CN106053642A - Gadobenate dimeglumine content detection control method - Google Patents
Gadobenate dimeglumine content detection control method Download PDFInfo
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- CN106053642A CN106053642A CN201610370055.0A CN201610370055A CN106053642A CN 106053642 A CN106053642 A CN 106053642A CN 201610370055 A CN201610370055 A CN 201610370055A CN 106053642 A CN106053642 A CN 106053642A
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- gadobenate dimeglumine
- dimeglumine injection
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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Abstract
The invention discloses a gadobenate dimeglumine injection content detection control method. The method adopts high performance liquid chromatography method to detect meglumine. Analysis conditions including the best mobile phase composition, elution program, flow rate, detection wavelength, chromatographic column and the like are optimized through a large number of experiments, it is proved through multiple times of experiments that the gadobenate dimeglumine injection content detection control method has good stability and repeatability, high analysis efficiency and good separation, can sensitively and accurately perform qualitative and quantitative detection, accordingly can objectively, comprehensively and accurately assess the quality of a gadobenate dimeglumine injection and has the important significance on gadobenate dimeglumine injection quality control and clinical curative effect guarantee.
Description
Technical field
The present invention relates to the method for quality control of a kind of pharmaceutical preparation, be specifically related to the quality control of Gadobenate Dimeglumine injection
Method.
Background technology
Gadobenate Dimeglumine injection, is a kind of novel paramagnetism gadolinium chelating agen, and its reinforcing degree is high, tool liver organization is special
Property, wider imaging time window and high security, make it to improve further MRI to the diagnosis of disease and Differential Diagnosis energy
Power, is a kind of novel gadolinium class contrast medium having broad prospect of application.Gadobenate Dimeglumine injection of the prior art does not also have accurately
Reliably, highly sensitive, the detection method of good stability.Therefore to control the clinical safety of Gadobenate Dimeglumine injection formulation well
Property, safeguard the interests of patient, necessary on the basis of prior art research design go out accurately to detect Gadobenate Dimeglumine note
Penetrate the detection method of effective ingredient Gadobenate Dimeglumine injection in liquid formulation.
Summary of the invention
Present invention aim to address the deficiencies in the prior art, it is provided that a kind of good separating effect, detection sensitivity is high, stable
Property good, reproducible, can objective, comprehensively and accurately evaluate Gadobenate Dimeglumine injection quality, to control Gadobenate Dimeglumine injection
The quality of liquor and guarantee curative effect are significant.
Technical scheme: in order to realize object above, the content detection of Gadobenate Dimeglumine injection provided by the present invention controls
Method, comprises the following steps:
(1) preparation of meglumine standard solution: take meglumine reference substance about 20mg, accurately weighed, put 100ml measuring bottle
In, it is dissolved in water and dilutes the solution made in every 1ml containing about meglumine 0.2mg, as standard solution.
(2) preparation of Gadobenate Dimeglumine injection liquid samples solution: precision pipettes Gadobenate Dimeglumine injection 1ml, puts 100ml measuring bottle
In, it is diluted with water to scale, shakes up；Precision pipettes 10ml again, puts in 100ml measuring bottle, is diluted with water to scale, molten as sample
Liquid.
(3) assay of Gadobenate Dimeglumine injection in Gadobenate Dimeglumine injection liquid samples: the most accurate aspiration step (1) gadolinium
Shellfish Portugal amine injection standard solution and step (2) the Gadobenate Dimeglumine each 10uL of injection liquid samples solution, be injected separately into efficient liquid phase
Carrying out chromatography, calculate the content of meglumine in Gadobenate Dimeglumine injection liquid samples by external standard method, chromatographic condition is differential refraction
Detector, column temperature: 30～45 DEG C, flow phase: volume ratio be 0.45:0.3:100～0.90:0.3:100 triethylamine-formic acid-
The mixed solution of water, flow velocity: 0.7～1.3ml/min, chromatographic column: be the chromatographic column of filler with hydrogen cation exchange resin.
