CN108414656A - A method of measuring the stripping curve of Simvastatin Tablets - Google Patents
A method of measuring the stripping curve of Simvastatin Tablets Download PDFInfo
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- CN108414656A CN108414656A CN201810085566.7A CN201810085566A CN108414656A CN 108414656 A CN108414656 A CN 108414656A CN 201810085566 A CN201810085566 A CN 201810085566A CN 108414656 A CN108414656 A CN 108414656A
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- G—PHYSICS
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- 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
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- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
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Abstract
The present invention relates to a kind of methods for the stripping curve measuring Simvastatin Tablets, include the following steps：(1) preparation of dissolution medium；Using Tween 80 as medium, solution temperature is not higher than 40 DEG C, the preparation of dissolution medium；(2) Simvastatin reference substance is taken to be configured to reference substance solution；(3) according to dissolution method, the preparation of test solution；(4) it is 4~5 DEG C to use high effective liquid chromatography for measuring stripping quantity, sample room injector temperature；(5) step (3) and step (4) are repeated twice or more than twice；(6) it assesses；Using similarity estimate, similar factors f2 is calculated, the similitude using similar factors f2 for relatively copying preparation stripping curve and reference preparation stripping curve.This method has the characteristics that science, durable and reproducible, can be not only used for imitation medicine and the former quality conformance appraisal for grinding medicine, or the consistency of quality provides guarantee between drug batch.
Description
Technical field
The present invention relates to technical field of analytical chemistry, and in particular to a kind of side for the stripping curve measuring Simvastatin Tablets
Method.
Background technology
From 2012, national Shi Yaojian general bureaus (CFDA) just started imitation medicine quality conformance appraisal, i.e., will
The imitation medicine for having been approved by listing grinds drug quality and the consistent principle of curative effect by with original, carries out quality conformance by stages and in groups
Evaluation, makes imitation medicine grind medicine with original in quality and curative effect consistent.Scientific and reasonable solid pharmaceutical preparation stripping curve is wherein formulated, is
The important step of vivo biodistribution equivalence trial success rate is improved, and for drug characteristic stripping curve is included in corresponding quality mark
Standard provides foundation, and the consistency of drug quality provides guarantee afterwards before changing for the consistency of quality, technique between drug batch；It is pungent to cut down him
Spit of fland piece is one of the pilot kind of 15 imitation medicine quality evaluations early period.
In the prior art, Simvastatin Tablets stripping curve method is measured to record in United States Pharmacopeia and Japanese orange paper；
It is using SDS as the stripping curve method of dissolution medium that wherein United States Pharmacopeia, which records method, and this method dissolution rate is too fast, to imitated
Medicine with the former difference for grinding medicine technique without distinction, nearly all imitation medicine be all up to the stripping curve of reference preparation it is similar,
The quality good or not between each imitation medicine enterprise cannot be distinguished；Japanese orange paper method is pungent using 0.3% Tween-80 as dissolution medium
Cut down statin piece dissolution it is excessively slow, test period is long, to reference preparation itself exist excessively distinguish, and tween quality, operation
Mode etc. can influence the reproducibility of experimental data.
Invention content
It is an object of the invention to improve the deficiency in the presence of the prior art, provides and a kind of measuring the molten of Simvastatin Tablets
The method for going out curve has the characteristics that science, durable and reproducible, can be not only used for imitation medicine and the former uniform quality for grinding medicine
Property (similitude) appraisal, or the consistency of quality provides guarantee between drug batch.
The technical solution adopted by the present invention to solve the technical problems is：
A method of the stripping curve measuring Simvastatin Tablets includes the following steps：
(1) preparation of dissolution medium；Using Tween-80 as medium, solution temperature is not higher than 40 DEG C, configures Tween-80 concentration
For 0.4% dissolution medium；
(2) preparation of reference substance solution；Precision weighs appropriate Simvastatin reference substance in measuring bottle, and acetonitrile solution is added to dissolve
And it is diluted to scale, it shakes up；Precision is measured and is set in measuring bottle in right amount, and the dissolution medium being added in step (1) is diluted to scale,
It shakes up, as a contrast product solution；
(3) preparation of test solution；The dissolution medium waited in molten product and step (1) is taken, according to dissolution determination
Method, rotating speed be 50~100 revs/min, timing, when through 10,15,30,45,60,90,120 minutes, take respectively dissolution fluid 3~
10ml, and the isometric dissolution medium of temperature, the dissolution fluid such as covering take subsequent filtrate as test sample through filtering with microporous membrane in time
Solution；Include seven parts of test solutions it is hereby achieved that four groups of test solutions, in every group of test solution；
(4) it measures；Using high effective liquid chromatography for measuring stripping quantity, sample room injector temperature is 4~5 DEG C；
The test solution of reference preparation is made, respectively accurate measurement institute to wait for molten product with reference preparation according to step (3)
5~20 μ l of test solution and the reference substance solution of reference preparation are stated, inject liquid chromatograph, and record chromatogram；It presses
External standard method calculates separately out Simvastatin of the reference preparation at 10,15,30,45,60,90,120 minutes with peak area and dissolves out
Amount；
The test solution of imitated preparation is made, respectively accurate measurement institute to wait for molten product with imitated preparation according to step (3)
5~20 μ l of test solution and the reference substance solution of imitated preparation are stated, inject liquid chromatograph, and record chromatogram；It presses
External standard method calculates separately out Simvastatin of the imitated preparation at 10,15,30,45,60,90,120 minutes with peak area and dissolves out
Amount；
(5) it repeats；It repeats step (3) and step (4) twice or more than twice, calculate separately out reference preparation and imitated makes
Average stripping quantity of the agent at 10,15,30,45,60,90,120 minutes, and it is depicted as reference preparation respectively and imitated preparation exists
Stripping curve in dissolution medium；
(6) it assesses；Using similarity estimate, using reference preparation and imitated preparation 10,15,30,45,60,90,
It is bent for relatively copying preparation dissolution to calculate similar factors f2, the similar factors f2 for average stripping quantity data at 120 minutes
The similitude of line and reference preparation stripping curve；When judging similitude using the value of similar factors f2, similar factors f2 be more than or
When equal to 50, imitated preparation is similar to the Dissolution profiles of reference preparation, when similar factors f2 is less than 50, copies preparation and reference
The stripping curve of preparation is dissimilar.
