CN107167529B - The measuring method of the Reinheitszahl and uncertainty of phenol and hydroquinone standard substance - Google Patents
The measuring method of the Reinheitszahl and uncertainty of phenol and hydroquinone standard substance Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 161
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 title claims abstract description 130
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 239000000126 substance Substances 0.000 title claims abstract description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 90
- 238000004817 gas chromatography Methods 0.000 claims abstract description 48
- 239000002994 raw material Substances 0.000 claims abstract description 24
- 238000013094 purity test Methods 0.000 claims abstract description 18
- 238000012790 confirmation Methods 0.000 claims abstract description 17
- 238000011156 evaluation Methods 0.000 claims abstract description 17
- 238000013112 stability test Methods 0.000 claims abstract description 14
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims abstract description 13
- 238000012216 screening Methods 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 claims abstract description 3
- 238000012360 testing method Methods 0.000 claims description 48
- 238000005259 measurement Methods 0.000 claims description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000012535 impurity Substances 0.000 claims description 32
- 238000010792 warming Methods 0.000 claims description 31
- 238000012856 packing Methods 0.000 claims description 30
- 238000007689 inspection Methods 0.000 claims description 28
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 24
- 239000012085 test solution Substances 0.000 claims description 17
- 238000001514 detection method Methods 0.000 claims description 15
- 238000004364 calculation method Methods 0.000 claims description 13
- 239000013557 residual solvent Substances 0.000 claims description 13
- 241001269238 Data Species 0.000 claims description 12
- 239000007789 gas Substances 0.000 claims description 12
- 238000010606 normalization Methods 0.000 claims description 12
- 230000003068 static effect Effects 0.000 claims description 12
- 238000004458 analytical method Methods 0.000 claims description 11
- 238000003556 assay Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 239000012159 carrier gas Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000005070 sampling Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 238000009826 distribution Methods 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000001543 one-way ANOVA Methods 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052593 corundum Inorganic materials 0.000 claims description 4
- 238000005868 electrolysis reaction Methods 0.000 claims description 4
- 238000010812 external standard method Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 claims description 4
- 230000010287 polarization Effects 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000005979 thermal decomposition reaction Methods 0.000 claims description 4
- 229910001845 yogo sapphire Inorganic materials 0.000 claims description 4
- 239000002131 composite material Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000007619 statistical method Methods 0.000 claims description 3
- 238000007707 calorimetry Methods 0.000 claims description 2
- 230000010355 oscillation Effects 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 238000004153 renaturation Methods 0.000 claims 1
- 238000003672 processing method Methods 0.000 abstract description 2
- 230000009897 systematic effect Effects 0.000 abstract description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 18
- 239000002537 cosmetic Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000654 additive Substances 0.000 description 6
- 238000005457 optimization Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 5
- 230000005540 biological transmission Effects 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000012797 qualification Methods 0.000 description 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000011067 equilibration Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000000686 essence Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- -1 moisture Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000012925 reference material Substances 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 208000003351 Melanosis Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910052571 earthenware Inorganic materials 0.000 description 1
- 238000009415 formwork Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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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
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/3563—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing solids; Preparation of samples therefor
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/3577—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing liquids, e.g. polluted water
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/42—Measuring deposition or liberation of materials from an electrolyte; Coulometry, i.e. measuring coulomb-equivalent of material in an electrolyte
- G01N27/423—Coulometry
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N5/00—Analysing materials by weighing, e.g. weighing small particles separated from a gas or liquid
- G01N5/04—Analysing materials by weighing, e.g. weighing small particles separated from a gas or liquid by removing a component, e.g. by evaporation, and weighing the remainder
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N2021/3595—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using FTIR
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Abstract
The invention discloses the measuring methods of the Reinheitszahl and uncertainty of a kind of phenol and hydroquinone standard substance.Screening is carried out to raw material, so that purity is qualified, combined using gas chromatography-mass spectrometry and fourier transform infrared spectroscopy and qualitative confirmation is carried out to sample to be tested, combined using the method for three kinds of GC method, HPLC method and DSC method different principles and purity testing is carried out to sample to be tested, after sample to be tested is dispensed, uniformity and stability test are carried out again, uncertainty caused by purity testing is calculated, each uncertainty is carried out synthesis and obtains overall uncertainty by uncertainty caused by uniformity and stability is calculated according to step 4.The present invention is qualitative accurate, reduces systematic error, statistical data processing method is rigorous, and uncertainty evaluation method is comprehensive, ensure that magnitude accuracy, stability and tractability, obtains high-purity phenol and hydroquinone purity rubric substance.
Description
Technical field
The present invention relates to cosmetics detection fields, especially a kind of for detecting phenol generalization in Freckle removing cosmetics and shampoo
The purity rubric substance method of production of object is closed, phenolic compound refers mainly to phenol and hydroquinone.
Background technique
The accurate detection of additive is most important to the safety of cosmetics in cosmetics, since phenol and hydroquinone are
Banned substance in cosmetics, therefore the difficulty of this kind of trace additives accurately detected is greatly increased.Currently, in cosmetics
The quantitative detection of additive kind mostly uses greatly direct Detection Method, still, in actual application, different for same sample
The testing result that testing agency provides is not quite similar, or even differs greatly.Compared with n-compound, additive kind in cosmetics
Standard substance not only has typical magnitude accurately measure or strict difinition, moreover it is possible to guarantee characteristic magnitude in the specific time time limit
With ability within the specified scope is kept under storage requirement, there is magnitude tracing, to improve Cosmetic Manufacture, quality control,
The evaluation and confirmation of the detection level and additive kind materials analysis methods of inspection are of great significance.
Summary of the invention
It is of the invention to propose a kind of phenol and hydroquinone standard substance in order to solve the problems, such as background technique
Reinheitszahl and uncertainty measuring method, can Accurate Determining phenol and hydroquinone Reinheitszahl, and establish for this is pure
The definite value of angle value carries out Evaluation of Uncertainty.
The present invention is achieved through the following technical solutions:
Step 1: screening being carried out to raw material, so that purity is qualified and carries out next step, the product after qualification is as to be measured
Sample carries out next step；
Step 2: being combined using gas chromatography-mass spectrometry and fourier transform infrared spectroscopy and sample to be tested is carried out
Qualitative confirmation；
Step 3: using based on gas-chromatography (GC) method, high performance liquid chromatography (HPLC) method and differential scanning calorimetry (DSC)
The method of three kinds of different principles of method, which is combined, carries out purity testing to sample to be tested；
Step 4: after sample to be tested is dispensed, then carrying out uniformity and stability test；
The stability includes short-term stability and long-time stability.
Step 5: uniformity is calculated according to step 4 in uncertainty caused by purity testing is calculated according to step 3
With uncertainty caused by stability, each uncertainty is subjected to synthesis and obtains overall uncertainty.
The step 1: raw material screening specifically:
The raw material of industry is first subjected to purity initial survey using HPLC method (see step 3-1.2), judges whether Reinheitszahl is qualified, it is pure
Angle value thinks qualified progress next step not less than 99%, unqualified, recrystallization processing is carried out, until purity is qualified.At this time
Product as sample to be tested carry out next step.
The Reinheitszahl qualification refers to purity not less than 99%.
The raw material is phenol or hydroquinone.The method of the present invention for develop include phenol purity rubric substance and
Hydroquinone purity rubric substance.
The step 2: qualitative confirmation specifically:
After test solution and solid preform is respectively prepared in sample to be tested, then gas chromatography-mass spectrography is respectively adopted
(GC-MS) method and Fourier Transform Infrared Spectroscopy (FT-IR) method collect mass spectrogram and infrared spectrogram, mass spectrogram and infrared
Spectrogram is compareed with standard spectrogram, according to matching degree it is qualitative confirmation raw material authenticity, if raw material really if carry out next step.
Test solution is made in sample to be tested of the purity initial survey after qualified in the step 2 and solid preform is specifically:
It for sample to be tested, is on the one hand dissolved in pure methanol and test solution is made, on the other hand use potassium bromide (KBr) solid preform method
Mixed grinding is simultaneously pressed into solid thin-sheet with mold.
Collecting mass spectrogram using gas chromatography-mass spectrography (GC-MS) method in the step 2 is specifically:
By test solution sample introduction into chromatographic column, setting injector temperature is 250 DEG C, and transmission line temperature is 280 DEG C, is carried
Gas velocity is 1mL/min, and sample volume is 10 μ L, split ratio 10:1, then gradually heating mode, mass spectrum part are equal using two ladders
Using full scan mode, scanning range 12-500m/z, the solvent delay time is 3min, collects mass spectrogram.
For the test solution of phenol, chromatographic column warming temperature are as follows: 60 DEG C of initial temperature are used, after keeping 1min, with
The rate of 15 DEG C/min is warming up to 270 DEG C, keeps 10min.
For hydroquinone raw material, chromatographic column warming temperature are as follows: 60 DEG C of initial temperature are used, with the rate liter of 10 DEG C/min
Temperature is to 110 DEG C, after keeping 0.5min, then with the rate of 10 DEG C/min is warming up to 180 DEG C, keeps 3min.