Preferably, the content detection control method of the Gadobenate Dimeglumine injection that the present invention provides, step (3) center pillar
Temperature: 35 DEG C, the mixed solution of the triethylamine-formic acid-water of flowing phase: 0.65:0.3:100, flow velocity: 1.0ml/min, differential refraction
Detector is Agilent differential refraction detector detector.
Preferably, the content detection control method of Gadobenate Dimeglumine injection of the present invention, step (3) is described
The chromatographic column that cation exchange resin is filler be Shiseido hydrogen cation-exchange chromatography post.
In Gadobenate Dimeglumine injection, meglumine compound polarity is relatively big, does not has ultraviolet in 200nm～400nm wave-length coverage
Absorb, it is impossible to use common liquid phase process to detect, in order to strictly control the quality of Gadobenate Dimeglumine injection well, formulate inspection
The method surveying Gadobenate Dimeglumine injection content, the present invention screens suitable method, selection, the stream to chromatographic column through great many of experiments
Dynamic phase composition, the flowing elution program of phase, flow velocity, detection wavelength and chromatographic column are screened.
1, the present invention is according to the construction features of Gadobenate Dimeglumine injection, screens optimal chromatographic column by great many of experiments, real
Testing result to show, this chromatographic column can preferably separate meglumine, and peak shape is symmetrical, and peak is difficult to superposition, and separating effect is more preferable.
2, the present invention is directed to the compound characteristics of meglumine, be dissolved in water and index of refraction can be produced impact, select differential
Refraction detector, uses differential refraction detector according to the therefore present invention, can be the sensitiveest detect that Gadobenate Dimeglumine is injected
Meglumine in liquid.
3, meglumine is easily ionized into ionic condition, causes separating and eluting weak effect, and the present invention is according to meglumine chemistry
Character, to flowing phase composition carried out a large amount of screening, determine use 0.45:0.3:100～0.90:0.3:100 triethylamine-
The mixed solution of formic acid-water., it is ensured that meglumine reaches good separating effect on a column, does not haves peak overlapping
Or conditions of streaking, and can guarantee that and have good separating degree on a column.
4, the flowing velocity of flowing phase is also investigated by the present invention simultaneously, and as flow velocity is too fast, separating degree is not ideal enough,
Therefore the present invention has investigated 1.5mL/min, 1mL/min, 0.8mL/min, 0.6mL/min, 0.5mL/min, 0.4mL/min respectively
Different in flow rate, test result indicate that, when the flow velocity of the phase that flows is 1.0mL/min, the peak shape of meglumine is best, separating degree
Good, theoretical cam curve is the highest, and therefore the present invention uses the flow velocity of flowing phase to be 1.0mL/min.
5, the column temperature of chromatographic column is screened by the present invention simultaneously, has investigated chromatographic column at 30 DEG C, 35 DEG C, 40 DEG C and 45
Under the conditions of DEG C, the separating effect of compound, test result indicate that, chromatographic column separating effect under the conditions of 35 DEG C is best, separates and repeats
Property and stability are best.Therefore the present invention uses the column temperature of chromatographic column to be 35 DEG C.
Beneficial effect: compared to the prior art the content detection control method of the Gadobenate Dimeglumine injection that the present invention provides has
Have the advantage that
The present invention, according to active component structural property feature in Gadobenate Dimeglumine injection injection, is screened by great many of experiments
Go out optimal flowing phase composition, elution program, flow velocity, the analysis condition such as detector, chromatographic column, show through many experiments checking,
The content detection control method of the Gadobenate Dimeglumine injection that the present invention provides can detect active component, therefore sensitive, accurately
There is the highest analysis efficiency, can overcome that existing detection method medium sensitivity is low, accuracy is low, poor stability etc. is many lacks
Point, and the separating degree of the quality determining method good stability that the present invention provides, meglumine and other impurity is good, can be qualitative, quantitative
Meglumine is analyzed in detection.Therefore, the content detection control method of the Gadobenate Dimeglumine injection that the present invention provides can be objective, complete
The quality in face, accurately evaluation Gadobenate Dimeglumine injection, to controlling the quality of Gadobenate Dimeglumine injection and ensureing clinical efficacy tool
Significant.