Preferably, in the step (1), the dissolution medium includes four kinds, respectively dissolution medium A, B, C and D,
In, dissolution medium A is 0.4% Tween-80 aqueous solution, and dissolution medium B is pH=1.2, contains 0.4% Tween-80 solution, and dissolution is situated between
Matter C is pH=4.0, contains 0.4% Tween-80 buffer solution, and dissolution medium D is pH=6.8, the buffering containing 0.4% Tween-80 is molten
Liquid.
Preferably, in the step (1), the solution temperature (i.e. bath temperature) of the Tween-80 is controlled at 37~40 DEG C
Between.
Preferably, in the step (1), the Tween-80 is using Sigma or ACROS or injection stage Tween-80；
Experiment shows that in the Tween medium of both brands, stability can just be met the requirements.
Preferably, in the step (1), the configuration process of dissolution medium A is：24g Tween-80s are weighed to be placed in measuring bottle,
Add 700~800ml water, after being dissolved in water-bath, 6000ml be diluted to the water of degassing, mixing to get.
Preferably, in the step (1), the configuration process of dissolution medium B is：24g Tween-80s are weighed to be placed in measuring bottle,
Add 700~800ml water, after being dissolved in water-bath, 45.9ml hydrochloric acid is added, 6000ml is diluted to the water of degassing, mixing, i.e.,
.
Preferably, in the step (1), the configuration process of dissolution medium C is：7.32g sodium acetate trihydrates are weighed to be placed in
In measuring bottle, adds 2mol/L acetum 123ml, be dissolved in water and be diluted to 600ml；Separately weighing 24g Tween-80s is placed in another amount
In bottle, add 700~800ml water, after being dissolved in water-bath, the solution in two measuring bottles is mixed, is diluted to the water of degassing
6000ml, mixing to get.
Preferably, in the step (1), the configuration process of dissolution medium D is：Weigh 40.8g potassium dihydrogen phosphates and
5.376g sodium hydroxides are placed in measuring bottle, are dissolved in water and are diluted to 600ml；Separately weighing 24g Tween-80s is placed in another measuring bottle
In, add 700~800ml water, after being dissolved in water-bath, the solution in two measuring bottles is mixed, is diluted to the water of degassing
6000ml, mixing to get.
Preferably, in the step (2), a concentration of 10 μ g/ml of Simvastatin in the reference substance solution.
Preferably, in the step (3), the rotating speed is 75 revs/min.
Preferably, in the step (3), the miillpore filter is polyether sulfone, and the aperture of the polyether sulfone is 0.22 μm.
Preferably, in the step (4), the sample room injector temperature is 5 DEG C.
Preferably, in the step (4), when using high effective liquid chromatography for measuring stripping quantity, the parameter of liquid chromatograph
For：ACQUITY UPLC BEH C18,2.1 × 50mm, 1.7 μm；Using octadecylsilane chemically bonded silica as filler, wave is detected
A length of 238nm, column temperature are 40 DEG C, and sample size is 5 μ l；With 0.02mol/L potassium dihydrogen phosphates-methanol (20:80) it is mobile phase, if
Constant current speed is that the retention time of Simvastatin is made to be 4 minutes；In addition, number of theoretical plate should be not less than by the calculating of Simvastatin peak
3000, tailing factor should be not more than 2.0.
Preferably, it in the step (6), selects to copy preparation and reference system when 15,30,60,120 minute four time point
The average stripping quantity data of agent, calculate the value of the similar factors f2.To utilize the relatively more imitated preparation of the value of similar factors f2
The similitude of stripping curve and reference preparation stripping curve.
Compared with prior art, using a kind of method for the stripping curve measuring Simvastatin Tablets provided by the invention, tool
There is following advantageous effect：
1, in the present invention, the concentration of dissolution medium Tween-80 is set as 0.4%, is shown by many experiments：It is dense using this
The stripping curve that the dissolution medium of degree is measured, discrimination is preferable, can moderately distinguish imitation medicine and the former quality good or not for grinding medicine
And process variations.
2, in the present invention, the solution temperature of dissolution medium is controlled at 40 DEG C hereinafter, it is preferred that between 37~40 DEG C, by a large amount of
Experiment shows：Solution temperature is controlled at 40 DEG C or less, and there is Simvastatin higher stability can cause when the temperature is excessively high
Oxidation impurities increase in dissolution medium, influence the stability of Simvastatin, and stripping curve is significantly lower than normal value.
