CN110412180A - A method of measurement Nimodipine soft capsule residual solvent isopropanol - Google Patents
A method of measurement Nimodipine soft capsule residual solvent isopropanol Download PDFInfo
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- CN110412180A CN110412180A CN201810400777.5A CN201810400777A CN110412180A CN 110412180 A CN110412180 A CN 110412180A CN 201810400777 A CN201810400777 A CN 201810400777A CN 110412180 A CN110412180 A CN 110412180A
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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Abstract
The invention discloses a kind of methods for measuring Nimodipine soft capsule residual solvent isopropanol, belong to drug quality detection field.This method is to be detected by gas chromatography to residual solvent isopropanol in Nimodipine soft capsule, wherein, use specification for 3.0 μm of x of 30m x 0.53mm of J&W DB-624 chromatographic column, sample introduction, acquire isopropanol characteristic peak, chromatographic condition includes: that detector is flame ionization ditector, and detector temperature is 250 DEG C；Carrier gas is nitrogen, flow rate of carrier gas 4.0mL/min, split ratio 10:1；Column temperature is 40~210 DEG C, and starting column temperature is 40 DEG C, is maintained 5 minutes, rises to 210 DEG C with the heating rate of 40 DEG C/min, keeps 5min.Using method of the invention can effectively accurate detection go out Nimodipine soft capsule residual solvent isopropanol, high sensitivity is reproducible, and precision is high.
Description
Technical field
The invention belongs to drug quality detection fields, specifically, the present invention relates to a kind of measurement Nimodipine soft capsules
The method of residual solvent isopropanol.
Background technique
Nimodipine soft capsule is suitable for the cerebral angiospasm and acute brain blood after the Subarachnoid Hemorrhage of a variety of causes
The blood circulation of pipe disease convalescence improves.Critical process in production process of soft capsules is partially polished and writing ink is commonly used
Isopropanol is as solvent, but isopropanol has hypotoxicity to human body.In addition, the isopropanol solvent residual quantity in Nimodipine soft capsule
Size have a certain impact to the hardness of soft capsule, thus to soft capsule preparation in vivo dissolution rate release have certain shadow
It rings.Therefore, in order to improve the quality of Nimodipine soft capsule, detection isopropanol solvent residual is inevitable.
Summary of the invention
It is an object of the invention to effectively accurately detect to Nimodipine soft capsule residual solvent isopropanol.
To achieve the above object, the present invention provides a kind of sides for measuring Nimodipine soft capsule residual solvent isopropanol
Method, the method is to be detected by gas chromatography to residual solvent isopropanol in Nimodipine soft capsule, including following
Step
(1) isopropanol reference substance solution is prepared；
(2) isopropanol sample solution to be measured is prepared；
(3) use specification for 3.0 μm of x of 30m x 0.53mm of J&W DB-624 chromatographic column, sample introduction, acquisition isopropanol is special
Levy peak；Wherein, it is flame ionization ditector (FID) that chromatographic condition, which includes: detector, and detector temperature is 250 DEG C；Carrier gas
For nitrogen, flow rate of carrier gas 4.0mL/min, split ratio 10:1；Column temperature is 40~210 DEG C, and starting column temperature is 40 DEG C, maintains 5
Minute, 210 DEG C are risen to the heating rate of 40 DEG C/min, keeps 5min.
In the present invention, isopropanol pair in the method and step (1) of the measurement Nimodipine soft capsule residual solvent isopropanol
According to the preparation method of product solution are as follows: precision weighs 120mg isopropanol reference substance into the volumetric flask of 100mL and with diluting dilution agent
It is settled to 100mL, shifts 2.0mL into 100mL volumetric flask, dilution is settled to 100mL.
In the present invention, isopropyl to be measured in the method and step (2) of the measurement Nimodipine soft capsule residual solvent isopropanol
The preparation method of alcohol sample solution are as follows: weigh 4 counterpoises be 1.5g Nimodipine soft capsule into 250mL volumetric flask, first plus
Enter 50mL Extraction solvent, is shaken up manually until capsule is completely dissolved, finally dilution is settled to scale.
