CN107543884A - ACV purity rubric material and preparation method and application - Google Patents
ACV purity rubric material and preparation method and application Download PDFInfo
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Abstract
The invention discloses ACV purity rubric material and preparation method and application.Its preparation method, comprises the following steps：1) ACV material powder is sampled, the weight/mass percentage composition of ACV in the ACV material powder is determined using high performance liquid chromatography area normalization method, obtains the purity definite value of the ACV material powder；2) biodiversity percentage composition, non-volatile impurities weight/mass percentage composition and organic volatile impurities weight/mass percentage composition in the ACV material powder are determined, with reference to the purity definite value of the ACV material powder determined in step 1), calculated according to equation below I, that is, obtain the ACV purity rubric material of definite value；P=P0× [100% Xw‑Xn‑XvThe formula of] × 100% I.The present invention can be used for the detection of animal products drug residue as standard substance, and technical support and material guarantee are provided for national agricultural product quality and safety risk assessment and the foundation of monitoring traceability system.
Description
Technical field
The present invention relates to a kind of ACV purity rubric material and preparation method and application, belongs to stoichiometry acceptance of the bid
Quasi- transmission of quantity value technical field.
Background technology
Limit and use medicine abuse condition during livestock-raising serious, because it has stronger toxic side effect and toxicity
Effect, and the residual in animal tissue can be transmitted to the mankind by food chain, long-term micro intake can cause a variety of diseases, to people
The health of class damages.Limit turns into the important of Ministry of Agriculture's agricultural product quality and safety risk assessment and monitoring activity with medicine
Parameter, to ensure uniformity, comparativity, tractability and the value of measurement result accurately and reliably, it is badly in need of supporting corresponding
Standard substance.
ACV, English name：Acyclovir, is a kind of antiviral agent of wide spectrum, purine-containing nuclear compound, in body
Triphosphoric acid compound is inside converted into, viral interference archaeal dna polymerase, suppresses the duplication of viral DNA and plays antiviral effect.It is right
Virus plays the role of stronger.For the prevention and treatment of viral skin or mucosal infections, hepatitis B, herpe simplex are also used for
Property keratitis, varicella zoster virus infection etc..CAS：59277-89-3.Molecular formula C8H11N5O3.Relative molecular weight 225.20, melt
256-257 DEG C of point.It is slightly molten in glacial acetic acid or hot water for odorless, tasteless white crystalline powder, the slightly soluble in cold water,
Soluble,very slightly in ethanol, it is almost insoluble in ether or chloroform, it is readily soluble in dilute alkaline soln, it is also readily soluble in watery hydrochloric acid, also easily
It is dissolved in ammonia solution and dimethyl sulfoxide.Condition of storage：It is stored refrigerated.The molecular structural formula of ACV is as shown in Equation 1.
Formula 1
The content of the invention
It is an object of the invention to provide a kind of ACV purity rubric material and preparation method and application, energy of the present invention
It is used for the detection of animal products drug residue as standard substance, is traced back for national agricultural product quality and safety risk assessment with monitoring
The foundation of source system provides technical support and material guarantee.
The preparation method of ACV purity rubric material provided by the invention, comprises the following steps：
1) ACV material powder is sampled, the ACV is determined using high performance liquid chromatography area normalization method
The weight/mass percentage composition of ACV in material powder, obtain the purity definite value of the ACV material powder；
2) biodiversity percentage composition, non-volatile impurities weight/mass percentage composition in the ACV material powder are determined
With organic volatile impurities weight/mass percentage composition, determine with reference to the purity of the ACV material powder determined in step 1)
Value, calculates according to equation below I, that is, obtains the ACV purity rubric material of definite value；
P=P0× [100%-Xw-Xn-XvThe formula of] × 100% I；
Wherein, P be ACV purity rubric material definite value, P0For the purity definite value of ACV material powder, XwFor
Biodiversity percentage composition, XnFor non-volatile impurities weight/mass percentage composition, XvFor organic volatile impurities weight/mass percentage composition.
In above-mentioned method, the purity of the ACV material powder is 99.1~99.9%；
Using the weight/mass percentage composition of ACV in ACV material powder described in multiple laboratory simultaneous determinations；
Also include using JJG 1006-1994 to ACV material powder sampling in step 1)《Primary standard substance
Matter technical specification》Requirement uniformity testing is carried out using method of analysis of variance and stability test is carried out using line fitting approach
Step.
In the present invention, shown in the equation below of the uniformity testing：
Remember v1=m-1, v2=N-m；
Wherein, Q1The sum of squares of deviations between representative group, Q2The sum of squares of deviations in representative group,I-th group of average value is represented,Represent total flat
Average, xijRepresent i-th group of j-th of numerical value, v1The free degree between representative group, v2The representative group internal degree of freedom, s1Standard deviation between representative group
Difference, s2Representative group internal standard deviation；
According to the free degree (v1, v2) and given level of significance α, critical F can be checked inαValue.
In the present invention, prepare the ACV material powder and comprise the following steps：Tentatively confirm by qualitative and purity
Afterwards, it is placed into beveller and is fully ground, the raw material after grinding is put into vacuum drying oven, under conditions of 45 DEG C, low pressure (-
Below 0.1Mpa) to dry 24 hours, the ACV sterling raw material after being dried under reduced pressure is placed in a clean glassware, is filled
Divide stirring, mix.
