CN104997806A - Compound sodium acetate ringer injection and preparation method and quality control method thereof - Google Patents
Compound sodium acetate ringer injection and preparation method and quality control method thereof Download PDFInfo
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Abstract
The invention discloses a compound sodium acetate ringer injection. The compound sodium acetate ringer injection is composed of the following effective ingredients of sodium chloride, potassium chloride, magnesium chloride, sodium acetate, sodium citrate, calcium gluconate, anhydrous dextrose, activated carbon, diluted hydrochloric acid and water for injection. A preparation method of the compound sodium acetate ringer injection comprises the steps of weighing, concentrated preparation, diluted preparation, solution pH value adjustment, decarbonization, filtration, sterilization and packaging; a quality control method of the compound sodium acetate ringer injection comprises the detection of the calcium gluconate, the sodium acetate, the sodium citrate, the sodium chloride, the magnesium chloride and the potassium chloride. The compound sodium acetate ringer injection is safe, wide in application and free of toxic and side effects; the preparation method is simple and convenient in production operation, short in preparation time and low in cost, and the quality control method has the advantages that the precision of measured results is improved, the service life of an instrument is prolonged, and it is guaranteed that the clinic use of the injection is safer and more effective.
Description
Technical field
The present invention relates to medical art, particularly a kind of compound sodium acetate ringer's injection and preparation method thereof and method of quality control.
Background technology
Sodium acetate ringer injection is the alkalescence crystalloid fluid that a new generation is physiological, safe, and can find prescription information on U.S. FDA website, its component is: sodium chloride, potassium chloride, calcium chloride, sodium acetate, at present domestic list marketing.Relative to sodium lactate ringer's injection, there is following advantage: acetic Acid Metabolism speed is fast, does not cause body accumulation after infusion; Acetic acid does not raise blood lactase acid level, safer to the patient with severe symptoms itself with high lactate level; Acetic Acid Metabolism does not rely on liver and kidney, is applicable to the hepatic and renal function impaired subjects not tolerating lactic acid; For isotonicity solution, not easily cause hypo-osmoticity tissue edema.
The preparation method of the sodium acetate ringer injection that prior art is announced, its roughly step be first join sodium chloride with moistening needle-use activated carbon is dense, then reflux, be filtered in dilute preparing tank, join sodium acetate with moistening needle-use activated carbon is dense again, then reflux, be filtered in dilute preparing tank, finally rarely join standardize solution, backflow is adjust ph to 6.0 ~ 7.5 also, the qualified rear filtration fill of sample examination, with water-bath type sterilizing cabinet pressure sterilizing 110-120 DEG C, 25-35 minute.Existing employing needle-use activated carbon carries out dense method of joining and there is following problem: active carbon in an acidic solution absorption affinity is the strongest, in alkaline solution, (more than pH6-8) there will be peptization phenomenon and De contamination effect, thus impurity in increase medicinal liquid, and this kind is alkalescence crystalloid fluid, pH value is 7.0-8.0, if carry out dense joining there will be peptization and De contamination phenomenon with needle-use activated carbon, thus increase the impurity in medicinal liquid, the quality of impact transfusion; Sodium acetate ringer injection is electrolytes transfusion, first-selected overkill method should carry out sterilizing, and the probability of surviving method that existing preparation method adopts carries out sterilizing, does not meet " chemical drugs injection main technique requirements "; Existing preparation method production operation is complicated, and the preparation time is long, waste production cost.
About the method for quality control of sodium acetate ringer injection, prior art adopts titrimetry to the detection of calcium gluconate, take C.I. 14645. as indicator, use Calcium Disodium Versenate titration, and the requirement of titrimetry to operator is high, anthropic factor has a great impact measurement result, and therefore, degree of accuracy is not high; Although the detection of sodium acetate, sodium citrate adopts high performance liquid chromatography, the pH of mobile phase is lower (being generally 1.86), reduces the service life of chromatographic column, and the range of choice of chromatographic column is narrower.
Summary of the invention
The object of the invention is to the shortcoming overcoming prior art, a kind of compound sodium acetate ringer's injection be provided, this compound sodium acetate ringer's injection safely, be widely used, have no side effect;
Another object of the present invention is to the preparation method providing compound sodium acetate ringer's injection, it is safer that the method has the injection that production operation is easy, the preparation time is short, cost is low, adopt the method to prepare.
Another object of the present invention is the method for quality control providing compound sodium acetate ringer's injection, and the method increase the degree of accuracy of measurement result, extend the service life of instrument, Clinical practice is safer, effective.
Object of the present invention is achieved through the following technical solutions: a kind of compound sodium acetate ringer's injection, is made up of following effective ingredient:
Preferably, be made up of following effective ingredient:
The preparation method of compound sodium acetate ringer's injection, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, sodium chloride concentration is made to be 2 ~ 8%, stirring and dissolving, add 2/3 of active carbon total amount, boil 12 ~ 20min, be cooled to 95 ~ 105 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 12 ~ 18min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 12 ~ 18min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 5.5 ~ 6.0 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount; S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, filling and sealing, high temperature hot pressing sterilizing, lamp inspection, packs and obtains compound sodium acetate ringer's injection.
Further, fill described in step S5 is that fill is in the vertical polypropylene transfusion bag or polypropylene transfusion bottle of 250ml or 500ml.
Further, high temperature hot pressing sterilising temp described in step S5 is 121 DEG C, sterilization time is 12min.
The method of quality control of compound sodium acetate ringer's injection, it comprises the following steps:
(1) calcium gluconate detects
A. prepare need testing solution: precision measures this product 5.0ml, put in 100ml measuring bottle, add lanthanum solution 2.0ml, be diluted with water to scale, shake up, to obtain final product;
B. preparation standard product solution: precision measures calcium single element standard solution 1000 μ g/ml 5.0ml in 50ml measuring bottle, is diluted with water to scale, as calcium single element standard substance stock solution; Precision measures calcium single element standard substance stock solution 2.0ml, 3.0ml, 4.0ml respectively, puts in 100ml measuring bottle, adds lanthanum solution 2.0ml, be diluted with water to scale, shake up, to obtain final product;
C. measure: getting standard solution and need testing solution, according to atomic absorption spectrophotometry, take water as blank, measure light absorption value at 422.7nm wavelength place, calculate content by external standard method;
Standard limits: should be 90.0% ~ 110.0% of labelled amount.
Computing formula:
In formula, C
ca concentrationfor recording Ca mass concentration, μ g/ml.
(2) sodium acetate, sodium citrate detect
D. reference substance solution is prepared: precision takes citric acid reference substance 10mg in 10ml measuring bottle, is dissolved in water and is diluted to scale, shaking up, as citric acid reference substance stock solution; Another precision takes sodium acetate reference substance 10mg in 10ml measuring bottle, after adding citric acid reference substance stock solution 2.0ml, is diluted to scale, shakes up, to obtain final product with mobile phase;
E. preparing need testing solution: get this product 5ml in 10ml measuring bottle, be diluted to scale with mobile phase, is need testing solution;
F. measure: get need testing solution and each 20 μ l of reference substance solution respectively, injection liquid chromatography, record chromatogram, by external standard method with the content of calculated by peak area sodium acetate and sodium citrate; Standard limits: should be 90.0% ~ 110.0% of labelled amount.