3, in the present invention, injector temperature control in sample room is 4~5 DEG C of low temperature, is shown by many experiments：Using efficient liquid
When phase chromatography measures stripping curve (or stripping quantity) of Simvastatin, sample room injector temperature is excessively high, the degradation rate of sample
Aggravation, is unfavorable for the measurement of stripping curve, when sample room injector temperature is relatively low, the degradation amount very little of sample does not influence to dissolve out
The measurement result of curve.
4, in the present invention, dissolution medium is pungent to cut down preferably using Sigma or ACROS or the Tween-80 product of injection stage
Statin is met the requirements in this dissolution medium high stability, and when carrying out stripping curve measurement, measurement result is reproducible.
5, Simvastatin Tablets stripping curve assay method provided by the present invention has the spies such as science, durable, reproducible
Imitation medicine and former quality conformance (similitude) appraisal for grinding medicine may be implemented in point, or quality between drug batch
Consistency provides guarantee, and can prompt vivo biodistribution availability problem.
Description of the drawings
In order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, is that dissolution is situated between with 0.3%SDS
When matter, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 2 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, when using water as dissolution medium, institute
The stripping curve schematic diagram of the Simvastatin Tablets of measurement.
Fig. 3 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, is dissolution with 0.05%SDS water
When medium, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 4 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, is dissolution with 0.1%SDS water
When medium, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 5 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, is dissolution with 0.15%SDS water
When medium, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 6 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, is dissolution with 0.2%SDS water
When medium, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 7 is the former triturate provided in the embodiment of the present invention 1 and 3 imitation medicine preparations, is dissolution with 0.3%SDS water
When medium, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 8 is the former triturate provided in the embodiment of the present invention 1, when dissolution medium A2, B2, C2 and D2 is respectively adopted,
The stripping curve schematic diagram of the Simvastatin Tablets measured.
Fig. 9 is to be provided in the embodiment of the present invention 1 with a batch of former 18, triturate sample, and dissolution medium A2 is respectively adopted
When, the stripping curve schematic diagram of the Simvastatin Tablets measured.
Figure 10 is the former triturate provided in the embodiment of the present invention 2, and the assay method using Japanese orange paper is obtained
The stripping curve of Simvastatin Tablets, the comparison signal of the standard stripping curve of the Simvastatin Tablets recorded with Japanese orange paper
Figure.
Figure 11 is to provide former triturate and six kinds of imitated preparations in the embodiment of the present invention 2, and 0.5% Tween-80 is respectively adopted
When aqueous solution is dissolution medium, the contrast schematic diagram of the stripping curve of the Simvastatin Tablets measured.
Figure 12 is to be determined using a kind of method of the stripping curve of measurement Simvastatin Tablets provided in embodiment 3
The dissolution curve of former triturate Simvastatin Tablets in four kinds of dissolution mediums.
Figure 13 is to be determined using a kind of method of the stripping curve of measurement Simvastatin Tablets provided in embodiment 3
Former triturate and six kinds of imitated preparations in Simvastatin Tablets dissolution curve.
Specific implementation mode
Below in conjunction with attached drawing in the embodiment of the present invention, technical solution in the embodiment of the present invention carries out clear, complete
Ground describes, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Usually exist
The component of the embodiment of the present invention described and illustrated in attached drawing can be arranged and be designed with a variety of different configurations herein.Cause
This, the detailed description of the embodiment of the present invention to providing in the accompanying drawings is not intended to limit claimed invention below
Range, but it is merely representative of the selected embodiment of the present invention.Based on the embodiment of the present invention, those skilled in the art are not doing
The every other embodiment obtained under the premise of going out creative work, shall fall within the protection scope of the present invention.
Embodiment 1
In the prior art, it is dissolution that the method for the measurement Simvastatin Tablets stripping curve recorded in United States Pharmacopeia, which is with SDS,
Medium, therefore in the present embodiment uses 0.3% lauryl sodium sulfate (SDS) for medium according to the standard of United States Pharmacopeia,
And it is each configured to dissolution medium A1, B1, C1 and D1 that four kinds of SDS concentration are 0.3%, wherein wherein dissolution medium A1
For 0.3%SDS aqueous solutions, dissolution medium B1 is pH=1.2,0.3%SDS solution, and dissolution medium C1 is pH=4.0,0.3%
SDS buffer solutions, dissolution medium D1 are pH=6.8,0.3%SDS buffer solutions；
It is molten using above-mentioned four kinds by the former triturate of Simvastatin Tablets and 3 kinds of imitated preparations using high performance liquid chromatography
Go out the measurement that medium carries out stripping curve, with the consistency of 3 kinds of imitated preparations of assessment and former triturate；As shown in Figure 1, it is seen that four
Stripping curve is all very close to and having stripping curve of a stripping curve and remaining to overlap, 3 kinds of imitated preparations and original
Triturate has all reached 85% or more dissolution rate in 15 minutes, is compared at this time without similar factors f2, so that it may
To judge that the stripping curve for copying preparation is similar to the former stripping curve of triturate；It can be seen that：It is that dissolution is situated between with 0.3%SDS
Matter carries out the Conformance Assessment (assessment) that Simvastatin Tablets copy preparation, and discrimination is poor, is unable to effectively evaluating and goes out former development
The difference of agent and imitated preparation.