In above-mentioned method, the chromatographic condition of the high performance liquid chromatography area normalization method is as follows：
Chromatographic column：SB-Aq(250mm×4.6mm,5.0μm)；Mobile phase：It is made up of methanol and trifluoroacetic acid aqueous solution, first
The volume parts of alcohol and trifluoroacetic acid aqueous solution ratio is 5：95, the volume parts of trifluoroacetic acid and water in trifluoroacetic acid aqueous solution
Than for 0.001:100；Flow velocity：1.0mL/min；Sample size：20μL；UV wavelength：254nm；
100~1000mg/L ACV methanol solution is formulated as during the ACV material powder measure, specifically
Can be 100mg/L, 300mg/L, 500mg/L, 700mg/L, 1000mg/L or 700~1000mg/L.
In the present invention, HPLC uses Shimadzu LC-20A systems in the chromatographic condition.
Also include carrying out normality to the purity definite value of the ACV material powder in above-mentioned method, in step 1)
The step of inspection.
Also include using Cochran to the purity definite value of the ACV material powder in above-mentioned method, in step 1)
Criterion rejects the step of dubious value in array；
The calculation formula of the Cochran criterion：Table look-up to obtain C (α, m, n)；
Wherein, C be the ACV material powder purity definite value statistic, smaxFor mark maximum in measurement group
Quasi- deviation；siFor the standard deviation of i-th group of measured value；C (α, m, n) is Cochran-test value；
As C ＞ C (α, m, n), it is dubious value array, should be removed；As C ＜ C (α, m, n), without suspicious array, Ying Bao
Stay；
Purity value data using Rod Dixon criterion to ACV material powder described in multiple laboratory simultaneous determinations
Statistical check is carried out, the range method of upchecking rejects dubious value.
In the present invention, the purity value data of ACV material powder uses first described in multiple laboratory simultaneous determinations
The normality of promise method inspection data is carried up to Goss, the Cochran criterion is then carried out and rejects dubious value in array and using Di
Gram inferior criterion rejects dubious value.
In above-mentioned method, the moisture in the ACV material powder is determined using Karl_Fischer method；
Non-volatile impurities weight/mass percentage composition is using micro-wave digestion-inductive etc. in the ACV material powder
Gas ions mass spectrography, micro-wave digestion-inductively coupled plasma emission spectrography and ion-chromatographic determination；The microwave disappears
As, Se, Cd, Mn, Sn, Li, Cr, Cs, Ni, Pb in solution-inductively coupled plasma mass spectrometry measure non-volatile impurities,
At least one of Sr, Rb, Ti and Ba content；Described in the micro-wave digestion-inductively coupled plasma emission spectrography measure
At least one of Cu, Ca, Mg, K, Na, P, Mn, Mo, Zn, Fe and Co in non-volatile impurities content；The chromatography of ions
The content of method measure chlorion, nitrate ion and sulfate ion；
Organic volatile impurities quality percentage described in the ACV material powder is determined using headspace gas chromatography
Content.
Also include not knowing the definite value of the ACV purity rubric material in above-mentioned method, in step 2)
The step of degree analysis；The uncertainty of the ACV purity rubric material is made up of three parts：Standard substance it is uneven
The definite value process of the uncertainty of introducing, the uncertainty of the unstable introducing of standard substance and standard substance introduces uncertain
Degree.
In the present invention, the analysis of the definite value uncertainty of the ACV purity rubric material is using this area routine
Method is analyzed, and is that definite value result is divided to the purpose of analysis on Uncertainty of the ACV purity rubric material definite value
Property is dissipated reasonably to be characterized.
The ACV purity rubric material of the definite value obtained present invention also offers above-mentioned method.
The mass fraction 99.5% of ACV purity rubric material of the present invention, its uncertainty (k=2) are
0.4%.
ACV purity rubric material of the present invention is following 1) -6) application in any one：
1) as standard substance be applied to agricultural product production field of circulation herbal medicine and/or feed product in ACV into
Go-on-go is surveyed；
2) ACV medicament residue detects in animal products in field of food；
3) testing laboratory's quality control；
4) analytical instrument is calibrated as standard substance；
5) analysis method confirms evaluation；
6) to giving material definite value.
The present invention has advantages below：
The present invention is using high performance liquid chromatography (UV detectors) analysis method, Duo Jia laboratories cooperation definite value mode to standard
The purity of material carries out definite value, by using the preparation method, measuring method and measurement instrument for meeting metrological characteristic requirement, protects
The traceability of standard substance characteristic magnitude is demonstrate,proved, the uncertainty of standard value has considered sterling purity definite value, sample inequality
The partial uncertainty of uniform unstable introducing.
Brief description of the drawings
Fig. 1 is ACV long-time stability monitoring result.
Fig. 2 is ACV short-term stability monitoring result, and wherein Fig. 2 (a) is short-term stability result under the conditions of 20 DEG C,
Fig. 2 (b) is short-term stability result under the conditions of 40 DEG C, and Fig. 2 (c) is short-term stability result under the conditions of 60 DEG C.
Fig. 3 is that non-volatile impurities contain measurement, and wherein Fig. 3 (a) is the standard curve of chlorion, and Fig. 3 (b) is nitrate anion
Standard curve, Fig. 3 (c) are the standard curve of sulfate ion.
Fig. 4 is the chromatography of ions figure of ACV (2000mg/L).
Fig. 5 is ACV purity rubric material definite value uncertainty source analysis and rate the process figure.
Embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
Material used, reagent etc., unless otherwise specified, are commercially obtained in following embodiments.
In following embodiments, standard substance candidate ACV is purchased from TCI companies, and lot number is Lot CS4BD, and label is pure
Spend for 99.1% (HPLC) and 95.4% (Nonaqueous Titration), the packing specification of candidate is 50g.The raw material system
This center carries out screening final determination to the ACV raw material of Duo Jia manufacturers.In order to further confirm that the accurate of raw material can
Lean on, the means such as infra-red sepectrometry, nucleus magnetic hydrogen spectrum are respectively adopted principal component qualitative analysis has been carried out to the raw material of purchase.
The definite value of embodiment 1, ACV purity rubric material
ACV sterling raw material is placed into beveller and is fully ground, to grinding after qualitative and purity tentatively confirms
Raw material after mill is put into vacuum drying oven, and under conditions of 45 DEG C, low pressure (below -0.1Mpa) is dried 24 hours, and decompression is dry
ACV sterling raw material after dry is placed in a clean glassware, is sufficiently stirred, is mixed.It is (purple using liquid chromatography
External detector, UV) to the preliminary test of raw material progress uniformity, after the assay was approved, ACV candidate is dispensed to dry
In net cillin bottle, cillin bottle specification is 5.0mL, is cleaned before packing using strict washing measure, and each packaging unit is
100mg, this development are divided into 402 bottles of dress ACV sterling.Low temperature (4 DEG C), lucifuge storage are in case follow-up use.
The definite value step of ACV purity rubric material of the present invention is as follows：
1st, uniformity testing
According to JJG 1006-1994《Primary standard material technical specification》Requirement, uniformity has been carried out to standard substance
Examine.This research uses the uniformity of method of analysis of variance statistical check ACV purity rubric material, from the Ah former times Lip river of packing
15 packagings are randomly selected in Wei, after fully shaking up, different parts make even row three times in bottle, and weight-volumetric method is prepared
1000mg/L methanol solutions, using liquid-phase condition during definite value, examined using liquid chromatogram-area normalization method, acquisition it is equal
Even property data use method of analysis of variance, judge to whether there is between each group measured value to be by the comparison of between-group variance and intra-class variance
System sex differernce, if both ratios are less than the critical value of statistical check, then it is assumed that sample is uniform.
Uniformity testing formula is as follows：
Remember v1=m-1 (free degree between group), v2=N-m (the group internal degree of freedom)
According to the free degree (v1, v2) and given level of significance α, critical F can be checked inαValue.
The ACV purity rubric material uniformity testing result (%) of table 1
According to the data analysis of table 1, between the bottle of ACV purity rubric material of the present invention and bottle in measurement result standard
There was no significant difference for deviation, and the purity rubric material that can determine that packing is uniform, and the data of uniformity testing are counted
Analysis, as a resultTo uniformity standard deviation sHIt is calculated as follows：
2nd, study on the stability
The stability of standard substance includes long-time stability and short-term stability.Long-time stability refer to store bar in regulation
The stability of standard substance characteristics under part.Short-term stability refers to stabilization of the standard substance in transportation under traffic condition
Property.
According to directive/guide 35, stability can carry out statistical check by line fitting approach.
Specific formula is as follows：
Slope can be calculated with following formula：
Intercept can be calculated with following formula：
The standard deviation of every can be calculated with following formula on straight line：
The uncertainty related to slope can be calculated with following formula：
Ruo ∣ b1∣<t0.95,n-2·s(b1), then it is assumed that standard substance is stable.
Wherein, the uncertainty of stability introducing is：
(1) long-time stability are investigated
According to JJG1006-1994《Primary standard material technical specification》In requirement, standard substance study on the stability according to
Thin principle after first close.This research carried out steady at the 0th, 1,3,6 month respectively since in May, 2016, using liquid chromatography
Qualitative investigation.2 packagings are extracted every time, and solution is prepared using weight-volumetric method, it is each to pack parallel determination 3 times, stability inspection
Test result as shown in Table 2 and Figure 1.This purity rubric material is under conditions of 4 DEG C are kept in dark place, and purity value is stable within six months.
The ACV purity rubric material long-time stability monitoring result (%) of table 2
(2) short-term stability is investigated
Sample is placed in 20 DEG C, 40 DEG C and 60 DEG C insulating boxs (simulation traffic condition) and preserved, respectively the 1st, 3,5,7,9
It carries out STABILITY MONITORING, and detection method is identical with long-time stability monitoring.Data investigation is carried out using trend analysis, as a result such as
Shown in table 3 and Fig. 2.From table 3 and Fig. 2, this standard material can ensure purity under 60 DEG C and following traffic condition in 9 days
Value is stable.
The ACV purity rubric material short-term stability of table 3 investigates result (%)
In summary, 6 months long-time stability of ACV standard substance are good, in 20 DEG C, 40 DEG C, 60 DEG C of simulation fortune
Characteristic magnitude is stable under the conditions of defeated temperature, the haulage time of 9 days.