Collecting infrared spectrogram using Fourier Transform Infrared Spectroscopy (FT-IR) method in the step 2 is specifically: will
Sample restocking after solid preform is tested using DTGSKBr detector and KBr beam splitter, and sampling gain is set as 1.0, infrared light
Spectrum scanning range is 4000~400cm-1, Sample Scan 8 times, background scans 8 times, taking resolution ratio is 4.000cm-1, to obtain
Infrared spectrogram.
The step 3: purity testing specifically:
3-1: being directed to sample to be tested, and after test solution is made, simultaneous determination obtains two groups of purity Value Datas, two groups of purity
Value Data all has the data for carrying out that repeatedly measurement obtains；
In treatment process of the present invention, GC method and HPLC method are realized based on mass balance approach (writing a Chinese character in simplified form work " MB ") principle,
The impurity for also needing to be not responding to such as dissolvent residual, moisture and ash content uses head space-GC method, karl Fischer coulomb method and heat respectively again
The measurement of weight analysis method.
3-2: being directed to sample to be tested, measures Reinheitszahl using differential scanning calorimetry (DSC) method, obtains one group of Reinheitszahl number
According to this group of purity Value Data has the data for carrying out that repeatedly measurement obtains；
3-3: it for each sample to be tested, repeats step 3-1 and step 3-2 and measures, three groups of Reinheitszahl numbers will be obtained
According to progress data processing obtains the final Reinheitszahl of sample to be tested.
The step 3-1 specifically:
3-1.1: chromatogram is acquired using GC method, the initial of sample to be tested is calculated with area normalization method in chromatogram
Reinheitszahl IGC；
3-1.2: chromatogram is acquired with HPLC method, the initial of sample to be tested is calculated with area normalization method in chromatogram
Reinheitszahl IHPLC；
3-1.3: Static Headspace sample introduction-GC- hydrogen flameionization (FID) detector, karl Fischer coulomb meter is respectively adopted
Sample to be tested is measured with thermogravimetric analyzer, obtains the degree I of residual solvent respectivelysolv, moisture percentage
Content Imoi, ash content degree Iash(degree of three kinds of impurity)；
3-1.4: the two initial purity values obtained according to step 3-1.1 and 3-1.2 are obtained through step 3-1.3 respectively
Impurity degree, which calculates, obtains GC method and the corresponding two amendment Reinheitszahls I ' of HPLC methodGCAnd I 'HPLC；
3-1.5: it repeats step 3-1.1~3-1.4 and takes multiple measurements two groups of purity Value Datas of acquisition.
The step 3-1.1 specifically:
GC method test process after present invention optimization is as follows: by test solution sample introduction to low pole chromatographic column DB-1701
In (30m × 0.32mm × 0.25 μm), 280 DEG C of injector temperature of setting, 280 DEG C of fid detector temperature, carrier gas nitrogen flow velocity
1mL/min, sample volume 1 μ L, split ratio 2.5:1；Using three ladders, gradually heating mode is operated again, to collect chromatography
Chromatogram is calculated with area normalization method and obtains Reinheitszahl by figure.
For phenol, it is 65 DEG C when column temperature condition setting is initial, is warming up to 200 DEG C with the rate of 3 DEG C/min, then with 10
DEG C/rate of min is warming up to 260 DEG C, keep 6min.The temperature-rise period of phenol is
For hydroquinone, 50 DEG C when column temperature condition setting is initial, 220 DEG C are warming up to the rate of 8 DEG C/min, then with 15
DEG C/rate of min is warming up to 270 DEG C, keep 6min.The temperature-rise period of hydroquinone is
The present invention compares HP-5 (low pole, 30m × 0.25mm × 0.25 μm), DB-1701 (middle polarity, 30m ×
0.25mm × 0.25 μm), 3 kinds of opposed polarity chromatographic columns of DB-WAX (highly polar, 30m × 0.25mm × 0.25 μm) to impurity and
The separating resulting of principal component, the results showed that, outflow and detection of the DB-1701 chromatographic column most beneficial for impurity, and impurity and it is main at
Point theoretical cam curve is higher, separating effect more preferably, the separating effect of HP-2 chromatographic column takes second place, and DB-WAX chromatographic column is worst.
The step 3-1.2 specifically:
HPLC method test process after present invention optimization is as follows:
Using C18 chromatographic column (250mm × 4.6mm × 5 μm), setting sample volume is 10 μ L, column flow 1mL/min, column
Temperature is 25 DEG C, and the mobile phase acquisition testing wavelength for constructing raw material is the 3D data of 190nm~400nm, and wavelength separated degree is
1.2nm.With 271.0nm (phenol) and 289.0nm (hydroquinone) for definite value wavelength, so that chromatogram is collected, by chromatogram
It is calculated with area normalization method and obtains Reinheitszahl.
For phenol, flowing phase composition is+70% pure water of 30% methanol.
For hydroquinone, flowing phase composition is+30% pure water of 70% methanol.
The present invention compares the methanol of 5 kinds of different proportions on the basis of using C18 chromatographic column (250mm × 4.6mm × 5 μm)
(A) and pure water (B) be mobile phase (a.10%A+90B%；B.30%A+70%B；C.50%A+50%B；D.70%A+30%B；
E.90%A+10%B) to the influence of impurity and principal component separating resulting, under the conditions of similar in the impurity and principal component molecular weight,
It can guarantee the sequence appearance of each group of polarity size.The flowing of phenol and hydroquinone of the invention is determined by experimental analysis
Phase composition.
Detection of the impurity lower than instrument that will lead to low content in phenol since sample volume is too low is limited and can not be detected,
If sample volume (or column flow or column temperature) is excessively high, it will lead to impurity in phenol and separate bad, and principal component appearance with principal component
Peak shape is asymmetric.Thus select sample volume of the present invention for the concrete technology condition of 10 μ L.
The step 3-1.3 specifically:
(1) residual solvent degree measures:
For sample to be tested, issuable residual solvent type in sample to be tested is estimated according to technique for producing raw material, according to
It is secondary with Static Headspace method sample introduction, gas chromatography separation and fid detector method detection assay residual solvent degree.
Static Headspace sampling system determination condition is: 80 DEG C of equilibrium temperature, 90 DEG C of quantitative loop temperature, and 110 DEG C of line of transference temperature,
Equilibration time 30min, pressing time 2min；
Gas chromatography determination condition is: using Agilent DB-624 chromatographic column, 30m × 0.32mm × 0.50 μm carries
Gas velocity 1mL/min, split ratio 10:1 200 DEG C of injector temperature, originate 40 DEG C of column temperature, 15min are kept, with 10 DEG C/min journey
Sequence is warming up to 150 DEG C, keeps 10min；
Fid detector testing conditions are: 250 DEG C of temperature；The detected chromatogram of fid detector is used into external standard method meter
Calculate the concentration value of residual solvent.
(2) moisture percentage assay:
For sample to be tested, the degree for obtaining moisture is measured with karl Fischer coulomb meter, determination condition is:
Detecting environment temperature is 20 DEG C, humidity 40%, polarizing electrode DM143-5C, 5.0 μ A of polarization current, and instruction is single
Position is voltage (mV), and speed of agitator 45%, control terminal is 100.0mV；The electric current of electrolysis electrode is automatic termination, termination type
For opposite termination of drifting about, drift value is 3.0 μ g/min, and time range is 0~3600s.
(3) percent ash assay:
For sample to be tested, the concentration value for obtaining ash content is measured with thermogravimetric analyzer, determination condition is: using Al2O3Earthenware
Crucible is warming up to 650 DEG C in 25 DEG C of the initial temperature rates with 10 DEG C/min；The mass change in thermal decomposition process is recorded, thermogravimetric is obtained
Curve analyzes the concentration value of output ash content according to thermogravimetric curve.
The step 3-1.4 is specifically:
I'GC=(100%-Imoi-Isolv-Iash)×IGC
I'HPLC=(100%-Imoi-Isolv-Iash)×IHPLCFormula (1)
In formula, I'GCAnd I'HPLCThe respectively corresponding amendment of gas-chromatography (GC) method and high performance liquid chromatography (HPLC) method is pure
Angle value, I'GCAnd I'HPLCIt is by above-mentioned formula from IGCAnd IHPLCAmendment obtains, IGCAnd IHPLCRespectively gas-chromatography (GC) method and
The corresponding initial purity value obtained of high performance liquid chromatography (HPLC) method, Imoi、IsolvAnd IashRespectively indicate moisture, dissolvent residual and
The concentration value of ash content.
The step 3-2 specifically: differential scanning calorimetry surveys purity, uses 40 empty μ L standard aluminum crucibles for reference,
Sample weighting amount is 3.24~6.80mg, then using three ladders, gradually heating mode is operated, and then uses purity analysis software
Proteus Analysis obtains Reinheitszahl IDSC, and carry out repeatedly measurement and obtain two groups of purity Value Datas.