In the present invention, the Extraction solvent and diluent are the sulfuric acid that volume fraction is 1.2%, preparation method are as follows: use water
By 12mL diluting concentrated sulfuric acid to 1000mL, cooled to room temperature.
In the present invention, head space is used in the method and step (3) of the measurement Nimodipine soft capsule residual solvent isopropanol
Sampling system sample introduction, ml headspace bottle equilibrium temperature are 80 DEG C, equilibration time 10min.
In the present invention, transfer tube temperature is 100 DEG C in the headspace injection method.
In the present invention, gas phase circulation time is 25min in the headspace injection method.
In the present invention, sample introduction needle temperature is 90 DEG C in the headspace injection method, sample injection time 0.05min.
Method of the invention can effectively accurate detection go out Nimodipine soft capsule residual solvent isopropanol, high sensitivity,
Reproducible, precision is high, and in addition to this, advantages of the present invention part will become apparent from the description below, or passes through this
The practice of invention obtains.
Detailed description of the invention
Fig. 1 is the gas chromatogram of diluent of the present invention；
Fig. 2 is the isopropanol canonical plotting of the embodiment of the present invention 1；
Fig. 3 is the reference substance solution gas chromatogram of the embodiment of the present invention 2；
Fig. 4 is the blank solution gas chromatogram of the embodiment of the present invention 3；
Fig. 5 is the sample solution gas chromatogram of the embodiment of the present invention 4.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.The embodiments described below for explaining only the invention, and should not be understood as to this hair
Bright limitation.Particular technique or condition are not specified in embodiment, according to the literature in the art described technology or conditions
Or it is carried out according to product description.Reagents or instruments used without specified manufacturer, being can be by commercially available acquisition
Conventional products.
In one aspect of the invention, the invention proposes a kind of measurement Nimodipine soft capsule residual solvent isopropanols
Method.The method that measurement Nimodipine soft capsule residual solvent isopropanol is described in detail below according to the embodiment of the present invention.According to
The embodiment of the present invention, this method comprises:
Step (1): preparation reference substance solution
In this step, isopropanol reference substance solution is prepared according to the following steps: (a) configuring diluent: with water by 12mL
Diluting concentrated sulfuric acid is to 1000mL, cooled to room temperature；(b) the accurate volumetric flask for weighing 120mg isopropanol reference substance to 100mL
In and with dilution dilution agent be settled to 100mL；(c) accurate to measure the 2.0mL solution, it is placed in 100mL volumetric flask, uses dilution
Solution is settled to 100mL by agent；(d) solution 2mL is sealed immediately and is mixed into ml headspace bottle after measuring constant volume.
The weight that the present invention weighs isopropanol reference substance is not particularly restricted, and those skilled in the art can be according to reality
It is selected, a specific embodiment according to the present invention, the weight for weighing isopropanol reference substance can be 120mg, hair
Bright people is by experiment it was unexpectedly observed that the isopropanol for weighing the weight can significantly improve and measure Ni Modi in following detection step
The accuracy of flat soft capsule residual solvent isopropanol residual content.
The type of diluent of the present invention is not particularly restricted, and those skilled in the art can select according to actual needs
It selects, a specific embodiment according to the present invention, diluent can be aqueous sulfuric acid, and inventor is to various concentration sulfuric acid solution
Investigated, be surprised to find that select through a large number of experiments volume fraction for 1.2% sulfuric acid as diluent, can be into one
Step improves the accuracy that Nimodipine soft capsule residual solvent isopropanol residual content is measured in following detection step, diluent
Gas chromatogram is as shown in Figure 1.
According to still another embodiment of the invention, the volume of reference substance solution can be 2.0mL after measurement constant volume, as a result,
It can be further improved the accuracy that Nimodipine soft capsule residual solvent isopropanol residual content is measured in following detection step.