3rd, standard substance definite value
According to the property analysis and experimental result of ACV, according to《National standard reference material technology specification》
(JJF1006-1994) requirement, ACV purity rubric material definite value are fixed using 10 laboratory joints through Qualification Approval
Value, valued methods are the high performance liquid chromatography area normalization method by optimization.After principal component purity combines definite value, then it is right
Moisture in purity rubric material, non-volatile impurities, volatile impurity carry out Accurate Determining, finally true using mass balance approach
The value of fixed this purity rubric material.The measuring instrument and glass apparatus that 10 laboratory definite values are used have passed through metering inspection
It is fixed.10 laboratories are respectively aquatic product quality supervision and inspection center of the Ministry of Agriculture (Shanghai), Academy of Agricultural Sciences, Shanghai City agriculture
Target level of product quality is supervised with detection technique research institute, Jiangsu Province Animal product quality verification test center, Ministry of Agriculture's agricultural production processed goods
Superintend and direct verification test center (Nanjing), Henan Province's veterinary drug feed supervision institute, matter mark institute of Henan Academy of Agricultural Sciences, Sichuan Province's livestock products
Safety detection center, matter mark institute of Sichuan Academy of Agricultural Sciences and agricultural product quality supervision and inspection center of the Ministry of Agriculture (Kunming).
ACV liquid chromatogram certification condition is as follows：：
Chromatographic column：Agilent ZORBAX SB-aq(250mm×4.6mm,5.0μm)；Mobile phase：By methanol and trifluoro second
Aqueous acid forms, and the volume parts ratio of methanol and trifluoroacetic acid aqueous solution is 5：95, the trifluoro second in trifluoroacetic acid aqueous solution
The volume parts ratio of acid and water is 0.001:100；Flow velocity：1.0mL/min；Sample size：20μL；UV wavelength：254nm；HPLC：Island
Tianjin LC-20A systems.
Under conditions of above-mentioned optimization is good, 100mg/L, 300mg/L, 500mg/L, 700mg/L, 1000mg/L etc. are compared
The ACV chromatogram response diagram of various concentrations.It can be derived that, in 700mg/L, ACV impurity is with regard to that can have by chromatogram
Maximum, most responses, definite value concentration can select to be not less than 700mg/L.
Table 4 respectively participates in definite value laboratory and its high performance liquid chromatography model
| Sequence number | Laboratory | Liquid phase model |
| 1 | Ministry of Agriculture's agricultural product quality research on standard center | Waters2695 |
| 2 | Aquatic product quality supervision and inspection center of the Ministry of Agriculture (Shanghai) | Agilent 1200 |
| 3 | Academy of Agricultural Sciences, Shanghai City matter mark institute | Waters2690-2487 |
| 4 | Jiangsu Province Animal product quality verification test center | Waters2695-2998 |
| 5 | Agricultural production processed goods supervision and inspection center of the Ministry of Agriculture (Nanjing) | Agilent 1100 |
| 6 | Veterinary drug feed supervision institute of Henan Province | Waters2695-2998 |
| 7 | Matter mark institute of Henan Academy of Agricultural Sciences | Shimadzu SPD-20AV |
| 8 | Livestock product safety inspection center of Sichuan Province | Agilent 1200 |
| 9 | Matter mark institute of Sichuan Academy of Agricultural Sciences | Agilent 1200 |
| 10 | Agricultural product quality supervision and inspection center of the Ministry of Agriculture (Kunming) | Waters2695-2998 |
Table more cooperation definite value baseline results of 5 ACV purity rubric material
Because more value data n=90, first using the normality that promise method inspection data is put forward up to Goss.
More than 6 cooperation definite value baseline results of table carry promise method inspection statistics table up to Goss
Obtained by the data of table 6：
Promise being proposed up to Gus through difference and examining critical section, Y value is somebody's turn to do between corresponding section α-α (- 2.57~1.28)
Group data are normal distribution.
According to《The judgement and processing of statistical disposition and explanation-normal sample outlier of GB/T 4883-2008 data》
It is suspicious data to judge which group is this 10 groups of data whether there is using Cochran criterion, according to Cochran criterion, is calculated
StatisticTable look-up to obtain C (α, m, n)=C (0.05,10,9)=0.2541, because C<C (0.05,
10,9), no suspicious data group.
Statistical check is carried out to 10 laboratory value datas using Rod Dixon criterion, by definite value result according to ascending
Order arrangement：x(1)=99.49%, x(2)=99.50%, x(3)=99.52%, x(4)=99.53% ..., x(n-2)=
99.55%, x(n-1)=99.55%, x(n)=99.56%
N=10, f (0.05,10)=0.635 is looked into by Rod Dixon check table
And because
r1And r2<F (0.05,11), therefore total data all should retain.
Table more cooperation definite value results of 7 ACV purity rubric material
4th, the measure of impurity content
(1) determination of moisture
Using the moisture in Karl_Fischer method measure solid matter especially sterling.It is used for definite value to what experiment was chosen
3 packaging units using METTLER TOLEDO DL39 series connection METTLER TOLEDO Stromboli instrument, according to national standard (GB/
T606 chemical reagent determination of moisture general methods karl-Fischer method) measure moisture, each unit survey is surveyed averages three times, as a result
As shown in table 8.
The ACV determination of moisture result (%) of table 8
(2) non-volatile impurities assay
1) inductively coupled plasma mass spectrometry
The present invention uses micro-wave digestion-inductively coupled plasma mass spectrometry (Microwave-assisted ICP-MS)
Detect the As, Se, Cd in ACV purity rubric material, Mn, Sn, Li, Cr, Cs, Ni, Pb, Sr, Rb, Ti, Ba contents, tool
Body experimentation is as follows.