For phenol, initial temperature is 0 DEG C, is warming up to 20 DEG C with the rate of 5 DEG C/min, then with the rate liter of 1 DEG C/min
Temperature is to 60 DEG C.The temperature-rise period of phenol is
For hydroquinone, initial temperature is 0 DEG C, is warming up to 155 DEG C with the rate of 20 DEG C/min, then with 10 DEG C/min's
Rate is warming up to 190 DEG C.The temperature-rise period of hydroquinone is
The step 3-3 specifically:
For same sample to be tested, the three groups of purity Value Datas measured with three kinds of methods are successively located in the following ways
Reason:
3-3.1: for three groups of purity Value Datas (as Reinheitszahl I' that repeatedly measurement obtainsGC, I'HPLCAnd IDSC), respectively
First carry out normal distribution inspection with coefficient of kurtosis method and coefficient of skew method, then with Grabbs method and Dixon method carry out from
Group's value, which is examined, rejects dubious value；
(i.e. I' between every two groups of Reinheitszahls of 3-3.2: three groups of purity Value DatasGCWith I'HPLCBetween, I'HPLCWith IDSCIt
Between, I'GCWith IDSCBetween) examined with the equally accurate that t method of inspection carries out average value, standard deviation is carried out with F method of inspection
Equally accurate is examined；
3-3.3: according to the equally accurate of average value and standard deviation as a result, final purity of the averaged as raw material
Value:
If the purity Value Data that step 3-3.1 retains meets the equally accurate of average value and standard deviation simultaneously, three groups are taken
The arithmetic mean of instantaneous value of purity Value Data；
If meeting the unequal accuracy of average value and standard deviation when the purity Value Data difference that step 3-3.1 retains, take
The weighted average of three groups of purity Value Datas.
Raw material is dispensed specifically in the step 4: being accurately weighed in 20 DEG C ± 3 DEG C of room temperature of toilet to be measured
Sample 50mg or so is dispensed into brown glass sample bottle, is obtained packing sample, is repeated the above steps, and packing sample 200 is obtained
Bottle, is numbered with number, saves under the conditions of refrigerating and being protected from light, and is used for subsequent uniformity and stability test.
In the step 4 after packing specifically:
4-1: uniformity testing
Respectively from 200 bottles of packing samples according to end to end, intermediate number randomly select 10 bottles of samples, it is molten to be configured to test sample
Liquid, oscillation measure Reinheitszahl according to HPLC method (see step 3-1.2), and every bottle of sample is measured in parallel 3 times；Single factor test side is used again
Poor analysis method is for statistical analysis to measurement result, calculates F statistical value, tables look-up and obtain F critical value, by comparing F statistical value
With F critical value, the uniformity of packing sample is examined；If F statistical value is less than F critical value, sample is uniform；If F statistical value is greater than
Equal to F critical value, then sample is uneven.
F statistical value calculation is as follows:
In formula, SinterAnd SintraIt respectively indicates between bottle and bottle internal variance, νinterAnd νintraRespectively indicate between bottle and in bottle from
By spending.
4-2: stability test
4-2.1 short-term stability
Several bottles are randomly selected from packing sample, is individually placed in 4 DEG C, 20 DEG C and 50 DEG C environment, respectively to the 1st day, the 2nd
It is configured to test solution, vibrates, measure according to HPLC method (see step 3-1.2) after each 1 bottle of taking-up in the 5th day and the 8th day
Reinheitszahl, every bottle of sample are measured in parallel 3 times, are averaged；The Reinheitszahl measured again with the packing sample being placed in 4 DEG C of environment
It for standard, tables look-up and obtains t critical value, calculate t statistical value ttest, short-term stability is examined by comparing t statistical value and t critical value
Property: if t statistical value is less than t critical value, sample short-term stability；If t statistical value is more than or equal to t critical value, sample is in short term not
Stablize.
T statistical value ttestCalculation formula is as follows:
In formula, x0And s0Respectively indicate the purity average value and purity rubric that the packing sample being placed in 4 DEG C of refrigerators measures
Deviation,Reinheitszahl and standard deviation that the packing sample being placed under each different temperatures environment measures, n are respectively indicated with s
Indicate the number (n=3 at this time) being measured in parallel.
4-2.2 long-time stability
Packing sample is stored in 20 DEG C of environment, 12 months stability is carried out using HPLC method (see step 3-1.2)
Monitoring, according to first close rear thin principle access time node, each timing node chooses 1 sample, and each sample is measured in parallel 3
It is secondary, it is averaged；Then in the case where potential kinetics mechanism is unknown, linear fit is carried out using linear model, is represented with x
Time represents the sample purity value of some timing node with y, and fitting is in alignment, is sentenced using the conspicuousness of the straight slope
The stability of disconnected sample.
Using the conspicuousness of the straight slope as stability, the stability for carrying out judgement sample is specifically to calculate straight slope
Standard deviation, after standard deviation examines critical value to be multiplied with the t that tables look-up and compared with the absolute value of straight slope, if straight slope
Absolute value is small, then sample is steady in a long-term；Otherwise sample is unstable for a long time.
The step 5 is to calculate to obtain overall uncertainty in the following ways:
5-1: uncertainty caused by GC method and HPLC method measurement Reinheitszahl is first obtained using following calculation method:
According to formula (1), I' will be obtained based on GC method and HPLC methodGCAnd I'HPLCCalculation formula merge are as follows:
I'GC-HPLC=(100%-Imoi-Isolv-Iash)×IGC-HPLC=f1(IGC-HPLC,Imoi,Isolv,Iash) formula (4)
I' will be obtainedGCAnd I'HPLCUncertainty caused by process merges into a uncertainty and considers u'GC-HPLC, according to
Formula (4), it is as follows to derive its calculation formula:
In formula (5), uGC-HPLCIt indicates to obtain IGCAnd IHPLCCaused Composite Seismogram, WithRespectively indicate first function f1(see formula (4) to IGC-HPLC, Imoi, Isolv, IashPartial derivative is sought,
umoi、usolvAnd uashRespectively indicate uncertainty caused by moisture, dissolvent residual and ash determination, first function f1It is expressed as f1
(IGC-HPLC,Imoi,Isolv,Iash)=(100%-Imoi-Isolv-Iash)×IGC-HPLC。
uGC-HPLCCalculation are as follows:uGCAnd uHPLCIt respectively indicates and obtains IGCAnd IHPLC
Caused partial uncertainty, by response factor difference, measurement reproducibility and the instrument of principal component in sample to be tested and impurity
Partial uncertainty caused by detection limits is obtained through synthesis, and response factor difference calculates the calibration response factor according to effective carbon number method
It calculates and obtains, effective carbon number is equal to the carbon atom contained in the molecular weight and the component molecular of component (principal component or impurity)
The ratio between number；umoi、usolvAnd uashRespectively in terms of moisture, dissolvent residual and the repeatability of ash determination.
5-2: it is calculated using the following equation uncertainty u caused by DSC method measurement Reinheitszahl againDSC:
Wherein, uDSC-AAnd uDSC-BIndicate the standard uncertainty of type A evaluation and type B evaluation in the measurement of DSC method, uDSC-AIt is
Repeatability by measuring DSC method is calculated；
For uDSC-B, since the principle of DSC method measurement purity is based on van' t Hoff equation, the equation is as follows:
IDSCIndicate that the Reinheitszahl of DSC method measurement sample, y indicate the molar fraction of impurity, T0And TmRespectively indicate pure sample
With the melting temperature of actual sample, △ HfIndicate that mole melting enthalpy, R are gas constant, Q is the heat that sample absorbs, and m is sample
Quality, M be sample molal weight.
Therefore, uDSC-BCalculation method it is as follows:
Wherein, um, uQ, uTRespectively the weighing error of balance, the calorimetry error of instrument, the temperature error of instrument this
The standard uncertainty of three mutual incoherent input quantities, Respectively indicate second function f2
To m, Q, T0, TmAsk partial derivative, c1, c2, c3Respectively indicate the calculated value of quality, heat and temperature；
Second function f2It indicates are as follows:
In formula, T0And TmThe melting temperature of pure sample and actual sample is respectively indicated, R is gas constant, and Q is sample absorption
Heat, m be sample quality, M be sample molal weight.
5-3: calculating divides uncertainty
The one-way analysis of variance result obtained according to uniformity testing is calculated by using the following formula uniformity and causes
Uncertainty uH:
The standard deviation for the fitting a straight line slope examined according to long-time stability is used multiplied by the STABILITY MONITORING time
Uncertainty u caused by stability is calculated in following formulas:
uS=s (b1) t formula (10)
5-4: overall uncertainty is calculated
Using following formula by uncertainty and uniformity caused by GC method, HPLC method and DSC method measurement purity and surely
Uncertainty caused by qualitative carries out COMPREHENSIVE CALCULATING and obtains overall uncertainty, and formula is as follows:
Wherein, uHIndicate uncertainty caused by uniformity, uSIndicate uncertainty caused by stability, u'GC-HPLCIt indicates
GC method and HPLC method obtain Composite Seismogram caused by purity correction value, uDSCIndicate not true caused by DSC method measurement Reinheitszahl
Fixed degree.
Purity initial survey in the step 1 and the Reinheitszahl measurement in the uniformity and stability test of the step 4 are equal
Process identical with the step 3-1.2.