Step (2): testing sample solution is prepared
In this step, prepare testing sample solution according to the following steps: (e) weighs Buddhist nun that 4 counterpoises are 1.5g not
Flat soft capsule is into 250mL volumetric flask；(f) 50mL Extraction solvent is added, is shaken up manually until capsule is completely dissolved；(g) it dilutes
It is settled to 250mL；(h) solution 2mL is sealed immediately and is mixed into ml headspace bottle after measuring constant volume.
The capsule shells of Nimodipine soft capsule are by glycerol, gelatin, and D-sorbite composition is dissolved in water, and Nimodipine is not
Be dissolved in water, thus the selection of Extraction solvent be it is crucial, need can sample dissolution and dissolution ingredient to be measured, and to measuring nothing
Interference.Inventor attempts to use water, low-concentration sodium hydroxide solution, low-concentration sulfuric acid solution is found in low concentration sulphur by experiment
Nimodipine soft capsule dissolution is best in acid solution, and Nimodipine soft capsule is insoluble in low-concentration sodium hydroxide solution.Invention
People investigates different low-concentration sulfuric acid solution further through a large amount of experiment, and discovery sulfuric acid solution concentration is higher, and dissolution is got over
Slowly, for the sulfuric acid that final choice volume fraction is 1.2% as Extraction solvent, which can be further improved subsequent detection
The accuracy of Nimodipine soft capsule residual solvent isopropanol residual content is measured in step.
According to one embodiment of present invention, the volume that the sulfuric acid that volume fraction is 1.2% is added is not particularly restricted,
Those skilled in the art can select according to actual needs, a specific embodiment according to the present invention, and volume point is added
Number can be 50mL for the volume of 1.2% sulfuric acid, further increased in following detection step as a result, and measure Nimodipine flexible glue
The accuracy of capsule residual solvent isopropanol residual content.
Still another embodiment in accordance with the present invention must make capsule by shaking after the sulfuric acid that volume fraction is 1.2% is added
It leaches completely, it should be noted that inventor is surprised to find that shake up manually and survey in following detection step by many experiments
The accuracy for obtaining Nimodipine soft capsule residual solvent isopropanol residual content, which has, to be significantly affected, inventors have found that manual
Ni Modi cannot be measured thus, it is possible to further increase using ultrasonic treatment or heat treatment in following detection step in shaking up
The accuracy of flat soft capsule residual solvent isopropanol residual content.
According to still another embodiment of the invention, the volume of reference substance solution can be 2.0mL after measurement constant volume, as a result,
It can be further improved the accuracy that Nimodipine soft capsule residual solvent isopropanol residual content is measured in following detection step.
Step (3): acquisition isopropanol characteristic peak
In this step, the spy of isopropanol reference substance solution and isopropanol sample solution to be measured is acquired by gas chromatography
Levy peak.Specifically, use specification for 3.0 μm of x of 30m x 0.53mm of J&W DB-624 chromatographic column, and sample introduction, acquisition characteristics peak；
Wherein, it is flame ionization ditector (FID) that chromatographic condition, which includes: detector, and detector temperature is 250 DEG C；Carrier gas is nitrogen
Gas, flow rate of carrier gas 4.0mL/min, split ratio 10:1；Column temperature is 40~210 DEG C, and starting column temperature is 40 DEG C, is maintained 5 minutes,
210 DEG C are risen to the heating rate of 40 DEG C/min, keeps 5min；And using headspace injection method sample introduction, ml headspace bottle equilibrium temperature
It is 80 DEG C, equilibration time 10min, transfer tube temperature is 100 DEG C, and gas phase circulation time is 25min, and sample introduction needle temperature is 90
DEG C, sample injection time 0.05min.Contain thus, it is possible to significantly improve and measure Nimodipine soft capsule residual solvent isopropanol residual
The accuracy of amount.