In order to explore a more moderate SDS concentration, so that the stripping curve of Simvastatin Tablets reaches preferable differentiation
Power has investigated influence of the SDS concentration variation to Simvastatin Tablets stripping curve (i.e. to copying preparation in further testing
Conformance Assessment influence)；
The Simvastatin Tablets of common a variety of production firms on Vehicles Collected from Market are selected, specifically, selection Hainan sea etherealize
Learn pharmaceutical Co. Ltd, upper Hisense's friendship everything pharmaceutcal corporation, Ltd, Shantou, Guangdong metal and stone pharmacy head factory, Shandeshi (China) pharmacy
The Simvastatin Tablets of Co., Ltd, Zhejiang Jingxin Pharmaceutical Co., Ltd's (import) and the production of Mo Shadong pharmaceutical Co. Ltds
For sample, wherein the Simvastatin Tablets of Mo Shadong pharmaceutical Co. Ltds production are former triturate, and the pungent of remaining company production cuts down him
Spit of fland piece is imitated preparation；Not additionally add surfactant in the case of, respectively with water, 0.05%SDS, 0.1%SDS,
0.15%SDS, 0.2%SDS and 0.3%SDS solution are dissolution medium, using high performance liquid chromatography, the dissolution to each sample
Curve is investigated, as shown in Fig. 2-Fig. 7；It can be seen from the figure that surfactant ought not be added, and the concentration of SDS is small
In the case of 0.2%, the stripping quantity of Simvastatin is very low；And when SDS concentration reaches 0.3%, Simvastatin it is molten
Extracting rate again very fast (too fast), just has reached release platform in 10 minutes, as shown in fig. 7, it is found that working as SDS a concentration of 0.2%
When, it is more moderate concentration (or perhaps more moderate surfactant concentration).
In further testing, dissolution medium is made with SDS a concentration of 0.2%, former triturate has been carried out further
Experiment：
First, by a concentration of 0.2% SDS solution, the dissolution medium of four kinds of pH value, respectively dissolution medium are configured to
A2, B2, C2 and D2, wherein wherein dissolution medium A2 is：0.2%SDS aqueous solutions, dissolution medium B2 are pH=1.2, are contained
0.2%SDS solution, dissolution medium C2 are pH=4.0, and buffer solution containing 0.2%SDS, dissolution medium D2 is pH=6.8, is contained
0.2%SDS buffer solutions；Then, using above-mentioned four kinds of dissolution mediums, using high performance liquid chromatography, to former triturate sample
Stripping curve be determined, as shown in Figure 8；Finally, using dissolution medium A2 as dissolution medium, same a collection of (20mg) original is ground
The stripping curve of formulation samples 18 (measure need 6 every time, in triplicate, be averaged, therefore need 18) is surveyed
It is fixed, as shown in Figure 9；
As can be seen from Figure 8, the stripping curve of Simvastatin Tablets (former triturate sample) in four kinds of dissolution mediums is poor
It is different larger；It can be seen in figure 9 that 18 reproducibility are also excessively poor in Simvastatin Tablets (former triturate sample) batch, and phase
46.8 are can only achieve like the maximum value of factor f2, is less than 50；In summary, molten using SDS as dissolution medium measurement Simvastatin Tablets
Go out curve method, there are problems (described in test results as described above), therefore can consider using SDS as dissolution medium and measure
The method of Simvastatin Tablets stripping curve is infeasible (or effect is bad).
Embodiment 2
In the prior art, the method for the measurement Simvastatin Tablets stripping curve recorded in Japanese orange paper (Japanese Pharmacopoeia),
It is using 0.3% Tween-80 as dissolution medium, rotating speed is 50 turns/min；Therefore in the present embodiment, using 0.3% Tween-80
For dissolution medium, with the production of Hangzhou Mo Shadong pharmaceutical Co. Ltds, lot number 120376,120374, specification is the pungent of 20mg
It is former triturate to cut down statin piece, is determined to the stripping curve of former triturate using the assay method of Japanese orange paper, and
It is compared with the standard stripping curve that Japanese orange paper is recorded, as shown in Figure 10, it can be seen that using Japanese orange paper side
The standard stripping curve that the stripping curve of the former triturate that method measures is recorded with Japanese orange paper there are significant difference, it is similar because
The maximum value of sub- f2 only has 37.3, and is not up to using the final dissolution rate of the former triturate measured by Japanese orange paper method
85%, similar factors comparison cannot be carried out.
In order to probe into influence of the concentration of Tween-80 to measurement Simvastatin Tablets stripping curve, following experiment has been done：
In a kind of scheme, the concentration of Tween-80 is increased to 0.4%, i.e., Tween-80 is a concentration of in dissolution medium
0.4%；Using 0.4% Tween-80 aqueous solution as dissolution medium, respectively to former triturate and 6 producers being collected into totally 6 batches
Imitated preparation (specification 20mg) has carried out primary fast sieve (respectively taking two panels), and the results are shown in Table 1：
1 0.4% Tween-80 aqueous solution of table, fast sieve results of the 75 turns/min of rotating speed to each imitated preparation
15,30,60,120 minutes are chosen to compare time point, sieve soon 6 imitated preparations and former triturate are compared
Compared with, can will, wherein the similar factors f2 of 3 producers be more than 50, to judge these three producers production the batch Simvastatin
Piece and former triturate are similar (i.e. the consistency of imitation medicine quality is preferable), and measure each imitated preparation by the method and developed with former
The stripping curve of agent usually has preferable distinction.