In formula, A
samplethe peak area of sodium acetate, citric acid test solution respectively,
A
rightthe peak area of sodium acetate, citric acid reference substance solution respectively,
C
rightsodium acetate, citric acid reference substance solution concentration respectively, unit mg/ml.
Wherein, chromatographic condition is:
Mobile phase: water, with phosphoric acid adjust pH to 2.0; Chromatographic column: octadecylsilane chemically bonded silica is filler;
Column temperature: 30 DEG C; Flow velocity: 1.0ml/min;
Determined wavelength: 215nm; Sampling volume: 20 μ l;
(3) detection of sodium chloride
G. preparation standard product solution: precision measure concentration be the sodium single element standard solution 3.0ml of 1000 μ g/ml in 100ml measuring bottle, be diluted with water to scale, as sodium single element standard substance stock solution; Measured sodium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml by precision respectively, respectively add caesium solution 2.0m, put in 100ml measuring bottle, be diluted with water to scale, shake up, to obtain final product; H. prepare need testing solution: precision measures this product 3.0ml, put in 250ml measuring bottle, be diluted with water to scale, shake up; Precision measures 2.0ml, puts in 100ml measuring bottle, adds caesium solution 2.0ml, is diluted with water to scale, shakes up, to obtain final product;
I. measure: get standard solution and need testing solution, measure at the wavelength place of 589nm according to atomic absorption spectrophotometry, calculate content;
In formula, W
1for the sodium chloride total amount surveyed in 1ml this product, unit is mg;
W
2for the sodium acetate total amount surveyed in 1ml this product, unit is mg;
W
3for the citric acid total amount surveyed in 1ml this product, unit is mg;
(4) mensuration of potassium chloride
J. preparation standard product solution: precision measure concentration be the potassium single element standard solution 2.0ml of 1000 μ g/ml in 50ml measuring bottle, be diluted with water to scale, as potassium single element standard substance stock solution; Precision measures potassium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, puts in 100ml measuring bottle, respectively adds cesium chloride solution 2.0ml, be diluted to scale with deionized water, shake up, to obtain final product;
K. prepare need testing solution: precision measures this product 10.0ml, put in 100ml measuring bottle, add deionized water and be diluted to scale, shake up; Precision measures 5.0ml, puts in 100ml measuring bottle, adds cesium chloride solution 2.0ml, adds deionized water and is diluted to scale, shake up;
L. measure: get standard solution and need testing solution, measure at the wavelength place of 766.5nm according to atomic absorption spectrophotometry, calculate content;
in formula: C
k+for the detected value of dilute sample
(5) mensuration of magnesium chloride
M. preparation standard product solution: precision measure concentration be 1000 μ g/ml magnesium single element standard solution 1.0ml in 100ml measuring bottle, be diluted with water to scale, as magnesium single element standard substance stock solution; Precision measures magnesium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, respectively adds lanthanum solution 5ml, puts in 100ml measuring bottle, be diluted to scale with deionized water, shake up, to obtain final product; N. prepare need testing solution: precision measures this product 1.0ml, add lanthanum solution 5ml, put in 100ml measuring bottle, add deionized water and be diluted to scale, shake up, to obtain final product;
O. measure: get standard solution and need testing solution, measure at the wavelength place of 285.2nm according to atomic absorption spectrophotometry, calculate content;
in formula: C
mg2+for the detected value of dilute sample
Wherein, described caesium solution gets 5.0g cesium chloride dissolve in 1% salpeter solution and be diluted to 100ml; Described lanthanum solution takes lanthanum chloride 6.6g, is diluted with water to 100ml with 0.1mol/L dissolving with hydrochloric acid.
This product is colourless or almost colourless clear liquid, is the sterile water solution of sodium chloride, potassium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium gluconate and glucose.Sodium chloride-containing (NaCl), potassium chloride (KCl), magnesium chloride (MgCl
26H
2o), sodium acetate (C
2h
3naO
23H
2o), sodium citrate (C
6h
22o
7na
32H
2o), calcium gluconate (C
12h
22caO
14h
2o) with glucose (C
6h
12o
6) all should be 90.0% ~ 110.0% of labelled amount.
The present invention has the following advantages: the invention provides a kind of compound sodium acetate ringer's injection, and this compound sodium acetate ringer's injection is a kind of is alkaline components containing sodium acetate, the electrolyte transfusion of 1% glucose.Sodium acetate replaces sodium lactate, avoids the accumulate poisoning phenomenon that a large amount of infusion lactate produces; The glucose of 1% avoids Hyperglycemia and glucose in urine occurs, body fat alienation when preventing liver function low.Because of its pH value, liquid is closest outward for the molar concentration of osmotic pressure and contained various particle and human body cell, pretends as balance liquid is applied widely clinically.Balance for supplementing extracellular fluid under other situations, keeping the skin wet and maintaining cylinder electrolyte, supply when reducing for circulation volume and interstitial fluid, corrects metabolic acidosis;
Preparation method dilute hydrochloric acid of the present invention adjusts solution ph to be 5.5 ~ 6.0, therefore there will not be peptization phenomenon and De contamination effect, thus reduces the impurity in medicinal liquid; Adopt high temperature hot pressing sterilizing (temperature be 121 DEG C, sterilization time be 12min) in the present invention, sterilization effect is better, has the advantage that production operation is easy, the preparation time is short, cost is low, and the injection adopting the method to prepare is safer; In the present invention, atom absorption method is adopted to the detection of calcium gluconate, the error of anthropic factor is eliminated compared to traditional titrimetry, improve the accuracy of measurement result, the detection mobile phase pH value of sodium acetate, sodium citrate is adjusted to 2.0, extend the service life of chromatographic column, widen the range of choice of chromatographic column, make selection more flexible, the present invention also measures the content of sodium chloride, magnesium chloride, potassium chloride, and method of quality control of the present invention makes the Clinical practice of compound sodium acetate ringer's injection safer, effective.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, and protection scope of the present invention is not limited to the following stated:
Embodiment 1: a kind of compound sodium acetate ringer's injection, is made up of following effective ingredient: sodium chloride: 5.000g; Potassium chloride: 0.150g; Magnesium chloride: 0.150g; Sodium acetate: 3.000g; Sodium citrate: 0.550g; Calcium gluconate: 0.624g; Anhydrous glucose: 9g; Active carbon: 0.7g; Dilute hydrochloric acid: 1ml; Water for injection adds to 1000ml.