The present invention passes through raw material screening, qualitative confirmation, purity testing, uniformity and stability test and uncertainty
It calculates, has obtained the standard substance of phenol and hydroquinone, to improve the accuracy that phenolic substances detects in cosmetics, together
When guarantee testing result traceability.
The beneficial effects of the present invention are:
The present invention can Accurate Determining phenol and hydroquinone Reinheitszahl, and establish for the Reinheitszahl definite value obtain not
The mode of degree of certainty.
The present invention is qualitative accurate comprehensive, and three kinds of method for detecting purity reduce because single valued methods bring system is missed
Difference, uniformity, stability and uncertainty evaluation method system are comprehensive, ensure that magnitude accuracy, stability and tractability,
Obtain high-purity (99% or more) phenol and hydroquinone purity rubric substance.
Measurement result of the present invention can get phenol and hydroquinone purity rubric substance, and be made by purity rubric substance
The testing result of respective additive is more accurate in cosmetics, and the magnitude tracing and magnitude that can be used for respective substance testing result pass
It passs, the evaluation of analysis method and detectability and the quality control in production process.
Detailed description of the invention
Fig. 1 is the method for the present invention flow diagram；
Fig. 2 is the mass spectrogram of the collected phenol of embodiment 1；
Fig. 3 is the infrared spectrogram of the collected phenol of embodiment 1；
Fig. 4 is the gas chromatogram of the collected phenol of embodiment 1；
Fig. 5 is the liquid chromatogram of the collected phenol of embodiment 1；
Fig. 6 is the differential scanning calorimetry curve graph of the collected phenol of embodiment 1；
Fig. 7 is the mass spectrogram of the collected hydroquinone of embodiment 2；
Fig. 8 is the infrared spectrogram of the collected hydroquinone of embodiment 2；
Fig. 9 is the liquid chromatogram of the collected hydroquinone of embodiment 2；
Figure 10 is the gas chromatogram of the collected hydroquinone of embodiment 2；
Figure 11 is the differential scanning calorimetry curve graph of the collected hydroquinone of embodiment 2.
Specific embodiment
Present invention will be further explained below with reference to the attached drawings and examples.
The embodiment of the present invention is as follows:
Embodiment 1: phenol
Step 1 --- raw material screening
The starting phenol produced using lark prestige Science and Technology Ltd..It is surveyed with HPLC method (see 1 step 3-1.2 of embodiment)
Determine Reinheitszahl, the sample to be tested after purity initial survey qualification is obtained after recrystallization 2 times.
Step 2 --- qualitative confirmation
With GC-MS method and the legal confirmation phenol of FT-IR.
Step 2-1, using the legal confirmation phenol of GC-MS
For phenol sample to be tested, test solution, sample introduction test is made after being dissolved in methanol.Test condition is as follows: setting
Injector temperature is 250 DEG C, and transmission line temperature is 280 DEG C, flow rate of carrier gas 1mL/min, and sample volume is 10 μ L, and split ratio is
10:1；Chromatographic column warming temperature are as follows: use 60 DEG C of initial temperature, after keeping 1min, be warming up to 270 with the rate of 15 DEG C/min
DEG C, keep 10min.
It can be obtained by attached drawing 2, molecular ion peak 94, obtain phenol Standard mass spectrogram, the two through NIST standard spectrogram library searching
It is 96% with degree.
Step 2-2, using the legal confirmation phenol of FT-IR
For phenol sample to be tested, solid thin-sheet, restocking test are pressed into mold using after KBr mixed grinding.Test
Condition is as follows: being tested using DTGS KBr detector and KBr beam splitter, sampling gain is set as 1.0, IR spectrum scanning range
For 4000~400cm-1, Sample Scan 8 times, background scans 8 times, taking resolution ratio is 4.000cm-1, to obtain infrared spectrogram
(see attached drawing 3).
It can be obtained by attached drawing 3, ν=3355.44cm-1(1) roomy absorption peak is the phenolic hydroxyl group O-H for being easy to happen association near
Stretching vibration peak, ν=3090.03cm-1(2), ν=3046.04cm-1(3), ν=3020.22cm-1(4) be on phenyl ring not
It is saturated the stretching vibration peak of c h bond, ν=1599.81cm-1(5), ν=1499.28cm-1(6) be phenyl ring skeletal vibration, ν
=1231.12cm-1(7) be C-O in phenolic hydroxyl group stretching vibration peak, ν=752.99cm-1(8) and ν=690.54cm-1(9), it is
Mono-substituted c h bond flexural vibrations peak on phenyl ring.Phenol Standard infrared spectrogram, the two matching degree are obtained through standard spectrogram library searching
It is 94%.
Step 3 --- purity testing
Phenol purity is measured with GC method, HPLC method and DSC method.
Step 3-1, for the sample to be tested of phenol, it is dissolved in pure methanol, test solution is made, using GC method and HPLC method
Simultaneous determination Reinheitszahl；The impurity that dissolvent residual, moisture and ash content are not responding to uses head space-GC method, karl Fischer coulomb respectively again
Method and thermogravimetry measurement.
Step 3-1.1, chromatogram is acquired using GC method, optimization acquisition condition is as follows:
It compares HP-5 (low pole, 30m × 0.25mm × 0.25 μm), DB-1701 (middle polarity, 30m × 0.25mm ×
0.25 μm), 3 kinds of opposed polarity chromatographic columns of DB-WAX (highly polar, 30m × 0.25mm × 0.25 μm) to impurity and principal component
Separating resulting, the results showed that, outflow and detection of the DB-1701 chromatographic column most beneficial for impurity, and the theory of impurity and principal component
The number of plates is higher, separating effect more preferably, therefore selects low pole chromatographic column DB-1701 (30m × 0.32mm × 0.25 μm).
280 DEG C of injector temperature of setting, 280 DEG C of fid detector temperature, carrier gas nitrogen flow velocity 1mL/min, 1 μ L of sample volume,
Split ratio 2.5:1；Chromatographic column temperature-rise period is
Collected chromatogram (see attached drawing 4) area normalization method is calculated into acquisition initial purity value and (uses IGCIt indicates).In attached drawing 4,
Peak 1 is solvent peak, and peak 2 is phenol, and peak 3 is impurity, and curve b is the enlarged drawing of curve a.
Step 3-1.2, chromatogram is acquired using HPLC method, optimization acquisition condition is as follows:
Compare 5 kinds of different proportions methanol (A) and pure water (B) be mobile phase (a.10%A+90B%；B.30%A+
70%B；C.50%A+50%B；D.70%A+30%B；E.90%A+10%B) to impurity and principal component separating degree, theoretical tray
The influence of number, peak width, symmetrical sexual factor determines that building flowing phase composition is 30% pure+70% pure water of methanol, using C18 chromatography
Column (250mm × 4.6mm × 5 μm), setting sample volume are 10 μ L, and column flow 1mL/min, column temperature is 25 DEG C, acquisition testing wave
The 3D data of a length of 190nm~400nm use collected chromatogram using 271.0nm phenol as definite value wavelength (see attached drawing 5)
Area normalization method calculates acquisition initial purity value and (uses IHPLCIt indicates).Peak 1 and peak 2 are impurity in attached drawing 5, and peak 3 is phenol, bent
Line b is the enlarged drawing of curve a.
Step 3-1.3, Static Headspace sample introduction-GC- hydrogen flameionization (FID) detector, karl Fischer library is respectively adopted
Logical sequence instrument and thermogravimetric analyzer are measured sample to be tested, respectively obtain residual solvent, moisture, ash content three kinds of impurity percentage
Than content (I is used respectivelysolv, ImoiAnd IashIt indicates).Specific determination condition is as follows:
(1) residual solvent degree measures:
For sample to be tested, according to technique for producing raw material, estimate that issuable residual solvent type is in sample to be tested
Acetone, successively with Static Headspace method sample introduction, gas chromatography separation and fid detector method detection acquisition chromatogram.
Static Headspace sampling system determination condition is: 80 DEG C of equilibrium temperature, 90 DEG C of quantitative loop temperature, and 110 DEG C of line of transference temperature,
Equilibration time 30min, pressing time 2min；
Gas chromatography determination condition is: using Agilent DB-624 chromatographic column, 30m × 0.32mm × 0.50 μm carries
Gas velocity 1mL/min, split ratio 10:1 200 DEG C of injector temperature, originate 40 DEG C of column temperature, 15min are kept, with 10 DEG C/min journey
Sequence is warming up to 150 DEG C, keeps 10min；
Fid detector testing conditions are: 250 DEG C of temperature；
The standard curve that pure C ketone solvent is established according to said determination condition contains with the percentage that external standard method calculates acetone
Amount (uses IsolvIt indicates).
(2) moisture percentage assay:
For sample to be tested, with the degree of karl Fischer coulomb meter measurement moisture, determination condition is:
Detecting environment temperature is 20 DEG C, humidity 40%, polarizing electrode DM143-5C, 5.0 μ A of polarization current, and instruction is single
Position is voltage (mV), and speed of agitator 45%, control terminal is 100.0mV；The electric current of electrolysis electrode is automatic termination, termination type
For opposite termination of drifting about, drift value is 3.0 μ g/min, and time range is 0~3600s.The moisture percentage content I of acquisitionmoi
It indicates.
