3.2.P.5Quality Control of Preparations
Quality Standards
Gadopentetate Dimeglumine Injection
This product is a sterile aqueous solution of gadopentetate dimeglumine. It contains gadopentetate dimeglumine (C14H20GdN3O10•2C7H17NO5)
Should be 95.0% to 105.0% of the labeled amount.
【Description】 The product is a clear, colorless to pale yellow or pale yellowish-green liquid.
【Identification】 (1) Carry out the test as described in the Thin-layer Chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0502).
Test solution Take an appropriate amount of the product, dilute with water to prepare a solution containing approximately 35mg of gadopentetate dimeglumine per 1ml (equivalent to meglumine14.6mg).
Reference Solution Dissolve an appropriate amount of gadopentetate dimeglumine reference standard in water and dilute to prepare a solution containing approximately 56mg per 1ml (equivalent to 14.6mg of dimeglumine).
Chromatographic Conditions Use a silica gel GF254 thin-layer plate, with a developing solvent system of n-butanol-glacial acetic acid-water (4︰1︰2).
Assay Spot 2μl each of the test solution and the reference solution on the same thin-layer plate, develop, dry, spray with ninhydrin-cadmium acetate solution (prepared by dissolving 0.1g of ninhydrin and 0.25g of cadmium acetate in 1ml of glacial acetic acid, diluting with ethanol to 50ml, and mixing well), and heat at 120°C for 10 minutes to develop the color.
Result Interpretation The position and color of the principal spot in the test solution should be identical to those of the principal spot in the reference solution.
(2) Carry out the test as described in Thin-layer Chromatography (Chinese Pharmacopoeia 2020 Edition, General Rule 0502).
Test solution Dilute an appropriate amount of the product with water to prepare a solution containing about 35mg of gadopentetate dimeglumine per 1ml (equivalent to 20.4mg of gadopentetic acid).
Reference solution Dilute the reference solution from Identification (1) with water to prepare a solution containing about 28mg per 1ml (equivalent to 20.4mg of gadopentetic acid).
Chromatographic conditions Use silica gel GF254 thin-layer plates, with a mobile phase of methanol-acetonitrile-water-glacial acetic acid (5︰2︰2 ︰0.2).Assay Method Draw 2μl each of the test solution and the reference solution, spot them on the same thin-layer plate, develop, and air-dry. Spray with a cerium sulfate-arsenite solution (take 5g of cerium sulfate, place it in a 100ml volumetric flask, set it in an ice bath, add 50ml of 0.5mol/L sulfuric acid solution cooled to 0°C, shake to dissolve, filter, and refrigerate as solution A; separately, take 2.5g of sodium arsenite, dissolve it in 15ml of 1mol/L sodium hydroxide solution, refrigerate at 0°C, carefully add it to 32.5ml of 1mol/L sulfuric acid solution cooled to 0°C, dilute with water to 50ml as solution B; mix equal volumes of solution A and solution B immediately before use, and use within 5 minutes), then spray with a 1% o-phenylenediamine acetone solution.
Result Interpretation The position and color of the principal spot in the test solution should be identical to those of the principal spot in the reference solution.
(3) In the chromatograms obtained in the assay, the retention time of the principal peak in the test solution should correspond to that of the principal peak in the reference
solution.
(4) Take 5 ml of the product, place it in a 25 ml volumetric flask, dilute with water to the mark, mix well, and measure according to the ultraviolet-visible spectrophotometry
(Chinese Pharmacopoeia2020 Edition, Part IV, General Rule0401). The maximum absorption is observed at a wavelength of275 nm.
For the above items (2) and (3), either one may be selected for testing.
[Inspection] pH value: Take the product and inspect it according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0631 pH Value Determination Method). The pH value should be
7.0 to 7.9.
Color Take the sample and examine it according to the method (General Rule 0901, Method I of Part IV, Chinese Pharmacopoeia 2020 Edition), comparing it with yellow No. 4 or yellow-green
No. 4 standard color solution, and it should not be darker.
Meglumine Take the sample and measure the optical rotation at 25°C according to the method (General Rule 0621 of Part IV, Chinese Pharmacopoeia 2020 Edition), calculate using the following formula
The calculated meglumine content should be 39.6%~43.9% of the labeled amount of gadopentetate dimeglumine.
Meglumine content (%)=measured optical rotation*1000
24.9*469 × 100%
Pentetic acid Accurately measure 2ml of the sample, place it in a 100ml conical flask, add 20ml of water, and 10ml of dilute xylenol orange solution.
Shake well, adjust the pH to 5.0 with 0.1mol/L sodium hydroxide solution or glacial acetic acid, and titrate with gadolinium sulfate solution (0.001mol/L).
Titrate until the solution changes from yellow to reddish-purple. Each 1ml of gadolinium sulfate solution (0.001mol/L) is equivalent to 0.7867mg of
pentetic acid (C14H23N3O10). Each 1ml of the preparation should contain 230–450μg of pentetic acid.