The preparation method of compound sodium acetate ringer's injection, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, make sodium chloride concentration be 2%, stirring and dissolving, adds 2/3 of active carbon total amount, boils 12min, be cooled to 60 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 12min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 12min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 5.5 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount;
S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, fill is in 250ml vertical polypropylene transfusion bag and seal, high temperature hot pressing sterilizing, and sterilising temp is 121 DEG C, sterilization time is 12min, lamp inspection after sterilizing, packs and obtains compound sodium acetate ringer's injection.
Embodiment 2: a kind of compound sodium acetate ringer's injection, is made up of following effective ingredient: sodium chloride: 7.000g; Potassium chloride: 0.372g; Magnesium chloride: 0.298g; Sodium acetate: 4.000g; Sodium citrate: 0.647g; Calcium gluconate: 0.748g; Anhydrous glucose: 12g; Active carbon: 1.2g; Dilute hydrochloric acid: 3ml; Water for injection adds to 1000ml.
The preparation method of compound sodium acetate ringer's injection, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, make sodium chloride concentration be 8%, stirring and dissolving, adds 2/3 of active carbon total amount, boils 20min, be cooled to 80 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 18min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 18min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 6.0 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount;
S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, fill is in the polypropylene transfusion bottle of 500ml and seal, high temperature hot pressing sterilizing, and sterilising temp is 121 DEG C, sterilization time is 12min, lamp inspection after sterilizing, packs and obtains compound sodium acetate ringer's injection.
Embodiment 3: a kind of compound sodium acetate ringer's injection, is made up of following effective ingredient: sodium chloride: 5.432g; Potassium chloride: 0.341g; Magnesium chloride: 0.180g; Sodium acetate: 3.832g; Sodium citrate: 0.627g; Calcium gluconate: 0.700g; Anhydrous glucose: 11g; Active carbon: 0.8g; Dilute hydrochloric acid: 1.67; Water for injection adds to 1000ml.
The preparation method of compound sodium acetate ringer's injection, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, make sodium chloride concentration be 3%, stirring and dissolving, adds 2/3 of active carbon total amount, boils 14min, be cooled to 68 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 14min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 14min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 5.6 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount;
S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, fill is in the vertical polypropylene transfusion bag of 500ml and seal, high temperature hot pressing sterilizing, sterilising temp is 121 DEG C, sterilization time is 12min, lamp inspection after sterilizing, packs and obtains compound sodium acetate ringer's injection.
Embodiment 4: a kind of compound sodium acetate ringer's injection, is made up of following effective ingredient: sodium chloride: 6.370g; Potassium chloride: 0.298g; Magnesium chloride: 0.203g; Sodium acetate: 3.402g; Sodium citrate: 0.588g; Calcium gluconate: 0.673g; Anhydrous glucose: 10.0g; Active carbon: 1g; Dilute hydrochloric acid: 2ml; Water for injection adds to 1000ml.
The preparation method of compound sodium acetate ringer's injection, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, make sodium chloride concentration be 5%, stirring and dissolving, adds 2/3 of active carbon total amount, boils 16min, be cooled to 72 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 16min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 16min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 5.7 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount;
S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, fill is in 250ml polypropylene transfusion bottle and seal, high temperature hot pressing sterilizing, and sterilising temp is 121 DEG C, sterilization time is 12min, lamp inspection after sterilizing, packs and obtains compound sodium acetate ringer's injection.
Embodiment 5: a kind of compound sodium acetate ringer's injection, is made up of following effective ingredient: sodium chloride: 5.241g; Potassium chloride: 0.150g; Magnesium chloride: 0.253g; Sodium acetate: 4.000g; Sodium citrate: 0.578g; Calcium gluconate: 0.725g; Anhydrous glucose: 11g; Active carbon: 1.1g; Dilute hydrochloric acid: 2.5ml; Water for injection adds to 1000ml.
The preparation method of compound sodium acetate ringer's injection, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, make sodium chloride concentration be 7%, stirring and dissolving, adds 2/3 of active carbon total amount, boils 18min, be cooled to 62 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 16min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 16min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 6.0 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount;
S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, fill is in 250ml polypropylene transfusion bottle and seal, high temperature hot pressing sterilizing, and sterilising temp is 121 DEG C, sterilization time is 12min, lamp inspection after sterilizing, packs and obtains compound sodium acetate ringer's injection.
Embodiment 6: the method for quality control of compound sodium acetate ringer's injection, it comprises the following steps:
1. detection method
(1) calcium gluconate detects
A. prepare need testing solution: precision measures this product 5.0ml, put in 100ml measuring bottle, add lanthanum solution 2.0ml, be diluted with water to scale, shake up, to obtain final product;
B. preparation standard product solution: precision measures calcium single element standard solution 1000 μ g/ml 5.0ml in 50ml measuring bottle, is diluted with water to scale, as calcium single element standard substance stock solution; Precision measures calcium single element standard substance stock solution 2.0ml, 3.0ml, 4.0ml respectively, puts in 100ml measuring bottle, adds lanthanum solution 2.0ml, be diluted with water to scale, shake up, to obtain final product;
C. measure: getting standard solution and need testing solution, according to atomic absorption spectrophotometry, take water as blank, measure light absorption value at 422.7nm wavelength place, calculate content by external standard method;
Standard limits: should be 90.0% ~ 110.0% of labelled amount.
Computing formula:
In formula, C
ca concentrationfor recording Ca mass concentration, μ g/ml.
(2) sodium acetate, sodium citrate detect
D. reference substance solution is prepared: precision takes citric acid reference substance 10mg in 10ml measuring bottle, is dissolved in water and is diluted to scale, shaking up, as citric acid reference substance stock solution; Another precision takes sodium acetate reference substance 10mg in 10ml measuring bottle, after adding citric acid reference substance stock solution 2.0ml, is diluted to scale, shakes up, to obtain final product with mobile phase;
E. preparing need testing solution: get this product 5ml in 10ml measuring bottle, be diluted to scale with mobile phase, is need testing solution;
F. measure: get need testing solution and each 20 μ l of reference substance solution respectively, injection liquid chromatography, record chromatogram, by external standard method with the content of calculated by peak area sodium acetate and sodium citrate; Standard limits: should be 90.0% ~ 110.0% of labelled amount.
In formula, A
samplethe peak area of sodium acetate, citric acid test solution respectively,
A
rightthe peak area of sodium acetate, citric acid reference substance solution respectively,
C
rightsodium acetate, citric acid reference substance solution concentration respectively, unit mg/ml.
Wherein, chromatographic condition is:
Mobile phase: water, with phosphoric acid adjust pH to 2.0;
Chromatographic column: octadecylsilane chemically bonded silica is filler, C
18, 5 μm, 250 × 4.6mm;
Column temperature: 30 DEG C; Flow velocity: 1.0ml/min;
Determined wavelength: 215nm; Sampling volume: 20 μ l.