(3) percent ash assay:
For sample to be tested, the concentration value for obtaining ash content is measured with thermogravimetric analyzer, determination condition is: using Al2O3
Crucible is warming up to 650 DEG C in 25 DEG C of the initial temperature rates with 10 DEG C/min；The mass change in thermal decomposition process is recorded, heat is obtained
Weight curve (uses I according to the degree that thermogravimetric curve analyzes output ash contentashIt indicates).
3-1.4, the Reinheitszahl obtained according to step 3-1.1 and 3-1.2, the impurity percentage obtained respectively through step 3-1.3
Than content, acquisition amendment Reinheitszahl is calculated according to formula (1) and (uses I' respectivelyGCAnd I'HPLCIt indicates).
Step 3-2, for the sample to be tested of phenol, phenol Reinheitszahl is measured using DSC method.Determination condition is as follows:
Use 40 empty μ L standard aluminum crucibles for reference, sample weighting amount is 3.24~6.80mg, and temperature-rise period isIt acquires DSC curve (see attached drawing 6), curve is carried out using software
Purity analysis obtains Reinheitszahl and (uses IDSCIt indicates).
Step 3-3 repeats step 3-1 and step 3-2 and carries out 10 measurements, obtain 10 for the sample to be tested of each phenol
It is secondary to measure corresponding three groups of Reinheitszahls, carry out the final Reinheitszahl that data processing obtains sample to be tested.
Step 3-3.1
3-3.1: three groups of Reinheitszahl (I' are directed toGC, I'HPLCAnd IDSC), coefficient of kurtosis method and coefficient of skew method are first used respectively
Normal distribution inspection is carried out, then carries out outlier inspection with Grabbs method and Dixon method, the results showed that without dubious value, is protected
Residual is according to progress next step；
3-3.2: every two groups of Reinheitszahl (I' are directed toGCWith I'HPLC, I'HPLCWith IDSC, I'GCWith IDSC) equally accurate inspection is carried out,
T inspection result shows that the average value of three groups of data is equally accurate, and F inspection result shows that the standard deviation of three groups of data such as is at the essences
Degree；
3-3.3: data processed result is shown in Table 1.Since three groups of data are equally accurate measurement, then the arithmetic of three groups of Reinheitszahls is taken
Average value is final Reinheitszahl, i.e., are as follows:
1 three kinds of methods of table measure phenol Reinheitszahl result
Step 4 --- packing
Phenol 50mg or so is accurately weighed in 20 DEG C ± 3 DEG C of room temperature of toilet, is dispensed into brown glass sample bottle,
Packing sample is obtained, is repeated the above steps, about 200 bottles of sample of packing is obtained, is numbered with number, is protected under the conditions of refrigerating and being protected from light
It deposits.For uniformity and stability test.
Step 5 --- uniformity testing
Phenol uniformity testing the results are shown in Table 2.It is for statistical analysis to data using one-way analysis of variance method, according to
Formula (2) obtainsI.e. F statistical value is 2.24, looks into F inspection and faces
Known to dividing value table: F0.05 (9,20)=2.39, i.e., F critical value is 2.39, therefore F statistical value < F critical value, show the packing of phenol
Sample has preferable uniformity.
2 phenol uniformity testing result of table
Step 6 --- stability test
Step 6-1 short-term stability is examined
The short-term stability inspection result of 3 phenol of table
The short-term stability inspection result of phenol is shown in Table 3.The Reinheitszahl measured with the packing sample being placed in 4 DEG C of environment
For standard.It is obtained by table 3, purity rubric value is x0=99.60%, relative standard deviation s0=0.03%, it is measured in parallel secondary
Number n=3, freedom degree ν=n+n-2=4.Substitution formula (3) is calculated t statistical value and (uses ttestIt indicates).Look into t distribution bilateral separate
Digit table is it is found that t(0.05,4)=2.78.It is obtained by table 3, at 20 °C, ttest<t(0.05,4), under the conditions of 50 DEG C, ttest>
t(0.05,4), show that packing sample is good in ordinary temperature stability, and the Reinheitszahl generation for dispensing sample under the high temperature conditions significantly declines
Subtract, therefore dispense sample to save at normal temperature.
Step 6-2 long-time stability are examined
The long-time stability inspection result of 4 phenol of table
The long-time stability inspection result of phenol is shown in Table 4.If the time is y=b to the equation of Reinheitszahl0+b1X, the mark of slope
Quasi- deviation is s (b1), obtained through regression analysis | b1|=8.6 × 10-3, s (b1)=3.78 × 10-3, looked into t and tables of critical values examined to obtain
t(0.95,4)=2.78, then | b1|<t0.95,4·s(b1), then slop estimation value is not significant, show when confidence level is 0.95, point
There is no significant changes for the Reinheitszahl of dress sample.
Step 7 --- uncertainty evaluation
Uncertainty evaluation caused by step 7-1 purity testing
Three kinds of methods carry out uncertainty result caused by purity testings it is as shown in the table (table 5:GC method and HPLC method；Table 6:
DSC method).
Uncertainty caused by 5 GC method of table and HPLC method measurement purity
Uncertainty caused by 6 DSC method purity testing of table
The uncertainty that purity testing introduces (uses uDIndicate), by the uncertainty combination of three kinds of methods, then obtain:
The uncertainty evaluation that step 7-2 uniformity and stability introduce
According to uniformity testing result and formula (9), the partial uncertainty of uniformity introducing is obtained are as follows:According to stability test result and formula (10), validity period t=12 a month
The uncertainty of long-time stability are as follows: uS=s (b1) t=4.5 × 10-2%
Step 8 --- conclusion
It is obtained according to step 3, the purity rubric value of phenol is 99.42%, according to step 7 and formula (11) stardard uncertairty
Degree is 0.10%, expanded uncertainty 0.20%, k=2.The uniformity that is stored within the time that is valid for one year, under room temperature and
It has good stability, can be used as Accurate Determining, transmission of quantity value and magnitude tracing of the purity rubric substance for phenol in cosmetics.
Through Subscriber Unit, (Shenzhen leads to detection technique Co., Ltd, in Shenzhen to the phenol purity rubric substance of the present embodiment
Examine joint inspection and survey Co., Ltd and Hangzhou environmental monitoring central station) it is on probation after, provided user's trial report, trial report table
Showing, the Certified Reference Material Homogeneity is good, and magnitude is accurate and reliable, and it is easy to use, it is quasi- to meet phenol degree in cosmetics
The requirement really measured has very high practical value and promotional value.
Embodiment 2: hydroquinone
Step 1 raw material screening
Pass through the commercially available hydroquinone raw material produced using lark prestige Science and Technology Ltd..With HPLC method (see implementation
2 step 3-1.2 of example) measurement Reinheitszahl, the sample to be tested after purity initial survey qualification is obtained after recrystallizing 3 times.
Step 2 --- qualitative confirmation
With GC-MS method and the legal confirmation hydroquinone of FT-IR.
Step 2-1, using the legal confirmation hydroquinone of GC-MS
For hydroquinone sample to be tested, test solution, sample introduction test is made after being dissolved in methanol.Test condition is as follows:
It is 250 DEG C that injector temperature, which is arranged, and transmission line temperature is 280 DEG C, flow rate of carrier gas 1mL/min, and sample volume is 10 μ L, split ratio
For 10:1；Chromatographic column warming temperature are as follows: chromatographic column warming temperature are as follows: 60 DEG C of initial temperature are used, with the rate liter of 10 DEG C/min
Temperature is to 110 DEG C, after keeping 0.5min, then with the rate of 10 DEG C/min is warming up to 180 DEG C, 3min is kept, using full scan mode
Scanning, scanning range 12-500m/z, solvent delay time are 3min.Collected mass spectrogram is compareed with standard mass spectrogram, is obtained
To matching degree 95%, show that sample to be tested is true (see attached drawing 7).
It can be obtained by attached drawing 7, molecular ion peak 109.9, obtain hydroquinone standard mass spectrogram, the two through standard spectrogram library searching
Matching degree is 95%.
Step 2-2, using the legal confirmation hydroquinone of FT-IR
For hydroquinone sample to be tested, solid thin-sheet, restocking test are pressed into mold using after KBr mixed grinding.
Test condition is as follows:
It is tested using DTGS KBr detector and KBr beam splitter, sampling gain is set as 1.0, IR spectrum scanning range
For 4000~400cm-1, Sample Scan 8 times, background scans 8 times, taking resolution ratio is 4.000cm-1, to obtain infrared spectrogram
(see attached drawing 8).