Gadolinium Determine by atomic absorption spectrophotometry (Chinese Pharmacopoeia 2020 Edition, General Rule 0406 , Method I).
Cesium Chloride Solution Take an appropriate amount of cesium chloride, dissolve it in water, and dilute to the mark to prepare a solution containing100mg per1ml.
Blank Solution Mix cesium chloride solution, hydrochloric acid (spectral pure), and water in a ratio of20:10:70 (V/V/V) to obtain.
Test Solution Precisely measure5ml of the sample (equivalent to gadopentetate dimeglumine 2.3g), place in a porcelain crucible, add nitric acid
1.0ml, mix well, place on an electric stove, and slowly char until completely carbonized. Incinerate at about800°C until completely ashed (approximately 1 hour),
After cooling, transfer to a desiccator, allow to cool to room temperature, then take out, add 5ml of water and (spectral purity) hydrochloric acid10ml, heat to dissolve
, transfer to a100ml volumetric flask, add 20ml of cesium chloride solution, dilute with water to the mark, and use as the test solution.
Standard stock solution Accurately weigh 5.75g of gadolinium oxide, place in a 100ml volumetric flask, add (spectral purity) hydrochloric acid10ml
and an appropriate amount of water, heat to dissolve, cool to room temperature, then dilute with water to the mark to obtain.
Reference solution Accurately transfer 1ml, 2ml, 3ml, 4ml, and 5ml of the standard stock solution1ml, 2ml, 3ml, 4ml, 5ml, respectively, into separate 50ml
volumetric flasks, add 10ml of cesium chloride solution10ml and 10ml of hydrochloric acid (spectral purity)10ml, dilute with water to the mark, and prepare solutions containing
1ml of gadolinium element1000μg, 2000μg, 3000μg, 4000μg and 5000μg, respectively.
Spectral line search 3000μg/mL reference solution.
AssaySubtract the background with blank solution, accurately measure the reference solution and test solution at368.4nmwavelength
Measure the absorbance and calculate using the standard curve method. (This method is a flame continuous emission spectrometry, requiring the use of a high-temperature burner and
Nitrous oxide-acetylene gas (no gadolinium hollow cathode lamp required)
Limit The gadolinium content of this product is15.9%-17.5% of the labeled amount of gadopentetate dimeglumine.
Related substancesDetermined by high-performance liquid chromatography (Chinese Pharmacopoeia2020 Edition, Part IV General Rule0512).
Copper nitrate solution Take 12.88g of copper nitrate trihydrate, dissolve in water and dilute to1000ml.
Copper nitrate sodium citrate solution Take 12.88g of copper nitrate trihydrate, 38.0g of sodium citrate dihydrate, dissolve in water and dilute
to1000ml.
Test solution Accurately measure1ml of the sample (approximately equivalent to gadopentetate dimeglumine469mg), transfer to a20ml volumetric flask,
Dilute to the mark with copper nitrate sodium citrate solution, and mix well.
Reference solution (1) Take an appropriate amount of nitrilotriacetic acid reference substance and ethylenediaminetetraacetic acid reference substance, accurately weigh, dissolve in copper
nitrate solution and quantitatively dilute to prepare a solution containing approximately0.02mg of nitrilotriacetic acid and0.4mg of ethylenediaminetetraacetic acid per1ml.
Mixed solution.
Reference solution (2) Accurately measure 1 ml of reference solution (1)1ml, transfer to a 20ml volumetric flask, and dilute with copper nitrate solution to
the mark, and mix well.
Mixed solution of reference solution (1) and test solution Accurately measure 1 ml of reference solution (1)1ml, transfer to a 20ml volumetric
Into the flask, dilute to the mark with the test solution, and mix well.
Chromatographic conditions Use octylsilane-bonded silica gel as the filler (MOS-1Hypersil, 125mm×4.6mm, 5μm,
ora chromatographic column with equivalent performance); using10%(W/V) aqueous solution of tetrabutylammonium hydroxide10ml, methanol10ml,
water 170ml, mix well, adjust the pH to 7.5±0.1 with phosphoric acid, then add methanol 90ml, and dilute with water to a final volume of
1000ml as mobile phaseA,using10%(W/V) aqueous solution of tetrabutylammonium hydroxide10ml, methanol 10ml,
water 170ml, mix well and adjustpHto7.5±0.1withphosphoric acid, add methanol450ml, and dilute with water to
1000ml as mobile phase B; perform gradient elution according to the table below at a flow rate of 2ml per minute; the detection wavelength is
254nm; injectionvolume20μl; after injection, elute with mobile phaseAandrecord the chromatogram until20min;
After the recording is completed, elute theB column with mobile phase for 20min, then equilibrate the column with mobile phaseA.