Laboratory apparatus and reagent：
Icp mses (ICP-MS) match Mo Feishier Co., Ltd ICP-MS X series 2, ten thousand
/ mono- assay balance, purity>99.99% high-purity argon gas, CEM microwave dissolvers (MARS SYSTEM), ultra-pure water, nitric acid are (excellent
Level is pure), hydrogen peroxide (top pure grade), As, Se, Cd, Mn, Mo, Co, Cu, Cs, Ni, Pb, Sr, Rb, Ti, Ba mixed standard solutions
(10mg/L)。
Experimental method：
The foundation of standard working curve：The mixed mark solution for being made through configuring various concentrations of standard working curve
(0.01ppm、0.1ppm、1.0ppm、10.0ppm、50.0ppm)。
Internal standard solution (In 114)：With ultrapure water as medium, wiring solution-forming concentration is 1 μ g/L.
Sample pre-treatments：Microwave Digestion.Uniform dry sample 0.100g is weighed, is accurate to 0.0001g, in 55mL digestion tubes
In, add 5mL nitric acid, soaked overnight, add 1mL hydrogen peroxide, cover molten sample lid, be placed in pressure pan, place into microwave sample dissolving dress
In putting, set microwave system to clear up program, start to clear up sample.After resolution is fully completed, inner canister is taken out, is positioned over and catches up with sour instrument
On, catch up with acid to remove to solution residue 1mL and be cooled to room temperature, be transferred to water in 10mL volumetric flasks, constant volume, mixed with 100 DEG C of heating
It is even standby.Do reagent blank simultaneously.Instrument condition：Nebulizer flow 1.02L/min；Purge number 45 times；Secondary air amount
0.80L/min；Cooling gas flow 13L/min.
2) inductively coupled plasma emission spectrography
The present invention uses micro-wave digestion-inductively coupled plasma emission spectrography (Microwave-assisted ICP-
AES the Cu in ACV purity rubric material) is detected, Ca, Mg, K, Na, P, Mn, Mo, Zn, Fe, Co contents, experimentation is such as
Under.
Laboratory apparatus and reagent：
Inductive coupling plasma emission spectrograph (ICP-AES) Shanghai optically focused tech equipment company ICP-5000, very much
One of assay balance, purity>99.99% high-purity argon gas, air compressor, recirculated cooling water, CEM microwave dissolvers (MARS
SYSTEM), ultra-pure water, nitric acid (top pure grade), hydrogen peroxide (top pure grade), Cu, Ca, Mg, K, Na, P, Mn, Mo, Zn, Fe, Co standards
Solution (100mg/L)
Experimental method：
The foundation of standard working curve：The mixed mark solution for being made through configuring various concentrations of standard working curve
(0.1ppm、1.0ppm、5.0ppm、10.0ppm)。
Sample pre-treatments：Microwave Digestion.Uniform dry sample 0.100g is weighed, is accurate to 0.0001g, in 55mL digestion tubes
In, add 5mL nitric acid, soaked overnight, add 1mL hydrogen peroxide, cover molten sample lid, be placed in pressure pan, place into microwave sample dissolving dress
In putting, set microwave system to clear up program, start to clear up sample.After resolution is fully completed, inner canister is taken out, is positioned over and catches up with sour instrument
On, catch up with acid to remove to solution residue 1mL and be cooled to room temperature, be transferred to water in 10mL volumetric flasks, constant volume, mixed with 100 DEG C of heating
It is even standby.Do reagent blank simultaneously.Instrument condition：Horizontal observed pattern；Rinse pump speed 100rpm；RF power：1150w；Analysis
Pump speed 50rmp；Nebulizer flow 0.6SLM；Analysis time 25s；Secondary air amount 1.0SLM；Cooling gas flow 12SLM.
The content of each element is shown in Table 9 in the ACV measured by both the above method.
Non-volatile inorganic element impurity measurement result in the ACV purity rubric material of table 9
3) chromatography of ions
Instrument and reagent：ICS-3000 types ion chromatograph (Dionex companies of the U.S.), sends out automatically equipped with EG40 leacheates
Raw device, electric conductivity detector and the chromatographic work stations of Chromeleon 6.80；Ionpac AS11-HC types splitter (250mm ×
4mm)；Ionpac AG11-HC types guard columns (50mm × 4mm)；ASRS-ULTRA anion suppressors；OnGuard RP posts are (beautiful
Dionex companies of state), 0.45 filter membrane (Milipore companies)；Ultrapure water system (Pine-Tree companies)；KQ100-DE ultrasounds
Ripple washer (Kunshan Ultrasonic Instruments Co., Ltd.).
Other acylate standard samples such as natrium nitrosum and caproic acid are Sigma companies high purity reagent, and solution used is used
Resistivity is prepared for 18.2M Ω cm ultra-pure waters.
Chromatographic condition：Chromatographic column：IonPac AS11-HC types splitter (250mm x4mm), IonPac AG11-HC types are protected
Guard post (50mm × 4mm)；Mobile phase：The isocratic elution 18min of 15mM KOH；Flow velocity：1.0ml/min；Suppressor regeneration mode：Outside
Water power is added to suppress；Electric conductivity detector detects；Sample size：25μL.With peak area quantification.
Experimental result：
The standard curve of chlorion, nitrate ion and sulfate ion is prepared, as a result as shown in table 10 and Fig. 3.