Inventor is by experiment it was unexpectedly observed that the chromatographic condition in detecting step can significantly affect the Buddhist nun that detection obtains
Not in Horizon soft capsule residual solvent isopropanol residual content accuracy.In view of this, inventor passes through many experiments, therefrom
Above-mentioned chromatographic condition has been determined, has significantly improved measure isopropanol residual content in Nimodipine soft capsule residual solvent as a result,
Accuracy.
Step (4): isopropanol residual content is determined
In this step, the remaining content of Nimodipine soft capsule residual solvent isopropanol is determined based on following formula:
Wherein, AIt is to be measuredIndicate the peak area of isopropanol to be measured in gas chromatography test map；AControlIndicate gas chromatography
The isopropanol peak area of isopropanol reference substance in test map；WIt is to be measuredIndicate the sample weighting amount of Nimodipine soft capsule to be measured, unit is
Milligram；WControlIndicate the sample weighting amount of isopropanol reference substance, unit is milligram；P indicates the purity of isopropanol in isopropanol reference substance,
Unit is milligram/milligram.Nimodipine soft capsule residual solvent isopropanol residual content is measured thus, it is possible to further increase
Accuracy.
Below with reference to specific embodiment, present invention is described, it should be noted that these embodiments are only to describe
Property, without limiting the invention in any way.
Unless stated otherwise, isopropanol reference substance and isopropyl to be measured are acquired by gas chromatography in embodiment below
The characteristic peak of alcohol.Specifically, use specification for 3.0 μm of x of 30m x 0.53mm of J&W DB-624 chromatographic column, and sample introduction, acquisition
Isopropanol characteristic peak；Wherein, it is flame ionization ditector (FID) that chromatographic condition, which includes: detector, and detector temperature is
250℃；Carrier gas is nitrogen, flow rate of carrier gas 4.0mL/min, split ratio 10:1；Column temperature is 40~210 DEG C, and starting column temperature is
It 40 DEG C, maintains 5 minutes, rises to 210 DEG C with the heating rate of 40 DEG C/min, keep 5min；And using headspace injection method into
Sample, ml headspace bottle equilibrium temperature are 80 DEG C, equilibration time 10min, and transfer tube temperature is 100 DEG C, and gas phase circulation time is
25min, sample introduction needle temperature are 90 DEG C, sample injection time 0.05min.
Embodiment 1
In the present embodiment, inventor is prepared for isopropanol reference substance stock solution.Specifically, being prepared using the following steps
Reference substance stock solution: (1) diluent is configured: with water by 12mL diluting concentrated sulfuric acid to 1000mL, cooled to room temperature；(2)
Precision weighs 300mg isopropanol reference substance into the volumetric flask of 500mL and is settled to 500mL with dilution dilution agent；(3) it falls up and down
Rotational oscillation shakes volumetric flask and is no less than 10 times, dissolves isopropanol reference substance sufficiently.
According to one embodiment of present invention, the weight of precise isopropanol reference substance is not particularly restricted, ability
Field technique personnel can select according to actual needs, a specific embodiment according to the present invention, can be with precise
300mg isopropanol reference substance, inventor is by experiment it was unexpectedly observed that the isopropanol reference substance of the weight is accurately weighed, by table 1
Precision pipettes, and can significantly improve the accuracy of testing result in following detection step.
1 reference substance stock solution of table pipettes
In the present embodiment, it is linear in the 4.8 μ g/mL concentration ranges of μ g/mL~144 to have investigated isopropanol by inventor,
Inventor be configured with concentration be respectively 4.8 μ g/mL, 12 μ g/mL, 24 μ g/mL, 48 μ g/mL and 144 μ g/mL isopropanol it is to be measured
Liquid, and the peak area of isopropanol in isopropanol prepare liquid is determined respectively, it is then mapped with peak area to concentration, obtains standard song
Line.The result shows that the testing result in the 4.8 μ g/mL concentration ranges of μ g/mL~144 is linearly very good with reference to Fig. 2.