(3) detection of sodium chloride
G. preparation standard product solution: precision measure concentration be the sodium single element standard solution 3.0ml of 1000 μ g/ml in 100ml measuring bottle, be diluted with water to scale, as sodium single element standard substance stock solution; Measured sodium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml by precision respectively, respectively add caesium solution 2.0m, put in 100ml measuring bottle, be diluted with water to scale, shake up, to obtain final product; H. prepare need testing solution: precision measures this product 3.0ml, put in 250ml measuring bottle, be diluted with water to scale, shake up; Precision measures 2.0ml, puts in 100ml measuring bottle, adds caesium solution 2.0ml, is diluted with water to scale, shakes up, to obtain final product;
I. measure: get standard solution and need testing solution, measure at the wavelength place of 589nm according to atomic absorption spectrophotometry, calculate content;
In formula, W
1for the sodium chloride total amount surveyed in 1ml this product, unit is mg;
W
2for the sodium acetate total amount surveyed in 1ml this product, unit is mg;
W
3for the citric acid total amount surveyed in 1ml this product, unit is mg;
(4) mensuration of potassium chloride
J. preparation standard product solution: precision measure concentration be the potassium single element standard solution 2.0ml of 1000 μ g/ml in 50ml measuring bottle, be diluted with water to scale, as potassium single element standard substance stock solution; Precision measures potassium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, puts in 100ml measuring bottle, respectively adds cesium chloride solution 2.0ml, be diluted to scale with deionized water, shake up, to obtain final product;
K. prepare need testing solution: precision measures this product 10.0ml, put in 100ml measuring bottle, add deionized water and be diluted to scale, shake up; Precision measures 5.0ml, puts in 100ml measuring bottle, adds cesium chloride solution 2.0ml, adds deionized water and is diluted to scale, shake up;
L. measure: get standard solution and need testing solution, measure at the wavelength place of 766.5nm according to atomic absorption spectrophotometry, calculate content;
in formula: C
k+for the detected value of dilute sample
(5) mensuration of magnesium chloride
M. preparation standard product solution: precision measure concentration be 1000 μ g/ml magnesium single element standard solution 1.0ml in 100ml measuring bottle, be diluted with water to scale, as magnesium single element standard substance stock solution; Precision measures magnesium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, respectively adds lanthanum solution 5ml, puts in 100ml measuring bottle, be diluted to scale with deionized water, shake up, to obtain final product; N. prepare need testing solution: precision measures this product 1.0ml, add lanthanum solution 5ml, put in 100ml measuring bottle, add deionized water and be diluted to scale, shake up, to obtain final product;
O. measure: get standard solution and need testing solution, measure at the wavelength place of 285.2nm according to atomic absorption spectrophotometry, calculate content;
in formula: C
mg2+for the detected value of dilute sample
Wherein, above-mentioned caesium solution gets 5.0g cesium chloride dissolve in 1% salpeter solution and be diluted to 100ml; Described lanthanum solution takes lanthanum chloride 6.6g, is diluted with water to 100ml with 0.1mol/L dissolving with hydrochloric acid.
2. testing result
(1) calcium gluconate testing result: in table 1.
Table 1: the gluconic acid calcium content of embodiment 1-5 compound sodium acetate ringer's injection
| Title | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Calcium gluconate labelled amount |
| Content (%) | 93.5 | 109.2 | 104.5 | 101.1 | 106.5 | 0.673g/1000ml |
(2) sodium acetate, sodium citrate testing result: in table 2, table 3.
Table 2: the sodium acetate content of embodiment 1-5 compound sodium acetate ringer's injection
| Title | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Sodium acetate labelled amount |
| Content (%) | 91.18 | 118.32 | 112.50 | 100.96 | 117.89 | 3.402g/1000ml |
Table 3: the sodium citrate content of embodiment 1-5 compound sodium acetate ringer's injection
| Title | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Sodium citrate labelled amount |
| Content (%) | 94.25 | 109.58 | 106.32 | 99.81 | 97.65 | 0.588g/1000ml |
Table 4: the sodium chloride content of embodiment 1-5 compound sodium acetate ringer's injection
| Title | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Sodium chloride labelled amount |
| Content (%) | 79.86 | 108.65 | 87.13 | 101.64 | 83.75 | 6.73g/1000ml |
Table 5: the KCE content of embodiment 1-5 compound sodium acetate ringer's injection
| Title | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Potassium chloride labelled amount |
| Content (%) | 51.23 | 123.95 | 114.02 | 100.65 | 51.06 | 0.298g/1000ml |
Table 4: the content of magnesium chloride of embodiment 1-5 compound sodium acetate ringer's injection
| Title | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Magnesium chloride labelled amount |
| Content (%) | 74.31 | 145.88 | 88.93 | 100.50 | 124.25 | 0.203g/1000ml |
Below by way of description of test beneficial effect of the present invention:
1. the Method validation experiment of gluconic acid-ca
1.1 electric eliminating agent consumptions are investigated
Because this product contains multiple cation composition, because degree of ionization in atom flame is different between each cation, there is ionization interference, cause ionization equilibrium to direction movement inconsistent generating ground state atom, thus stable absorption concentration cannot be obtained, according to this phenomenon, we consider the method-add a certain amount of ionization buffer solving ionization interference, investigate conventional ionizer lanthanum chloride consumption.
Divide sample thief 5.0ml in 100ml measuring bottle, add lanthanum chloride solution (concentration 6.6%) 1.0ml, 1.5ml, 2.0ml, 2.5ml, 3.0ml, 4.0ml respectively, be diluted with water to scale, as test solution 1
#, 2
#, 3
#, 4
#, 5
#, 6
#; Get above need testing solution, measure in wavelength 422.7nm wavelength place according to atomic absorption spectrophotometry light method (Chinese Pharmacopoeia version in 2010 two annex IV D), the results are shown in following table 5.
Table 5:
| Addition (ml) | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 |
| Absorbance (A) | 0.205 | 0.209 | 0.210 | 0.210 | 0.210 | 0.212 |
Result of the test shows, when the addition of lanthanum chloride solution is 1.5 ~ 3.0ml, absorbance is comparatively stable, determines that in this law, lanthanum chloride solution addition is 2ml.
1.2 the range of linearity
Precision measures calcium single element standard solution (1000 μ g/ml) 10.0ml and, in 100ml measuring bottle, is diluted with water to scale, shakes up, as calcium single element reference substance stock solution (100 μ g/ml).Precision measures this stock solution 1.0ml, 2.0ml, 3.0ml, 4.0ml, 6.0ml, 8.0ml, 10.0ml in 100ml measuring bottle respectively, and precision adds lanthanum chloride solution (6.6%) 2.0ml, is diluted with water to scale, shakes up.Getting above-mentioned each solution, according to atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D assay first methods), take water as blank, measures, the results are shown in Table 6 at 422.7nm wavelength place.
Table 6:
Result of the test shows, test sample concentration is that take concentration as abscissa (X), trap Y is vertical coordinate in good linear relationship within the scope of 0.991 μ g/ml ~ 5.129 μ g/ml, carry out linear regression, obtain regression equation Y=0.07217X r=0.9982.Investigate result according to the range of linearity, confirmed standard product solution concentration is 2 μ g/ml, 3 μ g/ml, 4 μ g/m; Test sample calcium ion concentration is 3.008 μ g/ml, all in the range of linearity.