The chromatography of ions standard liquid compound concentration of table 10 and measurement result
| Concentration of standard solution/ppm | Chlorion peak area | Nitrate anion peak area | Sulfate radical peak area |
| 0.1 | 0.036 | 0.019 | 0.0852 |
| 0.5 | 0.0984 | 0.0581 | 0.1374 |
| 1 | 0.1743 | 0.1134 | 0.2018 |
| 5 | 0.9316 | 0.6301 | 0.8015 |
| 10 | 1.9381 | 1.3298 | 1.7156 |
| 20 | 3.9721 | 2.7854 | 3.4592 |
It is 0.0000601% that chloride ion content, which is calculated in ACV sterling, by Fig. 4 integral result, nitrate anion from
Sub- content is 0.0000141%, sulfate ion content 0.0000341%.
In summary, non-volatile impurities content is seldom in ACV, and sterling definite value is influenceed to ignore.
(3) volatile impurities content determines
In ACV building-up process, organic solvent is inevitably used.In order to verify in sterling with the presence or absence of organic
Dissolvent residual, experiment carry out the detection of volatile organic composition in ACV sterling using headspace gas chromatography.
Key instrument and reagent：The type gas chromatographs of Agilent 6890, flame ionization ditector (FID) (U.S.
Agilent companies), the type head space automatic sampling instruments of Agilent 1888 (Agilent companies of the U.S.), the 10mL ml headspace bottles U.S.
Agilent companies), methanol (GBW06111), ethanol (GBW06112), acetone (GBW06115), acetonitrile (GBW06113), just oneself
Alkane (GBW06116), ethyl acetate (GBW06114) purity rubric material (China National Measuring Science Research Inst.)；Isopropanol, dichloromethane
Alkane standard items (Merck ＆ Co., Inc.).
Instrument condition of work：
Chromatographic column：DB-624 (60m × 0.25mm, 1.40 μm)；Flow rate of carrier gas：Hydrogen 40ml/min, air 400ml/
min；Temperature programming condition：Initial 45 DEG C of holdings 5min, is warming up to 120 DEG C, with 15 DEG C per minute with 7 DEG C per minute of speed
Speed is warming up to 230 DEG C, keeps 15min.
Sample size：1mL, split ratio：Do not shunt.
Heater box：70℃；Loop：90℃；Transmission line：110℃
Experimental procedure：10 μ L methanol, ethanol, acetone, isopropanol, acetonitrile, n-hexane, ethyl acetate, dichloromethane are taken respectively
Alkane solution reference material is dissolved in 990 μ L pure water simultaneously its quality of accurate recording respectively, is placed in ml headspace bottle and is sealed immediately with gland device
The good list for preparing is marked, to be determined.50.00mg (being accurate to 0.01mg) ACVs are weighed respectively in 10mL ml headspace bottles immediately with pressure
Lid device is sealed, to be determined.
The single target quality of table 11 and content record sheet
| Single entitling claims | Single mark quality/mg | Water quality/mg | Single mark content |
| Methanol | 9.65 | 1202.23 | 0.80% |
| Ethanol | 8.66 | 1224.05 | 0.70% |
| Acetonitrile | 9.54 | 1230.00 | 0.77% |
| Acetone | 9.06 | 1222.60 | 0.74% |
| N-hexane | 6.37 | 1236.92 | 0.51% |
| Isopropanol | 8.19 | 1223.00 | 0.67% |
| Chloroform | 9.31 | 1232.95 | 0.75% |
| Ethyl acetate | 9.54 | 1240.18 | 0.76% |
Experimental result：Sample and single target measure are carried out under experiment condition more than, does not detect dissolvent residual.
5th, the definite value result of ACV purity rubric material
The result principal component purity of purity definite value combines the result of definite value using 10 laboratories, deducts moisture, non-volatile
Property, volatile impurity etc..Definite value formula is as follows：
P=P0× [100%-Xw-Xn-Xv] × 100%.
Wherein, XwFor biodiversity percentage composition, XnFor non-volatile impurities weight/mass percentage composition, XvFor volatile impurity
Weight/mass percentage composition.
The ACV definite value result (%) of table 12
6th, Evaluation of Uncertainty
The uncertainty of ACV purity rubric material is made up of three parts：The uneven introducing of standard substance it is not true
Fixed degree；The uncertainty of the unstable introducing of standard substance；The uncertainty that the definite value process of standard substance introduces.
ACV purity rubric material uncertainty source analysis and rate the process are as shown in Figure 5.
(1) uncertainty that uniformity introduces
Uniformity assessment is carried out using one-way analysis of variance method.The then standard deviation s of uniformityHFormula meter can be used
Calculate：
In formula：sHFor uniformity standard deviation；For between-group variance；For intra-class variance；N is pendulous frequency in group.
In this case, sHIt is equal to partial uncertainty u caused by inhomogeneities between bottlebb, as formula
ubb=sH=0.0062%.
(2) uncertainty that stability introduces
According to the data of table 2, the uncertainty u for the long-time stability introducing that the term of validity is 6 monthsltsIt is as follows：ults=s
(b1) X=0.000508% × 6=0.00305%
The uncertainty u introduced according to the data of table 3, short-term stabilitystsIt is calculated as follows：
At 20 DEG C：usts1=s (b1) X=0.00201% × 9=0.018%
At 40 DEG C：usts2=s (b1) X=0.00378% × 9=0.034%
At 60 DEG C：usts3=s (b1) X=0.00010% × 9=0.029%
So：Using maximum uncertainty usts2=0.034% is the uncertainty of short-term stability.
