pass through above-mentioned verification process and the result, it was demonstrated that the chromatographic condition can accurately and effectively detect 2- ethyl -1,
The relevant material of 3- hexylene glycols, this method is simple and feasible.
The detection method of content of the present invention is compared with the conventional method compared with advantages below：
The detection method of the present invention can effectively detect the relevant material of sample, and by be not added with correction factor itself
Counter point calculates the content of each known impurities, reaches the purpose for controlling product related impurities exactly, improves the Quality Control of product
Method, foundation is provided for the security and validity of product after purification.The detection method of the present invention also has the degree of accuracy high, accurate
Spend the features such as high, reproducible, stability is good, specificity is strong.
Brief description of the drawings
Accompanying drawing 1：The detection method of embodiment 1 corresponds to gas chromatogram, and (3 small peaks correspond to impurity before and after second main peak in figure
Respectively impurity 3, impurity 1 and impurity 2)；
Accompanying drawing 2：The detection method of embodiment 2 corresponds to gas chromatogram, and (3 small peaks correspond to impurity before and after second main peak in figure
Respectively impurity 3, impurity 1 and impurity 2)；
Accompanying drawing 3：The detection method of embodiment 3 corresponds to gas chromatogram, and (3 small peaks correspond to impurity before and after second main peak in figure
Respectively impurity 3, impurity 1 and impurity 2)；
Accompanying drawing 4：The detection method of embodiment 4 corresponds to gas chromatogram, and (3 small peaks correspond to impurity before and after second main peak in figure
Respectively impurity 3, impurity 1 and impurity 2)；
Embodiment
Present disclosure is described further by herein below, present patent application protection domain is not limited to
Embodiment content.
Embodiment 1：
Chromatographic condition：Using (6%) cyanogen propyl group phenyl-(94%) methyl polysiloxane as the DB624 chromatographic columns of fixer, rule
Lattice are 30m × 0.53mm × 3 μm；Initial column temperature is 70 DEG C, maintains 3 minutes, 260 DEG C are warming up to 20 DEG C per minute of speed,
Maintain 16 minutes；Split ratio is 10:1, flow velocity is 3ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C.
Step 1, prepared by system suitability solution：Method is as follows：Weigh 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2,
Impurity 3 is each appropriate, plus absolute ethyl alcohol is configured to ethyl containing 2- -1,3- hexylene glycols 20mg/ml and impurity 1, impurity 2, impurity 3 are each
0.1mg/ml solution is as system suitability solution；
Step 2, prepared by need testing solution：Method is as follows：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is matched somebody with somebody
- 1,3- the hexylene glycols of ethyl containing 2- 20mg/ml solution is made as need testing solution；
Step 3, the preparation of contrast solution：Method is as follows：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles,
Scale is diluted with water to, is shaken up, contrast solution is obtained；
Step 4, gas chromatograph is injected：Method is as follows：It is accurate respectively to draw said system applicability solution, contrast solution
With each 1 μ l of need testing solution, gas chromatograph is injected, chromatogram is obtained；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, supplied by calculating
The content of each known impurities, unknown impuritie and total impurities in test sample solution.
Determination method takes the μ l of contrast solution 1 to inject gas chromatograph, adjusts detection sensitivity, makes 2- ethyl -1,3- hexylene glycols
The peak height at peak is about the 10% of full scale, and number of theoretical plate must not calculate less than 100000 by 2- ethyl -1,3- hexylene glycols peak.It is accurate
Reference substance solution and the need testing solution difference μ l of sample introduction 1 are measured, gas chromatograph is injected separately into, records chromatogram.Test sample is molten
If any impurity peaks in the chromatogram of liquid, more than 2 times of contrast solution 2- ethyl -1,3- hexylene glycol peak areas, the peak face of total impurities
Product sum cannot be greater than 6 times of contrast solution 2- ethyl -1,3- hexylene glycols peak area.As shown in Figure 1.
Embodiment 2
Chromatographic condition：Using (6%) cyanogen propyl group phenyl-(94%) methyl polysiloxane as the DB624 chromatographic columns of fixer, rule
Lattice are 30m × 0.53mm × 3 μm；Initial column temperature is 65 DEG C, maintains 3 minutes, 260 DEG C are warming up to 20 DEG C per minute of speed,
Maintain 16 minutes；Split ratio is 10:1, flow velocity is 3ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C.