1.3 accuracy test
Prepared by test liquid solution: precision takes calcium gluconate 0.5576g, 0.6892g, 0.8164g tri-parts in 100ml measuring bottle, be dissolved in water and be diluted to scale, precision measures each 10.0ml of above-mentioned three strength solution in 100ml measuring bottle respectively, is diluted with water to scale, obtains stock solution 1
#, 2
#, 3
#(calcium gluconate amount is respectively 80%, 100%, 120% of recipe quantity).Precision measures 1 respectively
#~ 3
#the each 5.0ml of stock solution, totally 9 parts (three concentration each three), in 100ml measuring bottle, each precision adds not containing calcium gluconate negative blank auxiliary solution 5.0ml, lanthanum chloride solution 2.0ml, adds water to scale, shakes up, to obtain final product.
Prepared by standard solution: precision measures calcium single element stock solution (100 μ g/ml) 2.0ml, 3.0ml, 4.0ml and, in 100ml measuring bottle, adds lanthanum chloride solution 2.0ml, add water to scale, shake up, to obtain final product respectively.
Getting need testing solution and reference substance solution by atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D), is that blank measures with water, measures at 422.7nm wavelength place, calculates the response rate, the results are shown in Table 7.
Table 7:
Result of the test shows, the method response rate is good, and blank auxiliary is noiseless.
1.4 specificity tests
Get the negative adjuvant solution of the not calcium ions under 1.3, measure by calcium gluconate determination, it absorbs angle value is 0.001, and blank negative adjuvant is noiseless to mensuration.
1.5 precision test
Sample thief, by drafting method, parallel sampling 6 times, investigates method repeatability, the results are shown in Table 8.
Table 8: calcium ion content measures replica test result
| Measure number of times | 1 | 2 | 3 | 4 | 5 | 6 | Meansigma methods | RSD％ |
| Calcium ion concentration μ g/ml | 3.032 | 3.039 | 3.027 | 3.085 | 3.089 | 3.035 | 3.0512 | 0.92 |
Result of the test shows, adopt the method determined, precision is good.
2. the Method validation experiment of sodium citrate, sodium acetate
2.1 ruggedness
2.1.1 column temperature is investigated
Sample thief measures according to high performance liquid chromatography (annex V D), and arranging column temperature is respectively 30 DEG C, 35 DEG C, 40 DEG C, and other chromatographic condition remains unchanged sample introduction, and record chromatogram, result is as shown in table 9.
Table 9:
2.1.2pH investigation is worth
Sample thief measures according to high performance liquid chromatography (annex V D), and preparing pH is respectively 1.6,1.86, the mobile phase of 2.1, and other chromatographic condition remains unchanged sample introduction, and record chromatogram, result is as shown in table 10.
Table 10:
2.1.3 flow velocity is investigated
Sample thief measures according to high performance liquid chromatography (annex V D), and arranging flow velocity is respectively 0.8ml/min, 1.0ml/min, 1.1ml/min, and other chromatographic condition remains unchanged sample introduction, and record chromatogram, result is as shown in table 11.
2.1.4 wavelength is investigated
Sample thief measures according to high performance liquid chromatography (annex V D), and arranging wavelength is respectively 210nm, 215nm, 220nm, and other chromatographic condition remains unchanged sample introduction, and record chromatogram, result is as shown in table 12.
Table 12:
2.1.5 stability of solution
Sample thief measures according to high performance liquid chromatography (annex V D), carries out assay respectively at standing time 0h, 2h, 4h, 8h, 12h, 24h, and other chromatographic condition remains unchanged sample introduction, and record chromatogram, result is as shown in table 13.
2.1.6 chromatographic column is investigated
Sample thief measures according to high performance liquid chromatography (annex V D), assay is carried out by Shimadzu chromatographic column (inertsil ods-3 C184.6*250mm 5um), other chromatographic conditions remain unchanged sample introduction, and record chromatogram, result is as shown in table 14.
Table 14:
2.1.7 ruggedness investigates data summarization, in table 15.
Table 15:
Result of the test shows, the good tolerance of the method.
2.2 the range of linearity
Linear solvent 1#: accurate sodium acetate reference substance 75.08mg and sodium citrate reference substance 15.12mg, put in 50ml volumetric flask, dilute by mobility and be settled to scale, to obtain final product;
Linear solvent 2#: accurate sodium acetate reference substance 62.60mg and sodium citrate reference substance 12.48mg, put in 50ml volumetric flask, dilute by mobility and be settled to scale, to obtain final product;
Linear solvent 3#: accurate sodium acetate reference substance 50.55mg and sodium citrate reference substance 10.06mg, put in 50ml volumetric flask, dilute by mobility and be settled to scale, to obtain final product;
Linear solvent 4#: precision measures 10ml linear solvent 1#, puts in 20ml volumetric flask, dilutes and be settled to scale, to obtain final product by mobility;
Linear solvent 5#: precision measures 10ml linear solvent 3#, puts in 20ml volumetric flask, dilutes and be settled to scale, to obtain final product by mobility.
Get linear solvent, measure according to high performance liquid chromatography (annex V D), record chromatogram, result is shown in table 16.
Table 16:
Result of the test shows, sodium acetate concentration is in 0.5mg/mL ~ 1.5mg/mL scope, and sodium citrate concentration all has good linear within the scope of 0.1mg/mL ~ 0.3mg/mL.
2.3 accuracy
By 80% of sodium acetate in compound sodium acetate ringer's injection and sodium citrate recipe quantity, 100%, 120% takes sodium acetate reference substance (82.42mg respectively, 101.35mg, 119.56mg), citric acid reference substance (16.64mg, 20.56mg, 24.53mg) in 50ml measuring bottle, add not containing sodium acetate and sodium citrate feminine gender blank auxiliary solution to scale, shake up, precision measures above three strength solution 5.0ml (above three groups of concentration, often organize each three of concentration) totally 9 in 10ml measuring bottle, add mobile phase and be diluted to scale, obtain test solution 1 ~ 9, measure according to high performance liquid chromatography (annex V D), calculate the response rate, result is shown in table 17.
Table 17:
Result of the test shows, the sodium acetate method response rate is 99.45%, RSD% is 0.13%; The sodium citrate method response rate is 99.24%, RSD% is 0.11%, and the response rate is good.
2.4 precision
2.4.1 repeated
Sample thief 6 parts, carries out assay according to high performance liquid chromatography (annex V D), and record chromatogram, result is shown in table 18.
Table 18:
Result of the test shows, this law repeatability is good.
2.4.2 Intermediate precision
Different personnel, different time, each sample thief 6 parts, carries out assay according to high performance liquid chromatography (annex V D), and record chromatogram, result is shown in table 19.
Table 19:
Result of the test shows, this law precision is good.