Accompanying drawing explanation
Fig. 1 is the high performance liquid chromatography detection analysis chart of Gadobenate Dimeglumine injection standard substance.
Fig. 2 is the high performance liquid chromatography detection analysis chart of Gadobenate Dimeglumine injection liquid samples.
Detailed description of the invention
Be further elucidated with the present invention below in conjunction with specific embodiment, it should be understood that these embodiments be merely to illustrate the present invention and
It is not used in restriction the scope of the present invention, after having read the present invention, those skilled in the art's shape various of equal value to the present invention
The amendment of formula all falls within the application claims limited range.
Implement the methodological study of the content detection control method of row 1 Gadobenate Dimeglumine injection
1.1 stability experiment
Take meglumine reference substance about 20mg, accurately weighed, put in 100ml measuring bottle, be dissolved in water and dilute and make in every 1ml
Containing about the solution of meglumine 0.2mg, as reference substance solution；Respectively 0,4,8,12,24 hours accurate absorption each 3uL of titer
Carrying out high-efficient liquid phase analysis, chromatographic condition is differential refraction detector, column temperature: 35 DEG C, and flow phase: volume ratio is 0.65:0.3:
The mixed solution of the triethylamine-formic acid-water of 100, flow velocity: 1.0ml/min, chromatographic column: with hydrogen cation exchange resin for filling out
The chromatographic column of material.Calculate the relative standard deviation of peak area (S).Specific experiment result is as shown in table 1.
Table 1 stability test result
Above stability experiment result shows, the content detection control method of the Gadobenate Dimeglumine injection that the present invention provides,
Good stability.
1.2 repeated experiment
Under the conditions of lucifuge, taking lot number 66131001 Gadobenate Dimeglumine injection, precision pipettes Gadobenate Dimeglumine injection 1ml, puts
In 100ml measuring bottle, it is diluted with water to scale, shakes up；Precision pipettes 10ml again, puts in 100ml measuring bottle, is diluted with water to scale,
As sample solution；6 parts of each 10uL of need testing solution of accurate absorption carry out high-efficient liquid phase analysis, and chromatographic condition is differential refraction inspection
Surveying device, column temperature: 30 DEG C, flow phase: volume ratio is the mixed solution of the triethylamine-formic acid-water of 0.45:0.3:100, flow velocity:
0.7ml/min, chromatographic column: be the chromatographic column of filler with hydrogen cation exchange resin.Measure 6 parts of Gadobenate Dimeglumine injection liquid samples
The content of middle meglumine.Specific experiment result is as shown in table 2:
Table 2 replica test result
Above repeated experiment result shows, the repeatability of the detection method of the Gadobenate Dimeglumine injection that the present invention provides
Good.
Implement the content detection control method of row 2 Gadobenate Dimeglumine injection, comprise the following steps:
(1) preparation of meglumine standard solution: take meglumine reference substance about 20mg, accurately weighed, put 100ml measuring bottle
In, it is dissolved in water and dilutes the solution made in every 1ml containing about meglumine 0.2mg, as standard solution.
(2) preparation of Gadobenate Dimeglumine injection liquid samples solution, takes 3 batch samples (lot number is 130601,130602,130603)
Detect: precision pipettes Gadobenate Dimeglumine injection 1ml, puts in 100ml measuring bottle, is diluted with water to scale, shakes up；Accurate shifting again
Take 10ml, put in 100ml measuring bottle, be diluted with water to scale, as sample solution.