Step 1, prepared by system suitability solution：Method is as follows：Weigh 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2,
Impurity 3 is each appropriate, plus absolute ethyl alcohol is configured to ethyl containing 2- -1,3- hexylene glycols 20mg/ml and impurity 1, impurity 2, impurity 3 are each
0.1mg/ml solution is as system suitability solution；
Step 2, prepared by need testing solution：Method is as follows：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is matched somebody with somebody
- 1,3- the hexylene glycols of ethyl containing 2- 20mg/ml solution is made as need testing solution；
Step 3, the preparation of contrast solution：Method is as follows：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles,
Scale is diluted with water to, is shaken up, contrast solution is obtained；
Step 4, gas chromatograph is injected：Method is as follows：It is accurate respectively to draw said system applicability solution, contrast solution
With each 1 μ l of need testing solution, gas chromatograph is injected, chromatogram is obtained.
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, supplied by calculating
The content of each known impurities, unknown impuritie and total impurities in test sample solution.
Determination method takes the μ l of contrast solution 1 to inject gas chromatograph, adjusts detection sensitivity, makes 2- ethyl -1,3- hexylene glycols
The peak height at peak is about the 10% of full scale, and number of theoretical plate must not calculate less than 100000 by 2- ethyl -1,3- hexylene glycols peak.It is accurate
Reference substance solution and the need testing solution difference μ l of sample introduction 1 are measured, gas chromatograph is injected separately into, records chromatogram.Test sample is molten
If any impurity peaks in the chromatogram of liquid, more than 2 times of contrast solution 2- ethyl -1,3- hexylene glycol peak areas, the peak face of total impurities
Product sum cannot be greater than 6 times of contrast solution 2- ethyl -1,3- hexylene glycols peak area.As shown in Figure 2.
Embodiment 3
Chromatographic condition：Using (6%) cyanogen propyl group phenyl-(94%) methyl polysiloxane as the DB624 chromatographic columns of fixer, rule
Lattice are 30m × 0.53mm × 3 μm；Initial column temperature is 70 DEG C, maintains 3 minutes, 260 DEG C are warming up to 19 DEG C per minute of speed,
Maintain 16 minutes；Split ratio is 10:1, flow velocity is 3ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C.
Step 1, prepared by system suitability solution：Method is as follows：Weigh 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2,
Impurity 3 is each appropriate, plus absolute ethyl alcohol is configured to ethyl containing 2- -1,3- hexylene glycols 20mg/ml and impurity 1, impurity 2, impurity 3 are each
0.1mg/ml solution is as system suitability solution；
Step 2, prepared by need testing solution：Method is as follows：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is matched somebody with somebody
- 1,3- the hexylene glycols of ethyl containing 2- 20mg/ml solution is made as need testing solution；
Step 3, the preparation of contrast solution：Method is as follows：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles,
Scale is diluted with water to, is shaken up, contrast solution is obtained；
Step 4, gas chromatograph is injected：Method is as follows：It is accurate respectively to draw said system applicability solution, contrast solution
With each 1 μ l of need testing solution, gas chromatograph is injected, chromatogram is obtained；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, supplied by calculating
The content of each known impurities, unknown impuritie and total impurities in test sample solution.
Determination method takes the μ l of contrast solution 1 to inject gas chromatograph, adjusts detection sensitivity, makes 2- ethyl -1,3- hexylene glycols
The peak height at peak is about the 10% of full scale, and number of theoretical plate must not calculate less than 100000 by 2- ethyl -1,3- hexylene glycols peak.It is accurate
Reference substance solution and the need testing solution difference μ l of sample introduction 1 are measured, gas chromatograph is injected separately into, records chromatogram.Test sample is molten
If any impurity peaks in the chromatogram of liquid, more than 2 times of contrast solution 2- ethyl -1,3- hexylene glycol peak areas, the peak face of total impurities
Product sum cannot be greater than 6 times of contrast solution 2- ethyl -1,3- hexylene glycols peak area.As shown in Figure 3.
Embodiment 4
Chromatographic condition：Using (6%) cyanogen propyl group phenyl-(94%) methyl polysiloxane as the DB624 chromatographic columns of fixer, rule
Lattice are 30m × 0.53mm × 3 μm；Initial column temperature is 70 DEG C, maintains 3 minutes, 260 DEG C are warming up to 20 DEG C per minute of speed,
Maintain 16 minutes；Split ratio is 10:1, flow velocity is 2.7ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C.