In further scheme, the concentration of Tween-80 is increased to 0.5%, i.e., the concentration of Tween-80 in dissolution medium
It is 0.5%；Using 0.5% Tween-80 aqueous solution as dissolution medium, respectively to former triturate and above-mentioned 6 be collected into producer totally 6
The imitated preparation (specification 20mg) of batch has carried out primary fast sieve (respectively taking two panels), as a result such as table 2 or as shown in figure 11：
2 0.5% Tween-80 aqueous solution of table, fast sieve results of the 75 turns/min of rotating speed to each imitated preparation
Compare the data of Tables 1 and 2 it is found that in dissolution medium Tween-80 concentration raising, factory similar with former triturate
Family is become by 3 for 4, so that the stripping curve of imitated preparation and the distinction of the stripping curve of former triturate reduce.
It to sum up tests, and considers influence of the Tween-80 excessive concentration to chromatographic system, it can be more severe to chromatographic requirement
The factor at quarter, it is believed that 0.4% tween is better condition.Tween-80 a concentration of 0.4% when it is most suitable, can be in Simvastatin
In the In Vitro Dissolution assessment (measuring stripping curve) of piece so that imitated preparation has good distinction with former triturate, can
Efficiently differentiate out the quality good or not and process variations of imitated preparation and former triturate.
In further experimental exploring, Tween-80 solution temperature has been investigated to measuring Simvastatin Tablets stripping curve
It influences.
Show that the stability of Sigma or ACROS or injection stage Tween-80 is preferable with concrete case by largely testing,
Stability requirement when stripping curve (the HPLC methods) using high effective liquid chromatography for measuring Simvastatin Tablets can be met so that
When carrying out stripping curve measurement, measurement result is reproducible；Therefore in this experiment, Tween-80 uses SIGMA or ACROS or note
A grade Tween-80 product is penetrated, dissolved in 37~40 DEG C of water-bath respectively and is dissolved in 80~90 DEG C of water-bath, is then distinguished
It is configured to 0.4% Tween-80 solution；Precision weighs suitable Simvastatin Tablets and is dissolved respectively with both solution, investigates
The stability in two kinds of dissolution mediums measures Simvastatin Tablets in different moments to Simvastatin Tablets respectively as shown in table 3 herein
Peak area.
Influence of the 3 Tween-80 solution temperature of table to stability
In general, the solution temperature of Tween-80 is too low, the dissolving of Tween-80 is insufficient；And when the solution temperature of Tween-80
When excessively high, as shown in table 3, solution temperature can affect to the stability of Simvastatin Tablets, and temperature is excessively high to be caused
Drug (Simvastatin Tablets) degradation aggravation, is unfavorable for carrying out high effective liquid chromatography for measuring stripping curve, because using efficient liquid
Phase chromatography measures time-consuming usually longer (logical production is 7 hours) of stripping curve, and the degradation of drug (Simvastatin Tablets) is too fast, meeting
There is the phenomenon that not measuring completely also, drug just degrades so that there are large errors for measurement result, in addition, can also cause molten
Go out oxidation impurities in medium to increase, influence the stability of Simvastatin, stripping curve is significantly lower than normal value.；Therefore preferably
In scheme, the solution temperature of Tween-80 should control 40 DEG C or less in experimental temperature, it is preferable that solution temperature (or water-bath temperature
Degree) it should be between 37~40 DEG C, at this point, Simvastatin has higher stability.
It in further experimental exploring, has investigated in liquid chromatogram instrument, sample room injector temperature is to measuring pungent cut down
The influence of statin piece stripping curve.
By above-mentioned experimental result, using Tween-80 as medium, solution temperature is not higher than 40 DEG C, and it is dense that four kinds of tweens are respectively configured
Dissolution medium A, B, C and D that degree is 0.4%, wherein dissolution medium A is 0.4% Tween-80 aqueous solution, dissolution medium B, C
And the pH value of D is respectively 1.2,4.0 and 6.8；The Simvastatin Tablets sample for taking equivalent, according to dissolution method (China
Pharmacopeia version the second methods of annex X C in 2010 or Chinese Pharmacopoeia the 4th method of version in 2015), rotating speed is 75 revs/min, timing, through 10
When minute, dissolution fluid 3ml is taken respectively, through filtering with microporous membrane, takes subsequent filtrate as experiment sample, and experiment sample is existed respectively
Place sample introduction in the sample room of different temperatures, by measure different moments experiment sample degradation amount (, practical measurement is pungent cuts down
Peak area of the statin piece in different moments), to probe into influence of the sample room injector temperature to experiment sample stability, experimental result
As shown in table 4.
Stability of the 4 Simvastatin Tablets experiment sample of table in the sample room of different temperatures
Using high effective liquid chromatography for measuring Simvastatin Tablets stripping curve (HPLC methods) when, it usually needs about 7
Hour, as shown in Table 4, in liquid chromatograph, when the injector temperature of sample room is higher, the drop of Simvastatin Tablets experiment sample
Solution amount is larger, and stability worse and worse, when the injector temperature of sample room is relatively low, get over by the degradation amount of Simvastatin Tablets experiment sample
Next smaller, it is as shown in the table, and when the injector temperature of sample room is 5 DEG C, 7 hours degradation amounts of Simvastatin Tablets experiment sample are insufficient
0.1% so that Simvastatin Tablets experiment sample has very high stability, can effectively ensure the quality of sample, not influence
The measurement result of stripping curve；In preferably scheme, using high effective liquid chromatography for measuring Simvastatin Tablets stripping quantity (or
Stripping curve) when, the injector temperature of sample room is most suitable between 4~5 DEG C.