2.5 specificity
By prescription preparation not containing the blank negative sample liquid of sodium acetate, sodium citrate, by legal system available test sample solution below sodium acetate and sodium citrate assay item, get in each 20 μ l injection liquid chromatographies of negative blank test solution, record chromatogram, result shows: under this chromatographic condition, blank auxiliary peak measures noiseless to main peak, the peak-to-peak separating degree of each chromatograph meets the pertinent regulations of Chinese Pharmacopoeia version in 2010 two annex V D, and method specificity is good.
2.6 quantitative limit and repeatability thereof
Get reference substance solution, dilution sample introduction, when signal to noise ratio is about 9 ~ 11, determines quantitative limit, carries out quantitative limit replica test, and record chromatogram, result is shown in table 20.
Table 20:
Result of the test shows, this law sodium acetate is quantitatively limited to 8.088ug/ml, and sodium citrate is quantitatively limited to 4.024ug/ml, and quantitative limit repeatability is good.
3. sodium chloride Method validation experiment
3.1 caesium solution additions investigate (1), the results are shown in Table 21.
Table 21:
Result of the test shows, it is close with the sodium chloride content that do not add measured by caesium solution to add caesium solution, add the mensuration that the sensitivity of caesium measured in solution and correlation coefficient are obviously better than not adding caesium solution, that is measured value precision is higher, closer to actual value.Therefore, we determine in method, add caesium solution.
3.2 caesium solution additions investigate (2), the results are shown in Table 22.
Table 22:
Result of the test shows, when the addition of cesium chloride solution is 1.5 ~ 2.5ml, absorbance is comparatively stable, determines that in this law, cesium chloride solution addition is 2ml.
3.3 the range of linearity
Precision measures sodium single element standard solution (1000 μ g/mL) 3.0mL and, in 100mL measuring bottle, is diluted with water to scale, shakes up, as sodium single element reference substance stock solution (30 μ g/mL).Precision measures this stock solution 0.5ml, 1.0mL, 2.0mL, 3.0mL, 4.0mL in 100mL measuring bottle respectively, respectively adds cesium chloride solution 2ml, is diluted with water to scale, shake up.By above-mentioned each solution, according to atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D assay first methods), measure at 589.0nm wavelength place, the results are shown in Table 23.
Table 23:
Result of the test shows, test sample concentration is that take concentration as abscissa (x), trap (y) is vertical coordinate, carries out linear regression, obtains regression equation y=0.47114x, r in good linear relationship within the scope of 0.15 μ g/mL ~ 1.2 μ g/mL
2=0.9992.
Investigate result according to the range of linearity, confirmed standard product solution concentration is 0.3 μ g/ml, 0.6 μ g/ml, 0.9 μ g/m; Test sample Na ion concentration is about 0.75 μ g/ml, all in the range of linearity.
3.4 accuracy
Prepared by standard solution: precision measures sodium single element standard solution (1000 μ g/ml) 3ml, puts in 100ml measuring bottle, is dissolved in water and is diluted to scale namely to obtain sodium Standard Reserving Solution (30 μ g/ml); Precision measures 1.0ml, 2.0ml, 3.0ml, 4.0ml and splits in 100ml measuring bottle, respectively adds cesium chloride solution 2ml, is diluted with water to scale, shake up, and makes the reference substance solution containing sodium 0.3 μ g, 0.6 μ g, 0.9 μ g, 1.2 μ g in every 1ml respectively.
Prepared by test liquid solution: take the raw material containing sodium ion by compound sodium acetate ringer's injection prescription precision: sodium chloride 0.63500g, sodium acetate 0.34197g, sodium citrate 0.05893g are in 100mL measuring bottle, be dissolved in water and be diluted to scale, as stock solution.Precision measures this solution each 2.4mL, 3.0mL, 3.6mL in 250mL measuring bottle respectively, add not containing the negative adjuvant solution 3.0mL of sodium ion, be diluted with water to scale (each three of above three groups of strength solution), shake up, more therefrom respectively precision measure 2ml, put in 100ml volumetric flask, add cesium chloride 2ml, be diluted with water to scale, shake up, obtain test liquid 1
#~ 9
#.
Get need testing solution and standard solution by atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D), measure at 589.0nm wavelength place, calculate the response rate, the results are shown in Table 24.
Table 24:
Result of the test shows, the method response rate is 98.88%, RSD is 0.63%, therefore method accuracy is good.
3.5 specificity
Get not containing the negative adjuvant solution of sodium ion, measure by sodium ions content algoscopy, it absorbs angle value is 0.000, and blank negative adjuvant is noiseless to mensuration.
3.5.1 precision
3.5.1.1 repeated
Sample thief 6 parts, measure according to above-mentioned sodium chloride content algoscopy, it the results are shown in Table 25.
Table 25:
Result of the test shows, this law repeatability is good.
3.5.1.2 Intermediate precision
Sample thief, shine above-mentioned sodium chloride content algoscopy replication 6 times, add up twice repeated data, it the results are shown in Table 26.
Table 26:
Result of the test shows, this law Intermediate precision is good.
4. potassium chloride Method validation experiment
4.1 ranges of linearity are investigated
Accurate amount potassium single element standard solution (1000 μ g/ml) 2.0ml in 100ml measuring bottle, is diluted with water to scale, shakes up, as sodium single element reference substance stock solution (20 μ g/ml).Precision measures this stock solution 1.0ml, 2.0ml, 4.0ml, 6.0ml, 8.0ml, 10.0ml in 100ml measuring bottle respectively, is diluted with water to scale, shakes up.By above-mentioned each solution, according to atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D), take water as blank, measure at 766.5nm wavelength place, the results are shown in Table 27.
Table 27: the relation of potassium element Atomic Absorption degree and concentration
Result of the test shows, test sample concentration is that take concentration as abscissa (X), trap Y is vertical coordinate, carries out linear regression, obtains regression equation Y=0.1996X r=0.9996 in good linear relationship within the scope of 0.2 μ g/ml ~ 2.0 μ g/ml.Investigate result according to the range of linearity, confirmed standard product solution concentration is 0.4 μ g/ml, 0.8 μ g/ml, 1.2 μ g/m; Test sample potassium concentration is 0.78 μ g/ml, all in the range of linearity.
4.2 accuracy test
Test liquid solution prepare: by potassium chloride in compound sodium acetate ringer's injection recipe quantity 80%, 100%, 120% take potassium chloride 240mg, 300mg, 365mg tri-concentration each three in 100ml measuring bottle, add water and make dissolving in right amount and be diluted to scale, precision measures the blank auxiliary liquid 10ml of each 10ml of above-mentioned solution and not chloride containing potassium in 100ml measuring bottle, be diluted with water to scale, shake up, obtain test sample stock solution 1
#~ 9
#; Precision measures test sample stock solution 1 respectively
#~ 9
#each 5.0ml, adds caesium solution 2.0ml in 100ml measuring bottle, is diluted with water to scale, shakes up, obtain test liquid 1
#~ 9
#.