Step 1, prepared by system suitability solution：Method is as follows：Weigh 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2,
Impurity 3 is each appropriate, plus absolute ethyl alcohol is configured to ethyl containing 2- -1,3- hexylene glycols 20mg/ml and impurity 1, impurity 2, impurity 3 are each
0.1mg/ml solution is as system suitability solution；
Step 2, prepared by need testing solution：Method is as follows：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is matched somebody with somebody
- 1,3- the hexylene glycols of ethyl containing 2- 20mg/ml solution is made as need testing solution；
Step 3, the preparation of contrast solution：Method is as follows：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles,
Scale is diluted with water to, is shaken up, contrast solution is obtained；
Step 4, gas chromatograph is injected：Method is as follows：It is accurate respectively to draw said system applicability solution, contrast solution
With each 1 μ l of need testing solution, gas chromatograph is injected, chromatogram is obtained；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, supplied by calculating
The content of each known impurities, unknown impuritie and total impurities in test sample solution.
Determination method takes the μ l of contrast solution 1 to inject gas chromatograph, adjusts detection sensitivity, makes 2- ethyl -1,3- hexylene glycols
The peak height at peak is about the 10% of full scale, and number of theoretical plate must not calculate less than 100000 by 2- ethyl -1,3- hexylene glycols peak.It is accurate
Reference substance solution and the need testing solution difference μ l of sample introduction 1 are measured, gas chromatograph is injected separately into, records chromatogram.Test sample is molten
If any impurity peaks in the chromatogram of liquid, more than 2 times of contrast solution 2- ethyl -1,3- hexylene glycol peak areas, the peak face of total impurities
Product sum cannot be greater than 6 times of contrast solution 2- ethyl -1,3- hexylene glycols peak area.As shown in Figure 4.
The purifying process of the 2- ethyl -1,3- hexylene glycols of embodiment 5
Step 1: 2- ethyls -1, the 3- hexylene glycol for measuring 100ml technical grades is added in the clean single port bottles of 250ml, accurately
The calcium hydride 1.5g of technical grade is weighed, it is slow under conditions of nitrogen protection to add in reaction bulb.50 DEG C are to slowly warm up to, after
Continuous 2 hours (thering is slow bubble to produce in course of reaction) of stirring.Reaction is down to room temperature after terminating.
Step 2：250ml Buchner funnel is cleaned up, and is put into drying box dry.Drying is finished, and paving 2 is laminated
Action is fast in suitable filter paper, reacting liquid filtering, filter process, 2- ethyls -1,3- hexylene glycol easily moisture absorption.Suction filtration is finished, filter
Liquid sealing preserve.
Step 3：Filter cake, which quickly steeps, to be stirred in 10ml ethanol after 5 minutes, plus 5ml water, handle without the hydrogenation reacted
Calcium.
Embodiment 6,
Refined research is carried out to 2- ethyls -1,3- hexylene glycol of technical grade according to the requirement of pharmaceutic adjuvant, note is complied with
Penetrate a grade auxiliary material requirement.Following experiment is devised according to conventional experience and documents and materials：
Method A：2- ethyls -1, the 3- hexylene glycol for measuring 100ml technical grades is added in the clean single port bottles of 250ml, accurately
The activated carbon 5g of medical grade is weighed, it is slow under conditions of nitrogen protection to add in reaction bulb.It is to slowly warm up to 50 DEG C, continuation
Stirring 2 hours；Reaction is down to room temperature after terminating.
250ml Buchner funnel is cleaned up in advance, and is put into drying box dry.Drying is finished, and spreads 1 layer suitably
Filter paper, the diatomite of filter paper upper berth 20g medical grades, reacting liquid filtering filters slow, material viscosity ratio is larger；2- ethyl -1,
The 3- hexylene glycols easily moisture absorption.Suction filtration is finished, filtrate sealing preserve.
Method B：2- ethyls -1, the 3- hexylene glycol for measuring 100ml technical grades is added in the clean single port bottles of 250ml, is put up
Vacuum distillation apparatus, uses oil pump vacuum distillation, when vacustat is between 8-14mmHg.Start slow heating, collect 135 DEG C
To 145 DEG C of cut 80g, cut sealing preserve.