(3) assay of Gadobenate Dimeglumine injection in Gadobenate Dimeglumine injection liquid samples: the most accurate aspiration step (1) gadolinium
Shellfish Portugal amine injection standard solution and step (2) the Gadobenate Dimeglumine each 10uL of injection liquid samples solution, be injected separately into efficient liquid phase
Carrying out chromatography, calculate the content of meglumine in Gadobenate Dimeglumine injection liquid samples by external standard method, chromatographic condition is differential refraction
Detector, column temperature: 45 DEG C, flow phase: volume ratio is the mixed solution of the triethylamine-formic acid-water of 0.90:0.3:100, flow velocity:
1.3ml/min, chromatographic column: be the chromatographic column of filler with hydrogen cation exchange resin.
The testing result of Gadobenate Dimeglumine injection in table 3 Gadobenate Dimeglumine injection
| Lot number | 130601 | 130602 | 130603 |
| Content | 99.8% | 98.5% | 99.7% |
By test result indicate that of table 1, table 2 and table 3, the detection method of the Gadobenate Dimeglumine injection that the present invention provides, Portugal
Methylamine peak shape is good, highly sensitive, compared to existing technology, and the content detection control method of the Gadobenate Dimeglumine injection that the present invention provides
Stability and reproducible, can objective, evaluate the quality of Gadobenate Dimeglumine injection comprehensively and accurately, to controlling Gadobenate Dimeglumine
The quality of injection and guarantee clinical efficacy are significant.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (3)
1. the content detection control method of a Gadobenate Dimeglumine injection, it is characterised in that comprise the following steps:
(1) preparation of meglumine standard solution: take meglumine reference substance about 20mg, accurately weighed, put in 100ml measuring bottle, add
The solution in every l ml containing about meglumine 0.2mg is made in water dissolution dilution, as standard solution；
(2) preparation of Gadobenate Dimeglumine injection liquid samples solution: precision pipettes Gadobenate Dimeglumine injection 1ml, puts in 100ml measuring bottle,
It is diluted with water to scale, shakes up；Precision pipettes 10ml again, puts in 100ml measuring bottle, is diluted with water to scale, as sample solution；
(3) assay of meglumine in Gadobenate Dimeglumine injection liquid samples: the most accurate aspiration step (1) Gadobenate Dimeglumine injection
Standard solution and step (2) the Gadobenate Dimeglumine each 10uL of injection liquid samples solution, be injected separately into efficient liquid phase and carry out chromatography,
Calculating the content of meglumine in Gadobenate Dimeglumine injection liquid samples by external standard method, chromatographic condition is differential refraction detector, column temperature: 30
～45 DEG C, flow phase: volume ratio is the mixed solution of the triethylamine-formic acid-water of 0.45:0.3:100 ~ 0.90:0.3:100, stream
Speed: 0.7～1.3ml/min, chromatographic column: be the chromatographic column of filler with cation exchange resin.
The content detection control method of Gadobenate Dimeglumine injection the most according to claim 1, it is characterised in that column temperature: 35
DEG C, flow phase: volume ratio is the triethylamine of 0.65:0.3:100, formic acid, the mixed solution of water, flow velocity: 1.0ml/min.
The content detection control method of Gadobenate Dimeglumine injection the most according to claim 1, it is characterised in that step (3)
Described is hydrogen form cation exchange chromatography post by the chromatographic column that cation exchange resin is filler.
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Cited By (2)
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| CN111751241A (en) * | 2019-03-26 | 2020-10-09 | 上海医药工业研究院 | Thermogravimetric analysis method for content of gadolinium in gadolinium contrast agent |
| CN115308323A (en) * | 2022-07-19 | 2022-11-08 | 山东新华鲁抗医药有限公司 | Method for measuring content of meglumine in lansoprazole for injection |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111751241A (en) * | 2019-03-26 | 2020-10-09 | 上海医药工业研究院 | Thermogravimetric analysis method for content of gadolinium in gadolinium contrast agent |
| CN115308323A (en) * | 2022-07-19 | 2022-11-08 | 山东新华鲁抗医药有限公司 | Method for measuring content of meglumine in lansoprazole for injection |
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