Prepared by standard solution: precision measures potassium single element stock solution (20 μ g/ml) 2.0ml, 4.0ml, 6.0ml and, in 100ml measuring bottle, adds caesium solution 2.0ml, add water to scale, shake up, to obtain final product respectively.
Getting need testing solution and reference substance solution by atomic absorption spectrophotometry light method (Chinese Pharmacopoeia version in 2010 two annex IV D), is that blank measures with water, measures at 766.5nm wavelength place, calculates the response rate, the results are shown in Table 28.
Table 28: Determination of Potassium measures recovery test result
Result of the test shows, the method response rate is 99.70%, RSD is 0.64%, therefore method accuracy is good.
4.3 specificity tests
Get the negative adjuvant solution not containing sodium ion under 2.5, measure by potassium content algoscopy, it absorbs angle value is 0.001, and blank negative adjuvant is noiseless to mensuration.
4.4 precision test
Sample thief, shine above-mentioned KCE content algoscopy replication 6 times, it the results are shown in Table 29.
Table 29: Precision test result
Result of the test shows, this law precision is good.
5. magnesium chloride Method validation experiment
5.1 lanthanum solution additions investigate (1), the results are shown in Table 30.
Table 30:
Result of the test shows, it is close with the content of magnesium chloride that do not add measured by lanthanum solution to add lanthanum solution, and add the mensuration that the sensitivity of lanthanum measured in solution and correlation coefficient are slightly better than not adding lanthanum solution, namely measured value precision is higher, closer to actual value.Therefore, we determine in method, add lanthanum solution.
5.2 lanthanum solution additions investigate (2), the results are shown in Table 31.
Table 31:
Result of the test shows, when the addition of lanthanum chloride solution is 4 ~ 7ml, absorbance is comparatively stable, determines that in this law, lanthanum chloride solution addition is 5ml.
5.3 the range of linearity
Standard solution is prepared precision and is measured magnesium single element standard solution (1000 μ g/ml) 1.0ml and in 100ml measuring bottle, be diluted with water to scale, as magnesium single element standard substance stock solution (10 μ g/ml).Precision measures magnesium single element standard substance stock solution 0.5ml, 1.0ml, 2.0ml, 3.0ml, 0.4ml respectively, respectively add lanthanum solution 5ml, put in 100ml measuring bottle, be diluted to scale with deionized water, shake up, by above-mentioned each solution, according to atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D assay first methods), take water as blank, measure at 285.2nm wavelength place, the results are shown in following table 32.
Table 32:
Result of the test shows, test sample concentration is that take concentration as abscissa (x), trap (y) is vertical coordinate, carries out linear regression, obtains regression equation y=1.60648x, r in good linear relationship within the scope of 0.05 μ g/mL ~ 0.4 μ g/mL
2=0.9959.
Investigate result according to the range of linearity, confirmed standard product solution concentration is 0.1 μ g/ml, 0.2 μ g/ml, 0.3 μ g/m; Test sample magnesium ion concentration is about 0.24 μ g/ml, all in the range of linearity.
5.4 accuracy
Standard solution is prepared precision and is measured magnesium single element standard solution (1000 μ g/ml) 1.0ml and in 100ml measuring bottle, be diluted with water to scale, as magnesium single element standard substance stock solution (10 μ g/ml).Precision measures magnesium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, respectively adds lanthanum solution 5ml, puts in 100ml measuring bottle, be diluted to scale with deionized water, shake up, to obtain final product.
Test liquid solution prepare: by compound sodium acetate ringer's injection prescription respectively precision take magnesium chloride 16.83mg, 20.48mg, 24.14mg in 100mL measuring bottle, be dissolved in water and be diluted to scale, as stock solution.Precision measures each 1.0mL of this solution in 100mL measuring bottle respectively, adds not containing the negative adjuvant solution 1.0mL of magnesium ion, respectively adds lanthanum solution 5ml, be diluted with water to scale (each three of above three groups of strength solution), shake up, obtain test liquid 1
#~ 9
#.
Get need testing solution and standard solution by atomic absorption spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV D), measure at 285.2nm wavelength place, calculate the response rate, the results are shown in Table 33.
Table 33:
Result of the test shows, the method response rate is 99.95%, RSD is 1.1%, therefore method accuracy is good.
5.5 specificity
Get the negative adjuvant solution not containing magnesium ion under 5.4, measure by magnesium ion content algoscopy, it absorbs angle value is 0.000, and blank negative adjuvant is noiseless to mensuration.
5.6 precision
5.6.1 repeated
Sample thief 6 parts, measure according to above-mentioned content of magnesium chloride algoscopy, it the results are shown in Table 34.
Table 34:
Result of the test shows, this law repeatability is good.
5.6.2 Intermediate precision
Sample thief, shine above-mentioned content of magnesium chloride algoscopy replication 6 times, add up twice repeated data, it the results are shown in Table 35.
Table 35:
Result of the test shows, this law Intermediate precision is good.
Claims (6)
1. a compound sodium acetate ringer's injection, is characterized in that, is made up of following effective ingredient:
Sodium chloride: 5.000 ~ 7.000g; Potassium chloride: 0.150 ~ 0.372g;
Magnesium chloride: 0.150 ~ 0.298g; Sodium acetate: 3.000 ~ 4.000g;
Sodium citrate: 0.550 ~ 0.647g; Calcium gluconate: 0.624 ~ 0.748g;
Anhydrous glucose: 9 ~ 12g; Active carbon: 0.7 ~ 1.2g;
Dilute hydrochloric acid: 1 ~ 3ml; Water for injection adds to 1000ml.
2. a kind of compound sodium acetate ringer's injection as claimed in claim 1, is characterized in that, be made up of following effective ingredient:
Sodium chloride: 6.370g; Potassium chloride: 0.298g;
Magnesium chloride: 0.203g; Sodium acetate: 3.402g;
Sodium citrate: 0.588g; Calcium gluconate: 0.673g;
Anhydrous glucose: 10.0g; Active carbon: 1g;
Dilute hydrochloric acid: 1.67ml; Water for injection adds to 1000ml.
3. the preparation method of a kind of compound sodium acetate ringer's injection as claimed in claim 1 or 2, it is characterized in that, it comprises the following steps:
S1. each raw material is taken by above-mentioned formula, for subsequent use;
S2. inject with water in right amount in dense preparing tank, add sodium chloride, sodium acetate, calcium gluconate, anhydrous glucose, sodium chloride concentration is made to be 2 ~ 8%, stirring and dissolving, add 2/3 of active carbon total amount, boil 12 ~ 20min, be cooled to 60 ~ 80 DEG C, concentrated wiring liquid is transferred in dilute preparing tank after taking off charcoal after filtration;
S3. add water for injection to full dose to dilute preparing tank, stir 12 ~ 18min, sampling detects calcium gluconate and sodium chloride content, and be 95 ~ 105% to gluconic acid calcium content, sodium chloride content is 95 ~ 105%;
S4. drop into potassium chloride, magnesium chloride, sodium citrate in dilute preparing tank, stirring and dissolving 12 ~ 18min, add 1/3 of active carbon total amount, after stirring, total chlorine amount is surveyed in sampling, is adjust solution ph to be 5.5 ~ 6.0 with dilute hydrochloric acid after 95 ~ 105% to total chlorine amount;
S5. through the de-charcoal of titanium rod, respectively after the filtering with microporous membrane of 0.45 μm and 0.22 μm, filling and sealing, high temperature hot pressing sterilizing, lamp inspection, packs and obtains compound sodium acetate ringer's injection.