Method C：2- ethyls -1, the 3- hexylene glycol for measuring 100ml technical grades is added in the clean single port bottles of 250ml, accurately
The calcium hydride 1.5g of technical grade is weighed, it is slow under conditions of nitrogen protection to add in reaction bulb.50 DEG C are to slowly warm up to, after
Continuous 2 hours (thering is slow bubble to produce in course of reaction) of stirring.Reaction is down to room temperature after terminating.
250ml Buchner funnel is cleaned up in advance, and is put into drying box dry.Drying is finished, and spreads 2 layers suitably
Action is fast in filter paper, reacting liquid filtering, filter process, 2- ethyls -1,3- hexylene glycol easily moisture absorption.Suction filtration is finished, and filtrate is close
Envelope is preserved.Filter cake, which quickly steeps, to be stirred in 10ml ethanol after 5 minutes, plus 5ml water, handle without the calcium hydride reacted.
Purified product detection data are as follows obtained by three kinds of process for purification：
The different process for purification sample detection results of table 10
Conclusion
Testing result to three kinds of method final products is analyzed, and either moisture or content are superior to essence to method C
Sample before system and obtained by method A, B；Therefore method for optimizing C uses and matter is added in crude product as the process for purification of the product
The method for measuring the calcium hydride of percentage 1.5% is refined.
Claims (7)
1. a kind of purification process of 2- ethyls -1,3- hexylene glycol, it is characterised in that comprise the following steps：
Step 1：2- ethyls -1,3- hexylene glycol and calcium hydride are taken, slow under nitrogen protection to add in reaction bulb, slow heating
To 50 DEG C, continue to stir 2 hours to there is no bubble formation, reaction is down to room temperature after terminating,
Step 2：By reacting liquid filtering, after filtering is finished, filtrate sealing preserve,
Step 3：Filter cake used steeps in ethanol and stirred when upper step is filtered, and adds water, and handles without the calcium hydride reacted,
Wherein, the addition of the calcium hydride presses quality volume percentage, is the 1.5% of 2- ethyl -1,3- hexylene glycol consumptions.
2. purification process according to claim 1, it is characterised in that comprise the following steps：
Step 1：2- ethyls -1,3- hexylene glycol and calcium hydride are taken, it is slow under conditions of nitrogen protection to add in reaction bulb, delay
It is slow to be warming up to 50 DEG C, continue to stir 2 hours to there is no bubble formation, reaction is down to room temperature after terminating,
Step 2：Buchner funnel is cleaned up, and is put into drying box dry, dry to finish, 2 layers of suitable filter paper of paving, reaction
Liquid is filtered, and action is fast in filter process, and 2- ethyls -1,3- hexylene glycol easily moisture absorption, suction filtration is finished, filtrate sealing preserve,
Step 3：Filter cake, which is quickly steeped in ethanol, to be stirred, and is added water, is handled without the calcium hydride reacted,
Wherein, the addition of the calcium hydride presses quality volume percentage, is the 1.5% of 2- ethyl -1,3- hexylene glycol consumptions.
3. a kind of detection method of content of 2- ethyls -1,3- hexylene glycol, it is characterised in that comprise the following steps：
Step 1, prepared by system suitability solution：Impurity 1, impurity 2, impurity 3 and 2- ethyl -1,3- hexylene glycols is taken to be configured to system
Applicability solution；
Step 2, prepared by need testing solution：2- ethyl -1,3- hexylene glycols are taken to be configured to need testing solution；
Step 3, the preparation of contrast solution：Need testing solution is taken to be configured to contrast solution after diluting；
Step 4, system suitability solution, contrast solution and need testing solution are injected into gas chromatograph respectively, obtains chromatogram；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, test sample is obtained by calculating
The content of each known impurities, unknown impuritie and total impurities in solution；
The detection method GC conditions are as follows：
Chromatographic column is the chromatographic column using cyanogen propyl group phenyl-methyl polysiloxane as fixer, or is selected and cyanogen propyl group phenyl-first
The close chromatographic column of based polysiloxane polarity；
Initial column temperature is 65~70 DEG C, is maintained 3 minutes, and 260 DEG C are warming up to 19~20 DEG C per minute of speed, maintains 16 points
Clock；Split ratio is 10:1, flow velocity is 2.7ml/min-3ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C,