Embodiment 3
A kind of method for the stripping curve measuring Simvastatin Tablets is provided in the present embodiment, is included the following steps：
The preparation of step (1) dissolution medium
Using Tween-80 as medium, Tween-80 solution temperature (or bath temperature) is not higher than 40 DEG C, in optimally scheme,
The solution temperature (i.e. bath temperature) of Tween-80 controls between 37~40 DEG C, and configuring tween concentration by this requirement is
0.4% four kinds of dissolution medium A or dissolution medium B or dissolution medium C or dissolution medium D, wherein
Dissolution medium A is 0.4% Tween-80 aqueous solution, and configuration process can be：Precision weighs 24g Tween-80s and is placed in
In measuring bottle, add 700~800ml water, be transferred in bulk container after being dissolved in 37~40 DEG C of water-baths, the water newly to deaerate is used in combination to dilute
To 6000ml, mixing to get.
Dissolution medium B is pH=1.2, contains 0.4% Tween-80 solution, and configuration process can be：Precision weighs 24g and spits
Temperature -80 is placed in measuring bottle, adds 700~800ml water, is transferred in bulk container after being dissolved in 37~40 DEG C of water-baths, is added
45.9ml hydrochloric acid is diluted to 6000ml with the water newly to deaerate, mixing to get.
Dissolution medium C is pH=4.0, contains 0.4% Tween-80 buffer solution, and configuration process can be：Precision weighs
7.32g sodium acetate trihydrates are placed in measuring bottle, and adding 2mol/L acetums, (precision weighs 120.0g glacial acetic acid waters and is diluted to
1000ml to get) 123ml, be dissolved in water and be diluted to 600ml (confirming pH value after being diluted with water 10 times)；Separately 24g is weighed to spit
Temperature -80 is placed in another measuring bottle, adds 700~800ml water, after being dissolved in 37~40 DEG C of water-baths, by the solution in two measuring bottles
Mixing is diluted to 6000ml with the water newly to deaerate, mixing to get.
Dissolution medium D is pH=6.8, contains 0.4% Tween-80 buffer solution, and configuration process can be：Precision weighs
40.8g potassium dihydrogen phosphates and 5.376g sodium hydroxides are placed in measuring bottle, and being dissolved in water and being diluted to 600ml (is diluted with water 10 times
After confirm pH value)；It separately weighs 24g Tween-80s to be placed in another measuring bottle, adds 700~800ml water, after being dissolved in water-bath, by two
Solution mixing in a measuring bottle, 6000ml is diluted to the water newly to deaerate, mixing to get.
When measuring the stripping curve of Simvastatin Tablets, due to the difference of pH value, each dissolution medium is required for being surveyed
It is fixed, that is, it needs to measure stripping curve of the Simvastatin Tablets in dissolution medium A, B, C and D respectively using this method.
In further prioritization scheme, Sigma or ACROS or injection stage Tween-80 that Tween-80 medium preferentially uses
Product；Sigma or ACROS or injection stage Tween-80 product usually have preferable stability, are conducive to use efficient liquid phase
Chromatography (HPLC methods) measures the stripping curve of Simvastatin Tablets.
The preparation of step (2) reference substance solution
Precision weighs 10mg Simvastatin reference substances and is placed in 50ml measuring bottles, adds acetonitrile to dissolve and is diluted to scale, shakes up,
Then accurate measure is placed in right amount in another measuring bottle respectively, the dissolution medium being separately added into appropriate step (1), is made every
Containing about the solution of 10 μ g Simvastatins in 1ml, shake up, as a contrast product solution.
The preparation of step (3) test solution
The dissolution medium waited in molten product and 900ml steps (1) is taken, according to dissolution method (Chinese Pharmacopoeia 2010
Year version the second methods of annex X C or Chinese Pharmacopoeia the 4th method of version in 2015), rotating speed is 50~100 revs/min, timing, through 10,15,
30,45,60,90,120 minutes when, take 3~10ml of dissolution fluid respectively, and the isometric corresponding dissolution of the temperature such as covering in time is situated between
Matter, dissolution fluid take subsequent filtrate as test solution through filtering with microporous membrane.
In optimally scheme, rotating speed can preferentially be set as 75 revs/min.
In further prioritization scheme, for miillpore filter using polyether sulfone, the aperture of polyether sulfone is 0.22 μm.
Step (4) measures
Stripping quantity is measured using high performance liquid chromatography (general rule 0512), sample room injector temperature is 4~5 DEG C；Optimizing
In ground scheme, sample room injector temperature can preferentially be set as 5 DEG C；
The confession of reference preparation is made to wait for molten product with reference preparation (i.e. previously described former triturate) according to step (3)
Test sample solution, accurate 5~20 μ l of test solution and corresponding reference substance solution for measuring the reference preparation, inject liquid respectively
Chromatography, and record chromatogram；By external standard method with peak area size calculate separately out reference preparation 10,15,30,45,60,
90,120 minutes when Simvastatin stripping quantity；In the dissolution medium of pH=1.2, the stripping quantity of Simvastatin cuts down him according to pungent
The sum of spit of fland acid and Simvastatin peak are calculated, (i.e. mentioned above in different time points so as to obtain reference preparation
10,15,30,45,60,90,120 minutes) when Simvastatin stripping quantity.