It can be obtained by attached drawing 8, ν=3261.34cm-1(1) roomy absorption peak is the phenolic hydroxyl group O-H for being easy to happen association at
Stretching vibration peak.ν=3030.11cm-1(2) be unsaturated c h bond on phenyl ring stretching vibration peak.ν=1517.92cm-1(3),
ν=1475.25 (4) are the skeletal vibration of phenyl ring, ν=1242.99cm-1(5), ν=1209.42cm-1(6), ν=
1191.72cm-1(7) be C-O in phenolic hydroxyl group stretching vibration peak, ν=827.22cm-1It (8) is the disubstituted C- of 1,4- on phenyl ring
H bond bending vibration peak.After being compareed with standard spectrogram, matching degree 94%.
Step 3 --- purity testing
Hydroquinone purity is measured with GC method, HPLC method and DSC method.
Step 3-1, for the sample to be tested of hydroquinone, be dissolved in pure methanol, test solution be made, using GC method and
HPLC method simultaneous determination Reinheitszahl；The impurity that dissolvent residual, moisture and ash content are not responding to uses head space-GC method, karr expense respectively again
Not coulomb method and thermogravimetry measurement.
Step 3-1.1, chromatogram is acquired using GC method, optimization acquisition condition is as follows:
It compares HP-5 (low pole, 30m × 0.25mm × 0.25 μm), DB-1701 (middle polarity, 30m × 0.25mm ×
0.25 μm), 3 kinds of opposed polarity chromatographic columns of DB-WAX (highly polar, 30m × 0.25mm × 0.25 μm) to impurity and principal component
Separating resulting, the results showed that, outflow and detection of the DB-1701 chromatographic column most beneficial for impurity, and the theory of impurity and principal component
The number of plates is higher, separating effect more preferably, therefore selects low pole chromatographic column DB-1701 (30m × 0.32mm × 0.25 μm).
280 DEG C of injector temperature of setting, 280 DEG C of fid detector temperature, carrier gas nitrogen flow velocity 1mL/min, 1 μ L of sample volume,
Split ratio 2.5:1；Chromatographic column temperature-rise period is
Collected chromatogram (see attached drawing 9) area normalization method is calculated into acquisition initial purity value and (uses IGCIt indicates).
In attached drawing 9, peak 1 is solvent, and peak 2 is hydroquinone, and peak 3 is impurity.Curve b is the enlarged drawing of curve a.
Step 3-1.2, chromatogram is acquired using HPLC method, optimization acquisition condition is as follows:
Compare 5 kinds of different proportions methanol (A) and pure water (B) be mobile phase (a.10%A+90B%；B.30%A+
70%B；C.50%A+50%B；D.70%A+30%B；E.90%A+10%B) to impurity and principal component separating degree, theoretical tray
The influence of number, peak width, symmetrical sexual factor determines that building flowing phase composition is 70% pure+30% pure water of methanol, using C18 chromatography
Column (250mm × 4.6mm × 5 μm), setting sample volume are 10 μ L, and column flow 1mL/min, column temperature is 25 DEG C, acquisition testing wave
The 3D data of a length of 190nm~400nm use collected chromatogram using 289.0nm phenol as definite value wavelength (see attached drawing 10)
Area normalization method calculates acquisition initial purity value and (uses IHPLCIt indicates).
In attached drawing 10, peak 1, peak 3 and peak 4 are impurity, and peak 2 is hydroquinone.Curve b is the enlarged drawing of curve a.
Step 3-1.3, Static Headspace sample introduction-GC- hydrogen flameionization (FID) detector, karl Fischer library is respectively adopted
Logical sequence instrument and thermogravimetric analyzer are measured sample to be tested, respectively obtain residual solvent, moisture, ash content three kinds of impurity percentage
Than content (I is used respectivelysolv, ImoiAnd IashIt indicates).Specific determination condition is as follows:
(1) residual solvent degree measures:
For sample to be tested, according to technique for producing raw material, estimate that issuable residual solvent type is in sample to be tested
Acetone, successively with Static Headspace method sample introduction, gas chromatography separation and fid detector method detection acquisition chromatogram.
Static Headspace sampling system determination condition is: 80 DEG C of equilibrium temperature, 90 DEG C of quantitative loop temperature, and 110 DEG C of line of transference temperature,
Equilibration time 30min, pressing time 2min；
Gas chromatography determination condition is: using Agilent DB-624 chromatographic column, 30m × 0.32mm × 0.50 μm carries
Gas velocity 1mL/min, split ratio 10:1 200 DEG C of injector temperature, originate 40 DEG C of column temperature, 15min are kept, with 10 DEG C/min journey
Sequence is warming up to 150 DEG C, keeps 10min；
Fid detector testing conditions are: 250 DEG C of temperature；
The standard curve that pure C ketone solvent is established according to said determination condition contains with the percentage that external standard method calculates acetone
Amount (uses IsolvIt indicates).
(2) moisture percentage assay:
For sample to be tested, with the degree of karl Fischer coulomb meter measurement moisture, determination condition is:
Detecting environment temperature is 20 DEG C, humidity 40%, polarizing electrode DM143-5C, 5.0 μ A of polarization current, and instruction is single
Position is voltage (mV), and speed of agitator 45%, control terminal is 100.0mV；The electric current of electrolysis electrode is automatic termination, termination type
For opposite termination of drifting about, drift value is 3.0 μ g/min, and time range is 0~3600s.The moisture percentage content I of acquisitionmoi
It indicates.
(3) percent ash assay:
For sample to be tested, the concentration value for obtaining ash content is measured with thermogravimetric analyzer, determination condition is: using Al2O3
Crucible is warming up to 650 DEG C in 25 DEG C of the initial temperature rates with 10 DEG C/min；The mass change in thermal decomposition process is recorded, heat is obtained
Weight curve (uses I according to the degree that thermogravimetric curve analyzes output ash contentashIt indicates).
3-1.4, the Reinheitszahl obtained according to step 3-1.1 and 3-1.2, the impurity percentage obtained respectively through step 3-1.3
Than content, acquisition amendment Reinheitszahl is calculated according to formula (1) and (uses I' respectivelyGCAnd I'HPLCIt indicates).
Step 3-2, for the sample to be tested of hydroquinone, hydroquinone Reinheitszahl is measured using DSC method.Determination condition is such as
Under:
Use 40 empty μ L standard aluminum crucibles for reference, sample weighting amount is 3.24~6.80mg, and temperature-rise period isAcquire DSC curve (see attached drawing 11), using software to curve into
Row purity analysis obtains Reinheitszahl and (uses IDSCIt indicates).
Step 3-3 repeats step 3-1 and step 3-2 and carries out 10 measurements, obtain for the sample to be tested of each hydroquinone
The corresponding three groups of Reinheitszahls of 10 measurements are obtained, the final Reinheitszahl that data processing obtains sample to be tested is carried out.
Step 3-3.1
3-3.1: three groups of Reinheitszahl (I' are directed toGC, I'HPLCAnd IDSC), coefficient of kurtosis method and coefficient of skew method are first used respectively
Normal distribution inspection is carried out, then carries out outlier inspection with Grabbs method and Dixon method, the results showed that without dubious value, is protected
Residual is according to progress next step；
3-3.2: every two groups of Reinheitszahl (I' are directed toGCWith I'HPLC, I'HPLCWith IDSC, I'GCWith IDSC) equally accurate inspection is carried out,
T inspection result shows that the average value of three groups of data is equally accurate, and F inspection result shows that the standard deviation of three groups of data such as is at the essences
Degree；
3-3.3: data processed result is shown in Table 7.Since three groups of data are equally accurate measurement, then the arithmetic of three groups of Reinheitszahls is taken
Average value is final Reinheitszahl, i.e., are as follows:
7 three kinds of methods of table measure hydroquinone Reinheitszahl result
Step 4 --- packing
Hydroquinone 50mg or so, packing to brown glass sample are accurately weighed in 20 DEG C ± 3 DEG C of room temperature of toilet
In bottle, packing sample is obtained, is repeated the above steps, about 200 bottles of sample of packing is obtained, is numbered with number, in refrigerating and be protected from light condition
Lower preservation.For uniformity and stability test.
Step 5 --- uniformity testing
The uniformity testing of hydroquinone the results are shown in Table 8.Statistical is carried out to data using one-way analysis of variance method
Analysis, obtains according to formula (2)I.e. F statistical value is 1.70, is looked into
F is examined known to tables of critical values: F0.05 (9,20)=2.39, i.e., F critical value is 2.39, therefore F statistical value < F critical value, show benzene
The packing sample of phenol has preferable uniformity.
The uniformity testing result of 8 hydroquinone of table
Step 6 --- stability test
Step 6-2 short-term stability is examined
The short-term stability inspection result of 9 hydroquinone of table
The short-term stability inspection result of hydroquinone is shown in Table 9, is measured with the packing sample being placed in 4 DEG C of environment pure
Angle value is standard.It is obtained by table 3, purity rubric value is x0=99.74%, relative standard deviation s0=0.01%, it is measured in parallel
Frequency n=3, freedom degree ν=n+n-2=4.Substitution formula (3) is calculated t statistical value and (uses ttestIt indicates).Look into t distribution bilateral
Table is it is found that t(0.05,4)=2.78.It is obtained by table 9, at 20 °C, ttest<t(0.05,4), under the conditions of 50 DEG C, ttest>
t(0.05,4), show that packing sample is good in ordinary temperature stability, and the Reinheitszahl generation for dispensing sample under the high temperature conditions significantly declines
Subtract, therefore dispense sample to save at normal temperature.