Characterized in that, the detection method can effectively detect following three kinds of impurity in 2- ethyl -1,3- hexylene glycols：
Impurity 1：
Impurity 2：
Impurity 3：
4. detection method of content according to claim 3, it is characterised in that comprise the following steps：
Step 1, prepared by system suitability solution：Weigh 2- ethyls -1,3- hexylene glycol and impurity 1, impurity 2, impurity 3 be each appropriate,
Plus absolute ethyl alcohol is configured to the -1,3- hexylene glycols 20mg/ml of ethyl containing 2- and impurity 1, impurity 2, each 0.1mg/ml of impurity 3 solution
It is used as system suitability solution；
Step 2, prepared by need testing solution：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is configured to concentration and is
20mg/ml solution is used as need testing solution；
Step 3, the preparation of contrast solution：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles, is diluted with water to quarter
Degree, shakes up, obtains contrast solution；
Step 4, it is accurate respectively to draw said system applicability solution, need testing solution and each 1 μ l of contrast solution, inject gas phase color
Spectrometer, obtains chromatogram；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, test sample is obtained by calculating
The content of each known impurities, unknown impuritie and total impurities in solution；
Wherein, chromatographic condition：Using the methyl polysiloxane of 6% cyanogen propyl group phenyl -94% as the chromatographic column of fixer；Initial column temperature is
70 DEG C, maintain 3 minutes, 260 DEG C are warming up to 20 DEG C per minute of speed, maintain 16 minutes；Split ratio is 10:1, flow velocity is
3ml/min, injector temperature is 250 DEG C, and detector temperature is 275 DEG C.
5. detection method of content according to claim 4, it is characterised in that the model DB624 chromatographic columns of chromatographic column, rule
Lattice are 30m × 0.53mm × 3 μm.
6. detection method of content according to claim 4 be used to detecting 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2,
The content of impurity 3.
7. detection method of content according to claim 5, it is characterised in that comprise the following steps：
Step 1, prepared by system suitability solution：Method is as follows：Weigh 2- ethyl -1,3- hexylene glycols and impurity 1, impurity 2, impurity
3 is each appropriate, plus absolute ethyl alcohol is configured to ethyl containing 2- -1,3- hexylene glycols 20mg/ml and impurity 1, impurity 2, each 0.1mg/ of impurity 3
Ml solution is as system suitability solution；
Step 2, prepared by need testing solution：Method is as follows：Weigh 2- ethyls -1,3- hexylene glycol appropriate, plus absolute ethyl alcohol is configured to
- 1,3- the hexylene glycols of ethyl containing 2- 20mg/ml solution is used as need testing solution；
Step 3, the preparation of contrast solution：Method is as follows：Precision measures need testing solution 0.5ml, puts in 100ml measuring bottles, adds water
Scale is diluted to, is shaken up, contrast solution is obtained；
Step 4, gas chromatograph is injected：Method is as follows：It is accurate respectively to draw said system applicability solution, contrast solution and confession
Each 1 μ l of test sample solution, inject gas chromatograph, obtain chromatogram；
Step 5, according to the chromatogram of system suitability solution, contrast solution and need testing solution, test sample is obtained by calculating
The content of each known impurities, unknown impuritie and total impurities in solution,
Chromatographic condition：Using the methyl polysiloxane of 6% cyanogen propyl group phenyl -94% as the DB624 chromatographic columns of fixer, specification is 30m
×0.53mm×3μm；Initial column temperature is 70 DEG C, is maintained 3 minutes, and 260 DEG C are warming up to 20 DEG C per minute of speed, maintains 16 points
Clock；Split ratio is 10:1, flow velocity is 3ml/min, and injector temperature is 250 DEG C, and detector temperature is 275 DEG C,
Determination method takes the μ l of contrast solution 1 to inject gas chromatograph, adjusts detection sensitivity, makes 2- ethyl -1,3- hexylene glycols peak
Peak height is about the 10% of full scale, and number of theoretical plate must not calculate less than 100000 by 2- ethyl -1,3- hexylene glycols peak, and precision is measured
Reference substance solution and the need testing solution difference μ l of sample introduction 1, are injected separately into gas chromatograph, record chromatogram, need testing solution
If any impurity peaks in chromatogram, more than 2 times of contrast solution 2- ethyl -1,3- hexylene glycol peak areas, the peak area of total impurities it
With cannot be greater than 6 times of contrast solution 2- ethyl -1,3- hexylene glycols peak area.
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