Embodiment 2
In the present embodiment, inventor is prepared for isopropanol reference substance solution.It is compareed specifically, being prepared using the following steps
Product solution: diluent (a) is configured: with water by 12mL diluting concentrated sulfuric acid to 1000mL, cooled to room temperature；(b) precision weighs
120mg isopropanol reference substance is settled to 100mL into the volumetric flask of 100mL and with dilution dilution agent；(c) accurate to measure 2.0mL
The solution is placed in 100mL volumetric flask, and solution is settled to 100mL using diluent, and solution 2mL is extremely pushed up after (d) measuring constant volume
It in empty bottle, seals and mixes immediately, wherein the concentration of isopropanol reference substance is 24 μ g/mL, the gas phase of isopropanol reference substance
Chromatogram is as shown in Figure 3.
Embodiment 3
In the present embodiment, inventor demonstrates the specificity of the method for the present invention.Specifically, firstly, inventor is according to Buddhist nun
The preparation of Horizon soft capsule preparation formula is not free of the blank soft capsule content of isopropanol, as positioning solution, and according to general
Method detects it, the results showed that, with reference to Fig. 4, isopropanol characteristic peak goes out peak position nearby without miscellaneous in gas chromatogram
Peak interference, i.e. other content object in Nimodipine soft capsule in addition to isopropanol are on detection isopropanol content without influence.
Embodiment 4
In the present embodiment, prepare testing sample solution according to the following steps: (e) weighs Buddhist nun that 4 counterpoises are 1.5g not
Horizon soft capsule into 250mL volumetric flask, (f) be added 50mL Extraction solvent, shake up manually until capsule be completely dissolved, it is (g) dilute
It releases and is settled to 250mL, solution 2mL is sealed immediately and mixed, wherein capsule to be measured into ml headspace bottle after (h) measuring constant volume
Solution concentration is 24mg/mL.The result shows that the unknown peak of isopropanol sample solution to be measured does not interfere isopropanol special with reference to Fig. 5
Levy peak.
Embodiment 5
In the present embodiment, inventor demonstrates the accuracy of the method for the present invention.Specifically, to weigh 150mg different by inventor
Propyl alcohol reference substance into 250mL volumetric flask, in Nimodipine soft capsule sample be added theoretical concentration (24 μ g/mL) 50%,
100%, 150% and 400% aqueous isopropanol prepares solution by table 2, in triplicate, with diluent constant volume of the invention.
The preparation of 2 rate of recovery sample solution of table
The solution level of each concentration prepares 3 parts of samples, and description according to the invention measures its isopropanol peak area and counts
Average recovery rate is calculated, the results are shown in Table 3.
3 recovery test result of table
As shown above, the average recovery rate of 50% horizontal sample is 97.5%, the average recovery rate of 100% horizontal sample
It is 100.4%, the average recovery rate of 150% horizontal sample is 98.7%, and the average recovery rate of 400% horizontal sample is
97.6%, the relative standard deviation between 12 parts of different level results is 1.9%, and accuracy is good.
Embodiment 6
In the present embodiment, inventor demonstrates the precision and repeatability of the method for the present invention.Specifically, inventor uses
100% horizontal recovery sample solution to be measured, according to description replication 6 times of conventional method, opposite mark between the result measured
Quasi- deviation is 1.6%, and as shown in table 4, method precision is good.
4 Precision test result of table
In addition, invention is repeated according to 6 parts of 100% horizontal recovery sample solutions to be measured have been prepared under precision item, according to one
As the description of method be measured in parallel 6 parts of isopropanol sample recovery rates to be measured, relative standard deviation between the result measured respectively
It is 1.0%, as shown in table 5, reproducibility is good.