Step 6-2 long-time stability are examined
The long-time stability of 10 hydroquinone of table investigate result
The long-time stability investigation of hydroquinone the results are shown in Table 10.If the time is y=b to the equation of Reinheitszahl0+b1X, tiltedly
The standard deviation of rate is s (b1), obtained through regression analysis | b1|=2.3 × 10-3, s (b1)=2.8 × 10-3, it is critical to be looked into t inspection
Value table obtains t(0.95,n-2)=2.78, then | b1|<t0.95,n-2·s(b1), then slop estimation value is not significant, show be when confidence level
When 0.95, dispensing the Reinheitszahl of sample, there is no significant changes.
Step 7 --- uncertainty evaluation
The uncertainty evaluation that step 7-1 definite value introduces
Uncertainty evaluation caused by step 7-1 purity testing
Uncertainty caused by step 7-1.1GC method and HPLC method measure
Three kinds of methods carry out uncertainty result caused by purity testings it is as shown in the table (table 11:GC method and HPLC method；Table
12:DSC method).
Uncertainty result caused by 11 GC method of table and HPLC method measurement purity
Uncertainty caused by 12 DSC method of table
Uncertainty caused by purity testing (is used into uDIndicate) by the uncertainty combination of three kinds of method for detecting purity, then
It obtains:
The uncertainty evaluation that step 7-2 uniformity and stability introduce
According to uniformity testing result and formula (9), partial uncertainty caused by uniformity is obtained are as follows:According to stability test result and formula (10), validity period t=12 a month
The uncertainty of long-time stability are as follows: uS=s (b1) t=3.4 × 10-2%
Step 8 --- conclusion
It is obtained according to step 3, the standard purity value of hydroquinone is 99.65%, is marked according to step 7 and formula (11)
Quasi- uncertainty is 0.09%, expanded uncertainty 0.18%, k=2.It is stored within the time that is valid for one year, under room temperature
It uniformity and has good stability, can be used as purity rubric substance for the Accurate Determining of hydroquinone, transmission of quantity value in cosmetics
And magnitude tracing.
Through Subscriber Unit, (Shenzhen leads to detection technique Co., Ltd, depth to the hydroquinone purity rubric substance of the present embodiment
Examine joint inspection in ditch between fields and survey Co., Ltd and Hangzhou environmental monitoring central station) it is on probation after, provided user's trial report, trial report
It indicating, the Certified Reference Material Homogeneity is good, and magnitude is accurate and reliable, and it is easy to use, meet hydroquinone percentage in cosmetics
The requirement of content Accurate Determining has very high practical value and promotional value.
As seen from the above-described embodiment, the method for the present invention is qualitative accurate, with the method simultaneous determination of three kinds of different principles
Reinheitszahl reduces because of single valued methods bring systematic error, and statistical data processing method is rigorous, uncertainty evaluation side
Method is comprehensive, ensure that magnitude accuracy, stability and tractability, obtains high-purity (99% or more) phenol and hydroquinone
Purity rubric substance.
Claims (7)
1. the measuring method of the Reinheitszahl and uncertainty of a kind of phenol and hydroquinone standard substance, it is characterised in that:
Step 1: screening being carried out to raw material, so that purity is qualified and carries out next step；
Step 2: being combined using gas chromatography-mass spectrometry and fourier transform infrared spectroscopy qualitative to sample to be tested progress
Confirmation；
Step 3: using based on gas-chromatography (GC) method, high performance liquid chromatography (HPLC) method and differential scanning calorimetry (DSC) method three
The method of kind different principle, which is combined, carries out purity testing to sample to be tested；
The step 3: purity testing specifically:
3-1: being directed to sample to be tested, and after test solution is made, simultaneous determination obtains two groups of purity Value Datas；
3-2: being directed to sample to be tested, measures Reinheitszahl using differential scanning calorimetry (DSC) method, obtains one group of purity Value Data；
3-3: for each sample to be tested, repeating step 3-1 and step 3-2 and measure, will obtain three groups of purity Value Datas, into
The final Reinheitszahl of row data processing acquisition sample to be tested；
The step 3-1 is specifically included:
3-1.1: chromatogram is acquired using GC method, chromatogram is calculated to the initial purity of sample to be tested with area normalization method
Value IGC；
3-1.2: chromatogram is acquired with HPLC method, chromatogram is calculated to the initial purity of sample to be tested with area normalization method
Value IHPLC；
3-1.3: Static Headspace sample introduction-GC- hydrogen flameionization (FID) detector, karl Fischer coulomb meter and heat is respectively adopted
Weight analysis instrument is measured sample to be tested, obtains the degree I of residual solvent respectivelysolv, moisture degree
Imoi, ash content degree Iash；
3-1.4: the impurity percentage obtained according to step 3-1.1 and the 3-1.2 two initial purity values obtained and step 3-1.3
Content calculates and obtains GC method and the corresponding two amendment Reinheitszahls I ' of HPLC methodGCAnd I 'HPLC；
3-1.5: it repeats step 3-1.1~3-1.4 and takes multiple measurements two groups of purity Value Datas of acquisition；
The step 3-1 is further specifically:
Step 3-1.1:
By test solution sample introduction into low pole chromatographic column DB-1701, it is arranged 280 DEG C of injector temperature, fid detector temperature
280 DEG C, carrier gas nitrogen flow velocity 1mL/min, sample volume 1 μ L, split ratio 2.5:1；It is operated again using gradually heating mode, from
And chromatogram is collected, chromatogram is calculated with area normalization method and obtains Reinheitszahl；
Wherein, for phenol, it is 65 DEG C when column temperature condition setting is initial, is warming up to 200 DEG C with the rate of 3 DEG C/min, then with 10
DEG C/rate of min is warming up to 260 DEG C, keep 6min；For hydroquinone, 50 DEG C when column temperature condition setting is initial, with 8 DEG C/
The rate of min is warming up to 220 DEG C, then is warming up to 270 DEG C with the rate of 15 DEG C/min, keeps 6min；
Step 3-1.2:
Using C18 chromatographic column, setting sample volume is 10 μ L, and column flow 1mL/min, column temperature is 25 DEG C, and acquisition testing wavelength is
The 3D data of 190nm~400nm, wavelength separated degree are 1.2nm；Respectively using 271.0nm and 289.0nm as phenol and to benzene two
Chromatogram is calculated with area normalization method to collect chromatogram and obtains Reinheitszahl by the definite value wavelength of phenol；
Wherein, for phenol, flowing phase composition is+70% pure water of 30% methanol；For hydroquinone, flowing phase composition is 70%
+ 30% pure water of methanol；
Step 3-1.3:
(1) residual solvent degree measures:
It is successively residual with Static Headspace method sample introduction, gas chromatography separation and fid detector method detection assay for sample to be tested
The degree of solvent is stayed, wherein the determination condition of each process is as follows；
Static Headspace sampling system determination condition is: 80 DEG C of equilibrium temperature, 90 DEG C of quantitative loop temperature, and 110 DEG C of line of transference temperature, balance
Time 30min, pressing time 2min；
Gas chromatography determination condition is: using Agilent DB-624 chromatographic column, 30m × 0.32mm × 0.50 μm, carrier gas stream
Fast 1mL/min, split ratio 10:1 200 DEG C of injector temperature, originate 40 DEG C of column temperature, 15min are kept, with 10 DEG C/min program liter
Temperature keeps 10min to 150 DEG C；
Fid detector determination condition is: 250 DEG C of temperature；The detected chromatogram of fid detector is residual with external standard method calculating
Stay the concentration value of solvent；
(2) moisture percentage assay: being directed to sample to be tested, and the percentage for obtaining moisture is measured with karl Fischer coulomb meter
Content, determination condition are: detection environment temperature is 20 DEG C, humidity 40%, polarizing electrode DM143-5C, 5.0 μ of polarization current
A, instruction unit are voltage, and speed of agitator 45%, control terminal is 100.0mV；The electric current of electrolysis electrode is automatic termination, is terminated
Type, which is that drift is opposite, to be terminated, and drift value is 3.0 μ g/min, and time range is 0~3600s；
(3) percent ash assay: being directed to sample to be tested, and the concentration value for obtaining ash content is measured with thermogravimetric analyzer, surveys
Fixed condition is: using Al2O3Crucible is warming up to 650 DEG C in 25 DEG C of the initial temperature rates with 10 DEG C/min；It records in thermal decomposition process
Mass change, obtain thermogravimetric curve, according to thermogravimetric curve analyze output ash content concentration value；
Step 3-1.4:
I'GC=(100%-Imoi-Isolv-Iash)×IGC
I'HPLC=(100%-Imoi-Isolv-Iash)×IHPLC
In formula, I'GCAnd I'HPLCRespectively gas-chromatography (GC) method and the corresponding amendment purity of high performance liquid chromatography (HPLC) method
Value, IGCAnd IHPLCThe respectively corresponding initial purity value obtained of gas-chromatography (GC) method and high performance liquid chromatography (HPLC) method,
Imoi、IsolvAnd IashRespectively indicate the concentration value of moisture, dissolvent residual and ash content；
Step 4: after sample to be tested is dispensed, then carrying out uniformity and stability test；
Step 5: uniformity and steady is calculated according to step 4 in uncertainty caused by purity testing is calculated according to step 3
Each uncertainty is carried out synthesis and obtains overall uncertainty by uncertainty caused by qualitative.