(3) uncertainty that definite value introduces
1) uncertainty that principal component purity definite value introduces
Using the average value of the result of the cooperation definite value measured value new as one group, the standard deviation conduct of this group of measured value is taken
The uncertainty of more definite values,
Each composition uncertainty that response difference introduces under different Detection wavelengths:
In formula, BimaxλFor the largest percentage content of the impurity component i under 5 Detection wavelengths；
BI definite values λFor the degree of impurity component i under definite value wavelength；
u2-iFor impurity component i partial uncertainty.
The response of each wavelength and uncertainty evaluation result, as shown in table 13.
The ACV Detection wavelength of table 13 introduces the evaluation of uncertainty
Liquid chromatogram measuring combined standard uncertainty:
2) uncertainty that moisture introduces
Balance claims the partial uncertainty very little that sample introduces, so the main uncertain source of moisture measurement is the weight of measurement
Renaturation uA, the measurement result X of moisturewFor 0.022%, standard deviation 0.001%, because determination of moisture is uncertain larger,
Therefore the uncertainty that determination of moisture introduces:u(XW)=0.022%.
3) uncertainty that other impurities introduce
Balance claims the partial uncertainty very little that sample introduces, so the mainly uncertain source of non-volatile impurities measurement is
The repeated u of measurementA, the measurement result X of non-volatile impuritiesnFor 0.00617%, because part inorganic elements is by environment, instrument
Background have a great influence, therefore, by the measurement result of non-volatile impurities be designated as non-volatile impurities measure uncertainty:u
(Xn)=0.00617%.
4) relative uncertainty degree that purity definite value introduces
5) standard uncertainty that purity definite value introduces
uchar=99.5% × uchar,rel=0.193%
(4) uncertainty of standard substance
The uncertainty of ACV purity rubric material definite value result by valued methods, standard substance inhomogeneities and
The uncertainty three parts composition that unstability is brought.The overall uncertainty calculation formula of standard substance is as follows：
Expanded uncertainty is：UCRM=k × uCRM=0.4% (k=2).
7th, ACV purity rubric material definite value result
In summary, the value of ACV purity rubric material and uncertainty are as shown in table 14.
Purity, the uncertainty of the ACV purity rubric material of table 14
| Composition | Value/% | Uncertainty/% (k=2) |
| ACV purity | 99.5 | 0.4 |
Above-mentioned is the ACV purity rubric material STABILITY MONITORING of 6 months, and sample refrigerates the bar being kept in dark place at 4 DEG C
Characteristic magnitude is stable under part.
Using：
1st, for evaluation analysis method：
Precise ACV purity rubric material, is configured to standard working solution, in blank using weight-volumetric method
The standard working solution is added in animal-derived food (chicken, egg) etc., is prepared into positive.5g animal-derived foods are weighed,
Using adding 2% trichloroacetic acid solution/acetonitrile (80:20) 10mL is extracted, and is homogenized 1min, concussion extraction 15min, 10000r/min
5min is centrifuged, takes supernatant to pass sequentially through MCX posts, ammoniacal liquor methanol 3mL elutions, eluent, N is collected with test tube2Drying, residue are used
Reserve liquid dissolves, upper machine testing.Measurement result shows that this method rate of recovery in 2.0-200.0ng/g is good, 2,10,50,200
Four concentration rate of recovery respectively reach 89.5%, 87.2%, 90.5% and 91.3%.
2nd, for giving material definite value：
20mg determinands Sparfloxacin and 10mg ACVs standard substance are dissolved in the deuterated acetic acid solvents of 2mL altogether,
After abundant dissolving, it is to be measured into quartzy nuclear magnetic tube to pipette 0.80mL, while by determinand Sparfloxacin and ethylparaben point
The ownership for determining chemical shift in deuterated acetic acid as reference sample is not dissolved in.The parameter of quantitative nuclear-magnetism measure is as follows：Nuclear-magnetism
Model：Avance III 400MHz, 1H NMR location parameters：90 °, sampling time 3.9846s of excitation pulse angle, sweep length：
8223.43Hz, relaxation delay 60s, add up sampling 16 times, probe temperature 293.4K, offset frequency：2464.5137Hz, receive and increase
Benefit 64.00, pulse train zg30；Electronic balance：UMX2, Mettler Toledo companies of Switzerland (scale division value：0.01mg)；It is deuterated
Reagent：Deuterated acetic acid (sigma companies of the U.S.).By compared with ACV and Sparfloxacin nuclear-magnetism figure, it may be determined that add
Ownership of the ACV as each proton peak in interior target Sparfloxacin sample, and the proton corresponding to clearly each proton peak
Number.Select that peak shape is sharp, non-interfering quantitative peak, calculated according to following nuclear-magnetism quantitative equation, Sparfloxacin purity is carried out
Definite value.Definite value result is as shown in Table 15.
In formula：PNMRThe purity of-the measured object measured using nuclear magnetic resonance method；
Ix- sample specifies the integral area at peak；
Istd- internal standard compound specifies the integral area at peak；
nstd- internal standard compound specifies the nuclear colony core number at peak；
nx- sample specifies the nuclear colony core number at peak；
MxThe molecular weight of-sample；
MstdThe molecular weight of-internal standard compound；
mstdThe quality of the internal standard compound of-addition；
mxThe sample weighting amount of-sample；
PstdThe purity of-internal standard compound.