5 reappearance test of table
Embodiment 7
In the present embodiment, inventor has investigated the detection limit and quantitative limit of isopropanol.Specifically, by further diluting
Isopropanol reference substance solution, i.e. precision pipette 100% reference substance solution 2mL (concentration is 0.48 μ g/mL) into 100mL volumetric flask
The ratio for obtaining a chromatography peak-to-peak signal and baseline noise will can be detected different under the conditions of the ratio 3-5 of signal and noise
The content of propyl alcohol is as detection limit.Precision pipettes 100% reference substance solution 5mL, and into 100mL volumetric flask, (concentration is 1.2 μ g/
ML) using the content for the isopropanol that can be detected under the conditions of signal and noise values 10-12 as quantitative limit, the results show that inspection
Survey is limited to 50ppm, is quantitatively limited to 20ppm, and the sensitivity of instrument is good.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office
It can be combined in any suitable manner in one or more embodiment or examples.In addition, without conflicting with each other, the skill of this field
Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples
It closes and combines.
As it will be easily appreciated by one skilled in the art that embodiment described above is only exemplary, not to limit this
Invention, any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in this hair
Within bright protection scope.
Claims (9)
1. a kind of method for measuring Nimodipine soft capsule residual solvent isopropanol, which is characterized in that the method is to pass through gas
Phase chromatography detects residual solvent isopropanol in Nimodipine soft capsule, comprising the following steps:
(1) isopropanol reference substance solution is prepared；
(2) isopropanol sample solution to be measured is prepared；
(3) use specification for 3.0 μm of x of 30m x 0.53mm of J&W DB-624 chromatographic column, sample introduction acquires isopropanol feature
Peak；Wherein, it is flame ionization ditector that chromatographic condition, which includes: detector, and detector temperature is 250 DEG C；Carrier gas is nitrogen,
Flow rate of carrier gas is 4.0mL/min, split ratio 10:1；Column temperature is 40~210 DEG C, and starting column temperature is 40 DEG C, is maintained 5 minutes, with
The heating rate of 40 DEG C/min rises to 210 DEG C, keeps 5min.
2. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 1, which is characterized in that institute
State the preparation method of isopropanol reference substance solution in step (1) are as follows: precision weighs the appearance of 120mg isopropanol reference substance to 100mL
It is settled to 100mL in measuring bottle and with dilution dilution agent, shifts 2.0mL into 100mL volumetric flask, dilution is settled to 100mL.
3. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 1, which is characterized in that institute
State the preparation method of isopropanol sample solution to be measured in step (2) are as follows: weigh Nimodipine soft capsule that 4 counterpoises are 1.5g extremely
In 250mL volumetric flask, 50mL Extraction solvent is first added, is shaken up manually until capsule is completely dissolved, finally dilution is settled to scale.
4. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 2, which is characterized in that institute
Stating diluent is the sulfuric acid that volume fraction is 1.2%, preparation method are as follows: with water by 12mL diluting concentrated sulfuric acid to 1000mL, naturally
It is cooled to room temperature.
5. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 3, which is characterized in that institute
Stating Extraction solvent is the sulfuric acid that volume fraction is 1.2%, preparation method are as follows: with water by 12mL diluting concentrated sulfuric acid to 1000mL, certainly
So it is cooled to room temperature.
6. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 1, which is characterized in that institute
It states and uses headspace injection method sample introduction in the method and step (3) of measurement Nimodipine soft capsule residual solvent isopropanol, ml headspace bottle is flat
The temperature that weighs is 80 DEG C, equilibration time 10min.
7. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 6, which is characterized in that institute
Stating transfer tube temperature in headspace injection method is 100 DEG C.
8. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 6, which is characterized in that institute
Stating gas phase circulation time in headspace injection method is 25min.
9. the method for measurement Nimodipine soft capsule residual solvent isopropanol according to claim 6, which is characterized in that institute
Stating sample introduction needle temperature in headspace injection method is 90 DEG C, sample injection time 0.05min.
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