2. the measurement side of the Reinheitszahl and uncertainty of a kind of phenol according to claim 1 and hydroquinone standard substance
Method, it is characterised in that: the step 1: raw material screening specifically: the raw material of industry is first subjected to purity initial survey using HPLC method, is sentenced
Whether disconnected Reinheitszahl is qualified, and Reinheitszahl thinks qualified progress next step not less than 99%, unqualified, carries out at recrystallization
Reason, until purity is qualified.
3. the measurement side of the Reinheitszahl and uncertainty of a kind of phenol according to claim 1 and hydroquinone standard substance
Method, it is characterised in that: the step 2: qualitative confirmation specifically: test solution and solid preform is respectively prepared in sample to be tested
Afterwards, then gas chromatography-mass spectrography (GC-MS) method is respectively adopted and Fourier Transform Infrared Spectroscopy (FT-IR) method collects
Mass spectrogram and infrared spectrogram, mass spectrogram and infrared spectrogram are compareed with standard spectrogram, according to the qualitative confirmation raw material of matching degree
Authenticity, if raw material really if carry out next step.
4. the measurement side of the Reinheitszahl and uncertainty of a kind of phenol according to claim 1 and hydroquinone standard substance
Method, it is characterised in that:
The step 3-2 specifically: use 40 empty μ L standard aluminum crucibles for reference, sample weighting amount is 3.24~6.80mg, then is adopted
It is operated with gradually heating mode, Reinheitszahl I is then obtained using purity analysis software Pro teus AnalysisDSC, go forward side by side
Repeatedly measurement obtains two groups of purity Value Datas to row；
For phenol, initial temperature is 0 DEG C, is warming up to 20 DEG C with the rate of 5 DEG C/min, then be warming up to the rate of 1 DEG C/min
60℃；
For hydroquinone, initial temperature is 0 DEG C, is warming up to 155 DEG C with the rate of 20 DEG C/min, then with the rate of 10 DEG C/min
It is warming up to 190 DEG C.
5. the measurement side of the Reinheitszahl and uncertainty of a kind of phenol according to claim 1 and hydroquinone standard substance
Method, it is characterised in that: the step 3-3 is particularly directed to same sample to be tested, the three groups of purity that will be measured with three kinds of methods
Value Data is successively handled in the following ways:
3-3.1: three groups of purity Value Datas are directed to, first carry out normal distribution inspection with coefficient of kurtosis method and coefficient of skew method respectively
It tests, then carries out outlier with Grabbs method and Dixon method and examine rejecting dubious value；
The equally accurate inspection of average value is carried out between every two groups of Reinheitszahls of 3-3.2: three groups of purity Value Datas with t method of inspection
It tests, is examined with the equally accurate that F method of inspection carries out standard deviation；
3-3.3: according to the equally accurate of average value and standard deviation as a result, final Reinheitszahl of the averaged as raw material:
If the purity Value Data that step 3-3.1 retains meets the equally accurate of average value and standard deviation simultaneously, three groups of purity are taken
The arithmetic mean of instantaneous value of Value Data；
If meeting the unequal accuracy of average value and standard deviation when the purity Value Data difference that step 3-3.1 retains, three groups are taken
The weighted average of purity Value Data.
6. the measurement side of the Reinheitszahl and uncertainty of a kind of phenol according to claim 1 and hydroquinone standard substance
Method, it is characterised in that: in the step 4 after packing specifically:
4-1: uniformity testing
Respectively from 200 bottles of packing samples according to end to end, intermediate number randomly select 10 bottles of samples, be configured to test solution,
Oscillation measures Reinheitszahl according to HPLC method, and every bottle of sample is measured in parallel 3 times；Again using one-way analysis of variance method to measurement
As a result for statistical analysis, F statistical value is calculated, tables look-up and obtains F critical value, by comparing F statistical value and F critical value, examines and divides
Fill the uniformity of sample；If F statistical value is less than F critical value, sample is uniform；If F statistical value is more than or equal to F critical value, sample
Product are uneven；
F statistical value calculation is as follows:
In formula, SinterAnd SintraIt respectively indicates between bottle and bottle internal variance, νinterAnd νintraRespectively indicate between bottle and in bottle freely
Degree；
4-2: stability test is divided into short-term stability and long-time stability
4-2.1 short-term stability
Several bottles are randomly selected from packing sample, is individually placed in 4 DEG C, 20 DEG C and 50 DEG C environment, respectively to the 1st day, the 2nd day,
After each 1 bottle of taking-up in 5th day and the 8th day, it is configured to test solution, is vibrated, measures Reinheitszahl according to HPLC method, every bottle of sample is flat
Row measurement 3 times, is averaged；The Reinheitszahl measured again using the packing sample being placed in 4 DEG C of environment is tabled look-up as standard and obtains t
Critical value calculates t statistical value ttest, short-term stability is examined by comparing t statistical value and t critical value: if t statistical value is less than t
Critical value, then sample short-term stability；If t statistical value is more than or equal to t critical value, sample short-term instability；
T statistical value ttestCalculation formula is as follows:
In formula, x0And s0It respectively indicates purity average value that the packing sample being placed in 4 DEG C of refrigerators measures and purity rubric is inclined
Difference,Reinheitszahl and standard deviation that the packing sample being placed under each different temperatures environment measures, n table are respectively indicated with s
Show the number of parallel determination；
4-2.2 long-time stability
Packing sample is stored in 20 DEG C of environment, 12 months STABILITY MONITORINGs are carried out using HPLC method, according to first close rear thin
Principle access time node, each timing node chooses 1 sample, and each sample is measured in parallel 3 times, is averaged；Then
In the case where potential kinetics mechanism is unknown, linear fit is carried out using linear model, the time is represented with x, some is represented with y
The sample purity value of timing node, fitting is in alignment, utilizes the stability of the conspicuousness judgement sample of the straight slope.
7. the measurement side of the Reinheitszahl and uncertainty of a kind of phenol according to claim 1 and hydroquinone standard substance
Method, it is characterised in that: the step 5 is to calculate to obtain overall uncertainty in the following ways:
5-1: uncertainty caused by GC method and HPLC method measurement Reinheitszahl is first obtained using following calculation method:
In formula, uGC-HPLCIt indicates to obtain IGCAnd IHPLCCaused Composite Seismogram, With
Respectively indicate first function f1To IGC-HPLC, Imoi, Isolv, IashAsk partial derivative, umoi、usolvAnd uashRespectively indicate moisture, solvent
Uncertainty caused by residual and ash determination, first function f1It is expressed as f1(IGC-HPLC,Imoi,Isolv,Iash)=(100%-
Imoi-Isolv-Iash)×IGC-HPLC；uGC-HPLCCalculation are as follows:uGCAnd uHPLCIt respectively indicates
Obtain IGCAnd IHPLCCaused partial uncertainty；umoi、usolvAnd uashRespectively with moisture, dissolvent residual and the weight of ash determination
Renaturation meter；
5-2: it is calculated using the following equation uncertainty u caused by DSC method measurement Reinheitszahl againDSC:
Wherein, uDSC-AAnd uDSC-BIndicate the standard uncertainty of type A evaluation and type B evaluation in the measurement of DSC method, uDSC-AIt is to pass through
The repeatability of measurement DSC method is calculated；
uDSC-BCalculation formula it is as follows:
Wherein, um, uQ, uTRespectively the weighing error of balance, the calorimetry error of instrument, the temperature error of instrument these three
The standard uncertainty of mutual incoherent input quantity,Respectively indicate second function f2To m,
Q、T0And TmAsk partial derivative, c1, c2And c3Respectively indicate the calculated value of quality, heat and temperature；
Second function f2It indicates are as follows:
In formula, T0And TmThe melting temperature of pure sample and actual sample is respectively indicated, R is gas constant, and Q is the heat that sample absorbs
Amount, m are the quality of sample, and M is the molal weight of sample；
5-3: calculating divides uncertainty
Caused by being calculated by using the following formula uniformity according to the one-way analysis of variance result that uniformity testing obtains not
Degree of certainty uH:
For the standard deviation for the fitting a straight line slope examined according to long-time stability multiplied by the STABILITY MONITORING time, use is following
Uncertainty u caused by stability is calculated in formulaS:
uS=s (b1)·t
5-4: overall uncertainty is calculated
Overall uncertainty calculation formula indicates as follows:
By uncertainty and step 5- caused by GC method obtained by step 5-1 and step 5-2, HPLC method and DSC method measurement purity
Uncertainty caused by 3 gained uniformities and stability substitutes into above formula, and overall uncertainty is calculated.
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