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|
|
0 | 100 | 0 |
20 | 100 | 0 |
21 | 0 | 100 |
41 | 0 | 100 |
42 | 100 | 0 |
85 | 100 | 0 |
System Suitability RequirementsIn the mixed solution of reference standard solution (1), the nitrilotriacetic acid peak and copper nitrate
The resolution between the peaks of copper nitrate and EDTA should meetthe requirements (for nitrilotriacetic acid and ethylenediaminetetraacetic acid
In thetest solution and reference solution (2), the retention times may vary slightly).
Assay Accurately measure copper nitrate solution, reference solution (2), copper nitrate sodium citrate solution, and test solution,
Reference solution (1) and test solution mixture20μl, inject into the chromatograph separately, and record the chromatograms.
Limit In the chromatogram of the test solution, if any impurity peaks appear between the start (excluding the solvent peak) and the copper nitrate peak,
Calculate by the external standard method using the peak area of nitrilotriacetic acid in the reference solution (2), record from the copper nitrate peak to the end of the chromatogram,
If any impurity peaks appear, calculate by the external standard method using the peak area of ethylenediaminetetraacetic acid in the reference solution (2), related substances
The total amount shall not exceed 0.3% of the labeled amount of pentetic acid (each 1ml of this product contains a total of 197mg of pentetic acid).
Heavy metals Take an appropriate amount of the product(equivalent to gadopentetic acid dimeglumine1.0g), add 20ml of water and sodium hydroxide test solution
5ml, shake well, and examine as directed (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0821 , Method III). The heavy metal content shall not
exceed 20 parts per million.
Bacterial Endotoxins Take the product and test according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV General Chapter 1143 Method 1),
The amount of endotoxin in each 1ml should be less than 0.5EU.
Sterility Take the product, process it by membrane filtration, and test according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV General Chapter 1101),
It should comply with the requirements.
Others should comply with the relevant requirements for injections (Chinese Pharmacopoeia2020 Edition, Part IV, General Chapter0102).
【Assay】 Determine by high-performance liquid chromatography (Chinese Pharmacopoeia2020 Edition, Part IV, General Chapter0512).
Test solution Pipette accurately2ml of the product, transfer to a200ml volumetric flask, dilute with water to volume, and mix well,
Pipette accurately15ml, transfer to a100ml volumetric flask, add10ml of acetonitrile, dilute with water to volume, and mix well.
Reference Solution Accurately weigh an appropriate amount of gadopentetate meglumine reference standard, dissolve in10%acetonitrile solution, and quantitatively
diluteto prepare a solution containing approximately0.6mgper1ml.
Chromatographic Conditions Use octadecylsilane-bonded silica gel as the stationary phase; the mobile phase is tetrabutylammonium perchlorate solution (dissolve
1.7gof tetrabutylammonium perchlorate in100mlof acetonitrile, dilute with water to1000ml); the detectionwavelength is
195nm; injection volume20μl.
System suitability requirements The number of theoretical plates, calculated based on the gadopentetate dimeglumine peak, should not be less than3000.
Assay Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.
Calculate using the external standard method based on peak area, multiply the obtained result by1.263.
【Category】 Diagnostic agent.
【Specification】Calculated asC14H20GdN3O10•2C7H17NO5 (1)10ml:4.69g (2)12ml:5.63g(3)15ml:7.04g(4)20ml:9.38g
【Storage】 Protect from light, store tightly closed at a temperature not exceeding30°C.
【Shelf life】36 months
【Reviewing authority】Guangdong Institute for Drug Control
【Marketing Authorization Holder】 Guangzhou Kangchen Pharmaceutical Co., Ltd.
Analytical Methods
Analytical Methods
Appearance
Inspection method: Visual inspection.
Method: Take the product and observe visually.
Acceptance criteria: Should be a clear, colorless to pale yellow or pale yellowish-green liquid.
Identification 1
Test method: Thin-layer chromatography.
Test conditions: Silica gel GF254 thin-layer plate was used, with n-butanol-glacial acetic acid-water (4:1:2) as the developing solvent.
Procedure:
Test solution: Take an appropriate amount of the sample, dilute with water to prepare a solution containing approximately 35mg of gadopentetate dimeglumine per 1ml
(equivalent to 14.6mg of meglumine).
Reference solution Dissolve an appropriate amount of gadopentetate dimeglumine reference standard in water and dilute to prepare a solution containing approximately 56mg per 1ml (equivalent to 14.6mg of dimeglumine).
Assay method Pipette 2μl each of the test solution and reference solution, spot them on the same thin-layer plate, develop, dry, and spray with ninhydrin-cadmium acetate solution (dissolve 0.1g of ninhydrin, 0.25g of cadmium acetate, and 1ml of glacial acetic acid in ethanol, dilute to 50ml, and mix well). Heat at 120°C for 10 minutes to develop the color.
Standard limit: The position and color of the principal spot in the test solution should be the same as that of the principal spot in the reference solution.
Identification 2
Test method: Thin-layer chromatography.
Test conditions: Silica gel GF254 thin-layer plate was used, with a mobile phase of methanol-acetonitrile-water-glacial acetic acid (5:2:2:
0.2) as the developing solvent.