Imitated preparation is made to wait for molten product with imitated preparation (needing the imitated preparation being measured) according to step (3)
Test solution, accurate 5~20 μ l of test solution and corresponding reference substance solution for measuring the imitated preparation respectively, note
Enter liquid chromatograph, and records chromatogram；By external standard method with peak area size calculate separately out imitated preparation 10,15,30,
45,60,90,120 minutes when Simvastatin stripping quantity；So as to obtain imitated preparation (institute i.e. above in different time points
10,15,30,45,60,90,120 minutes mentioned) when Simvastatin stripping quantity.
In further prioritization scheme, when using high effective liquid chromatography for measuring stripping quantity, the parameter of liquid chromatograph
For：ACQUITY UPLC BEH C18,2.1 × 50mm, 1.7 μm；Using octadecylsilane chemically bonded silica as filler, wave is detected
A length of 238nm, column temperature are 40 DEG C, and sample size is 5 μ l；With 0.02mol/L potassium dihydrogen phosphates-methanol (20:80) it is mobile phase, if
Constant current speed is that the retention time of Simvastatin is made to be 4 minutes or so；In addition, number of theoretical plate should be not less than by the calculating of Simvastatin peak
3000, tailing factor should be not more than 2.0.
Step (5) repeats
If reference preparation and each dry plate of imitated preparation is taken (12 to be usually less than, because for there are six stripping rotors respectively
Digestion instrument for, 12 be one of uniformity in doing stripping curve batch it is minimum measure quantity, therefore with a batch of measured quantity
Cannot be below 12) repeating said steps (3) and step (4) are twice or more than twice；Reference preparation and imitated system are measured every time
When agent, the stripping quantity of each reference preparation and imitated preparation in dissolution medium can be calculated separately out, so as to respectively
Calculate the average stripping quantity of reference preparation and imitated preparation at 10,15,30,45,60,90,120 minutes (time point), root
It,, can be with using average stripping quantity or Average dissolution as ordinate using the time as abscissa according to the average stripping quantity at each time point
It is depicted as the stripping curve of reference preparation and imitated preparation in corresponding dissolution medium respectively.
Step (6) is assessed
Using similarity estimate, using reference preparation and imitated preparation at 10,15,30,45,60,90,120 minutes
Average stripping quantity data, calculate similar factors f2, and similar factors f2 is molten for relatively more imitated preparation stripping curve and reference preparation
The similitude for going out curve, to carry out quality conformance evaluation；When similar factors f2 is greater than or equal to 50, preparation and reference system are copied
The Dissolution profiles of agent are similar, and consistency is preferable, when similar factors f2 is less than 50, copy the stripping curve of preparation and reference preparation
Dissmilarity, consistency are bad.The computational methods of similarity estimate and similar factors f2 be the prior art, due in step (5)
Through obtaining the average dissolution of reference preparation and imitated preparation at 10,15,30,45,60,90,120 minutes (time point) respectively
Amount, according to the average stripping quantity at this seven time points, so that it may to calculate the value of similar factors f2, to judge to copy preparation
With the similitude and quality conformance of reference preparation.
In further prioritization scheme, when can preferentially select 15,30,60,120 minute four time point, system is copied
The stripping quantity data of agent and reference preparation calculate the value of similar factors f2, can not only reach same effect, can also reduce calculating
Amount simplifies calculating process, convenient for utilizing the dissolution of the stripping curve and reference preparation of the relatively more imitated preparation of the value of similar factors f2
The similitude of curve.
Embodiment 4
According to a kind of method of the stripping curve of the measurement Simvastatin Tablets provided in embodiment 3, first to implementing in 1
The stripping curve of Simvastatin Tablets is determined in the original triturate, wherein
In step (1), the dissolution medium of use is respectively：Four kinds of dissolution mediums A, B, C and D described in embodiment 3；
In step (3), specifically using the 4th method of dissolution method (Chinese Pharmacopoeia the 4th method of version in 2015) (slurry
Dish method)；Rotating speed is 75 revs/min；
It is to wait for that molten product, the design parameter of former triturate are with former triturate in step (4)：
Simvastatin Tablets 40mg-k004053；
Active ingredient：Simvastatin；
Dosage form：Tablet；
Specification：40mg；
By measuring, stripping curve of the former triturate in four kinds of dissolution mediums is obtained, as shown in figure 12, it is seen then that former
Stripping curve of the triturate in four kinds of dissolution mediums is very close, and similitude is especially good, not only shows to utilize institute of the present invention
The method of offer can accurately measure the stripping curve of Simvastatin Tablets, but also can make the stripping curve of former triturate
For reference, the similitude and quality conformance of copying preparation are effectively assessed.
Therefore in further example, according to a kind of stripping curve of measurement Simvastatin Tablets for being provided in embodiment 3
Method is respectively determined the stripping curve of Simvastatin Tablets in above-mentioned former triturate and six kinds of imitated preparations, with assessment
The similitude and quality conformance of six kinds of imitated preparations, wherein six kinds of imitated preparations be respectively A factories described in embodiment 2, B factories,
The imitated preparation that C factories, D factories, E factories and F factories are produced, is respectively set to：Imitated preparation A, imitated preparation B, imitated formulation C,
Imitated preparation D, imitated preparation E, imitated preparation F；Measurement result is as shown in figure 13, in figure as it can be seen that former triturate and six kinds it is imitated
Preparation dissolution rate is moderate, preparation and former triturate it is imitated between there is preferable discrimination (power), so as to effectively area
The quality good or not and process variations of point imitated preparation and former triturate are realized to each imitated preparation similitude and quality conformance
Assessment.