4. the preparation method of a kind of compound sodium acetate ringer's injection as claimed in claim 3, is characterized in that, fill described in step S5 is that fill is in the vertical polypropylene transfusion bag or polypropylene transfusion bottle of 250ml or 500ml.
5. the preparation method of a kind of compound sodium acetate ringer's injection as claimed in claim 3, is characterized in that, high temperature hot pressing sterilising temp described in step S5 is 121 DEG C, sterilization time is 12min.
6. the method for quality control of compound sodium acetate ringer's injection, is characterized in that, it comprises the following steps:
(1) calcium gluconate detects
A. prepare need testing solution: precision measures this product 5.0ml, put in 100ml measuring bottle, add lanthanum solution 2.0ml, be diluted with water to scale, shake up, to obtain final product;
B. preparation standard product solution: precision measures calcium single element standard solution 1000 μ g/ml 5.0ml in 50ml measuring bottle, is diluted with water to scale, as calcium single element standard substance stock solution; Precision measures calcium single element standard substance stock solution 2.0ml, 3.0ml, 4.0ml respectively, puts in 100ml measuring bottle, adds lanthanum solution 2.0ml, be diluted with water to scale, shake up, to obtain final product;
C. measure: getting standard solution and need testing solution, according to atomic absorption spectrophotometry, take water as blank, measure light absorption value at 422.7nm wavelength place, calculate content by external standard method;
(2) sodium acetate, sodium citrate detect
D. reference substance solution is prepared: precision takes citric acid reference substance 10mg in 10ml measuring bottle, is dissolved in water and is diluted to scale, shaking up, as citric acid reference substance stock solution; Another precision takes sodium acetate reference substance 10mg in 10ml measuring bottle, after adding citric acid reference substance stock solution 2.0ml, is diluted to scale, shakes up, to obtain final product with mobile phase;
E. preparing need testing solution: get this product 5ml in 10ml measuring bottle, be diluted to scale with mobile phase, is need testing solution;
F. measure: get need testing solution and each 20 μ l of reference substance solution respectively, injection liquid chromatography, record chromatogram, by external standard method with the content of calculated by peak area sodium acetate and sodium citrate;
Wherein, chromatographic condition is:
Mobile phase: water, with phosphoric acid adjust pH to 2.0; Chromatographic column: octadecylsilane chemically bonded silica is filler;
Column temperature: 30 DEG C; Flow velocity: 1.0ml/min;
Determined wavelength: 215nm; Sampling volume: 20 μ l;
(3) detection of sodium chloride
G. preparation standard product solution: precision measure concentration be the sodium single element standard solution 3.0ml of 1000 μ g/ml in 100ml measuring bottle, be diluted with water to scale, as sodium single element standard substance stock solution; Measured sodium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml by precision respectively, respectively add caesium solution 2.0m, put in 100ml measuring bottle, be diluted with water to scale, shake up, to obtain final product; H. prepare need testing solution: precision measures this product 3.0ml, put in 250ml measuring bottle, be diluted with water to scale, shake up; Precision measures 2.0ml, puts in 100ml measuring bottle, adds caesium solution 2.0ml, is diluted with water to scale, shakes up, to obtain final product;
I. measure: get standard solution and need testing solution, measure at the wavelength place of 589nm according to atomic absorption spectrophotometry, calculate content;
(4) mensuration of potassium chloride
J. preparation standard product solution: precision measure concentration be the potassium single element standard solution 2.0ml of 1000 μ g/ml in 50ml measuring bottle, be diluted with water to scale, as potassium single element standard substance stock solution; Precision measures potassium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, puts in 100ml measuring bottle, respectively adds cesium chloride solution 2.0ml, be diluted to scale with deionized water, shake up, to obtain final product;
K. prepare need testing solution: precision measures this product 10.0ml, put in 100ml measuring bottle, add deionized water and be diluted to scale, shake up; Precision measures 5.0ml, puts in 100ml measuring bottle, adds cesium chloride solution 2.0ml, adds deionized water and is diluted to scale, shake up;
L. measure: get standard solution and need testing solution, measure at the wavelength place of 766.5nm according to atomic absorption spectrophotometry, calculate content;
(5) mensuration of magnesium chloride
M. preparation standard product solution: precision measure concentration be 1000 μ g/ml magnesium single element standard solution 1.0ml in 100ml measuring bottle, be diluted with water to scale, as magnesium single element standard substance stock solution; Precision measures magnesium single element standard substance stock solution 1.0ml, 2.0ml, 3.0ml respectively, respectively adds lanthanum solution 5ml, puts in 100ml measuring bottle, be diluted to scale with deionized water, shake up, to obtain final product;
N. prepare need testing solution: precision measures this product 1.0ml, add lanthanum solution 5ml, put in 100ml measuring bottle, add deionized water and be diluted to scale, shake up, to obtain final product;
O. measure: get standard solution and need testing solution, measure at the wavelength place of 285.2nm according to atomic absorption spectrophotometry, calculate content;
Wherein, described caesium solution gets 5.0g cesium chloride dissolve in 1% salpeter solution and be diluted to 100ml; Described lanthanum solution takes lanthanum chloride 6.6g, is diluted with water to 100ml with 0.1mol/L dissolving with hydrochloric acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108969474A (en) * | 2018-07-11 | 2018-12-11 | 安徽双鹤药业有限责任公司 | Sodium acetate woods lattice glucose injection and preparation method thereof |
| CN109507314A (en) * | 2018-10-29 | 2019-03-22 | 中科谱研（北京）科技有限公司 | The ion chromatography method of sodium, potassium, magnesium, calcium in Amino Acid Compound Injection |
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| CN108969474A (en) * | 2018-07-11 | 2018-12-11 | 安徽双鹤药业有限责任公司 | Sodium acetate woods lattice glucose injection and preparation method thereof |
| CN109507314A (en) * | 2018-10-29 | 2019-03-22 | 中科谱研（北京）科技有限公司 | The ion chromatography method of sodium, potassium, magnesium, calcium in Amino Acid Compound Injection |
| CN109528761A (en) * | 2018-12-20 | 2019-03-29 | 江西润泽药业有限公司 | The method for preparing sodium K-Mg-Ca glucose injection |
| CN110487949A (en) * | 2019-09-30 | 2019-11-22 | 聊城大学 | A kind of detection method of calcium gluconate tablet dissolution curve |
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