The Sparfloxacin purity Coriolis mass fraction nuclear-magnetism definite value result of table 15
Chicken drug residue measurement for outlet is fixed, and carrying out ACV in outlet chicken using national standard method detects
Outside, it is also necessary to which, using ACV standard substance, concrete operations are：Using the ACV purity rubric material of known purity,
Using gravimetric method preparing standard solution, drawing curve, meanwhile, by the testing sample obtained after sample treatment with
Standard working solution is detected by liquid chromatogram or liquid chromatography mass together, passes through Ah former times in calculated by peak area testing sample
Content is just directly traceable to SI units by this purity rubric material in Lip river Wei content, so energy sample to be analysed, adds number
According to accuracy, comparativity and tractability.
Claims (9)
1. the preparation method of ACV purity rubric material, comprises the following steps：
1) ACV material powder is sampled, the ACV raw material is determined using high performance liquid chromatography area normalization method
The weight/mass percentage composition of ACV in powder, obtain the purity definite value of the ACV material powder；
2) biodiversity percentage composition, non-volatile impurities weight/mass percentage composition in the ACV material powder are determined and is had
Machine volatile impurity weight/mass percentage composition, with reference to the purity definite value of the ACV material powder determined in step 1), press
Calculated according to equation below I, that is, obtain the ACV purity rubric material of definite value；
P=P0× [100%-Xw-Xn-XvThe formula of] × 100% I；
Wherein, P be ACV purity rubric material definite value, P0For the purity definite value of ACV material powder, XwFor moisture
Weight/mass percentage composition, XnFor non-volatile impurities weight/mass percentage composition, XvFor organic volatile impurities weight/mass percentage composition.
2. according to the method for claim 1, it is characterised in that：The purity of the ACV material powder be 99.1~
99.9%；
Using the weight/mass percentage composition of ACV in ACV material powder described in multiple laboratory simultaneous determinations；
Also include using JJG 1006-1994 to ACV material powder sampling in step 1)《Primary standard material skill
Art specification》Requirement using method of analysis of variance carry out uniformity testing and using line fitting approach carry out stability test step
Suddenly.
3. method according to claim 1 or 2, it is characterised in that：The color of the high performance liquid chromatography area normalization method
Spectral condition is as follows：
Chromatographic column：SB-Aq(250mm×4.6mm,5.0μm)；Mobile phase：Be made up of methanol and trifluoroacetic acid aqueous solution, methanol with
The volume parts ratio of trifluoroacetic acid aqueous solution is 5：95, the volume parts ratio of trifluoroacetic acid and water in trifluoroacetic acid aqueous solution is
0.001:100；Flow velocity：1.0mL/min；Sample size：20μL；UV wavelength：254nm；HPLC：
100~1000mg/L ACV methanol solution is formulated as during the ACV material powder measure.
4. according to the method any one of claim 1-3, it is characterised in that：Also include in step 1) to the Ah former times Lip river
The purity definite value of Wei material powder carries out the step of test of normality.
5. according to the method for claim 4, it is characterised in that：Also include in step 1) to the ACV material powder
Purity definite value using Cochran criterion reject array in dubious value the step of；
The calculation formula of the Cochran criterion：Table look-up to obtain C (α, m, n)；
Wherein, C be the ACV material powder purity definite value statistic, smaxFor standard deviation maximum in measurement group
Difference；siFor the standard deviation of i-th group of measured value；C (α, m, n) is Cochran-test value；
As C ＞ C (α, m, n), it is dubious value array, should be removed；As C ＜ C (α, m, n), without suspicious array, should retain；
The purity value data of ACV material powder described in multiple laboratory simultaneous determinations is carried out using Rod Dixon criterion
Statistical check.
6. according to the method any one of claim 1-5, it is characterised in that：The Ah former times is determined using Karl_Fischer method
Moisture in the Wei material powder of Lip river；
Non-volatile impurities weight/mass percentage composition uses micro-wave digestion-inductively coupled plasma in the ACV material powder
Constitution spectrometry, micro-wave digestion-inductively coupled plasma emission spectrography and ion-chromatographic determination；Micro-wave digestion-the electricity
Feel coupled plasma mass measure non-volatile impurities in As, Se, Cd, Mn, Sn, Li, Cr, Cs, Ni, Pb, Sr, Rb,
At least one of Ti and Ba content；The micro-wave digestion-inductively coupled plasma emission spectrography measure is described non-volatile
At least one of Cu, Ca, Mg, K, Na, P, Mn, Mo, Zn, Fe and Co in property impurity content；The ion-chromatographic determination
The content of chlorion, nitrate ion and sulfate ion；
Organic volatile impurities weight/mass percentage composition described in the ACV material powder is determined using headspace gas chromatography.
7. according to the method any one of claim 1-6, it is characterised in that：Also include in step 2) pure to ACV
The step of spending the definite value progress analysis on Uncertainty of standard substance.
8. the ACV purity rubric material for the definite value that the method any one of claim 1-7 obtains.
9. ACV purity rubric material described in claim 8 is following 1) -6) application in any one：
1) it is applied in agricultural product production field of circulation herbal medicine and/or feed product ACV into go-on-go as standard substance
Survey；
2) ACV medicament residue detects in animal products in field of food；
3) testing laboratory's quality control；
4) analytical instrument is calibrated as standard substance；
5) analysis method confirms evaluation；
6) to giving material definite value.
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