Comparison diagram 12 and Figure 13, it is seen that the stripping curve of Simvastatin Tablets is similar (linear and become in two figure Central Plains triturates
Gesture all same), method provided by the present invention, which is further illustrated, has good reproducibility.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
Those familiar with the art in the technical scope disclosed by the present invention, can easily think of the change or the replacement, and should all contain
Lid is within protection scope of the present invention.
Claims (10)
1. a kind of method for the stripping curve measuring Simvastatin Tablets, which is characterized in that include the following steps：
(1) preparation of dissolution medium；Using Tween-80 as medium, solution temperature is not higher than 40 DEG C, and it is a concentration of to prepare Tween-80
0.4% dissolution medium；
(2) preparation of reference substance solution；Precision weighs appropriate Simvastatin reference substance in measuring bottle, add acetonitrile solution dissolve and it is dilute
It releases to scale, shakes up；Precision is measured and is set in measuring bottle in right amount, and the dissolution medium being added in step (1) is diluted to scale, shakes
It is even, product solution as a contrast；
(3) preparation of test solution；The dissolution medium waited in molten product and step (1) is taken, according to dissolution method, is turned
Speed is 50~100 revs/min, and timing takes 3~10ml of dissolution fluid respectively when through 10,15,30,45,60,90,120 minutes, and
The isometric dissolution medium of temperature, the dissolution fluid such as covering take subsequent filtrate as test solution through filtering with microporous membrane in time；
(4) it measures；Using high effective liquid chromatography for measuring stripping quantity, sample room injector temperature is 4~5 DEG C；
The test solution of reference preparation is made, respectively the accurate measurement ginseng to wait for molten product with reference preparation according to step (3)
Than 5~20 μ l of the test solution of preparation and the reference substance solution, liquid chromatograph is injected, and record chromatogram；By external standard
Method calculates separately out Simvastatin stripping quantity of the reference preparation at 10,15,30,45,60,90,120 minutes with peak area；
The test solution of imitated preparation is made, accurate measurement is described imitative respectively to wait for molten product with imitated preparation according to step (3)
5~20 μ l of the test solution of preparation and the reference substance solution inject liquid chromatograph, and record chromatogram；By external standard
Method calculates separately out Simvastatin stripping quantity of the imitated preparation at 10,15,30,45,60,90,120 minutes with peak area；
(5) it repeats；Repeat step (3) and step (4) twice or more than twice；It calculates separately out reference preparation and imitated preparation exists
10,15,30,45,60,90,120 minutes when average stripping quantity, and be depicted as reference preparation respectively and imitated preparation is dissolving out
Stripping curve in medium；
(6) it assesses；Using similarity estimate, using reference preparation and imitated preparation at 10,15,30,45,60,90,120 minutes
When average stripping quantity data, calculate similar factors f2, the similar factors f2 is for relatively copying preparation stripping curve and ginseng
Than the similitude of preparation stripping curve.
2. the method for the stripping curve according to claim 1 for measuring Simvastatin Tablets, which is characterized in that the step
(1) in, the dissolution medium includes four kinds, respectively dissolution medium A, B, C and D, wherein dissolution medium A spits for 0.4%
Warm -80 aqueous solutions, dissolution medium B is pH=1.2, contains 0.4% Tween-80 solution, and dissolution medium C is pH=4.0, contains 0.4%
Tween-80 buffer solution, dissolution medium D are pH=6.8, contain 0.4% Tween-80 buffer solution.
3. the method for the stripping curve according to claim 2 for measuring Simvastatin Tablets, which is characterized in that the step
(1) in, the solution temperature of the Tween-80 is between 37~40 DEG C.
4. the method for the stripping curve according to claim 3 for measuring Simvastatin Tablets, which is characterized in that the step
(1) in, the Tween-80 is using Sigma or ACROS or injection stage Tween-80.
5. the method for the stripping curve according to claim 4 for measuring Simvastatin Tablets, which is characterized in that the step
(2) in, a concentration of 10 μ g/ml of Simvastatin in the reference substance solution.
6. the method for the stripping curve according to claim 5 for measuring Simvastatin Tablets, which is characterized in that the step
(3) in, the rotating speed is 75 revs/min.
7. the method for the stripping curve according to claim 6 for measuring Simvastatin Tablets, which is characterized in that the step
(3) in, the miillpore filter is polyether sulfone, and the aperture of the polyether sulfone is 0.22 μm.
8. the method for the stripping curve according to claim 7 for measuring Simvastatin Tablets, which is characterized in that the step
(4) in, the sample room injector temperature is 5 DEG C.
9. the method for the stripping curve according to claim 8 for measuring Simvastatin Tablets, which is characterized in that the step
(4) in, when using high effective liquid chromatography for measuring stripping quantity, the parameter of liquid chromatograph is：ACQUITY UPLC BEH C18,
2.1 × 50mm, 1.7 μm；Using octadecylsilane chemically bonded silica as filler, Detection wavelength 238nm, column temperature is 40 DEG C, into
Sample amount is 5 μ l；With 0.02mol/L potassium dihydrogen phosphates-methanol (20:80) it is mobile phase, sets guarantor of the flow velocity to make Simvastatin
It is 4 minutes to stay the time.
10. according to the method for the stripping curve of any measurement Simvastatin Tablets of claim 1-9, which is characterized in that institute
It states in step (6), selects the average stripping quantity number for copying preparation and reference preparation when 15,30,60,120 minute four time point
According to calculating the value of the similar factors f2.
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