CN103018190A - Medicine preparation and determination method of dissolution rate thereof - Google Patents
Medicine preparation and determination method of dissolution rate thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and discloses a medicine preparation comprising (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-hydrindene-5 amide sesquisulfate, and a determination method of the dissolution rate thereof. The dissolution rate method is determined through scientific experiment and researches. Water is adopted as a dissolution media; a rotation speed is 75rpm; and an absorption rate is determined at 257nm with an ultraviolet spectrophotometry method. The composition of the preparation is determined according to the dissolution rate method.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of the have inhibiting pharmaceutical preparation of tyrosine protein kinase and dissolution determination method thereof.
Background technology
Medicine is for human body, and medicine in vivo emission and absorption is the key of drug effect.And every a collection of product can not all carry out in vivo studies, has therefore produced in vitro test means-Dissolution Rate Testing, and it is more simple and easy to do than discharging analytical approach in the medicine body.The medicine that is used for the treatment of human diseases, solid pharmaceutical preparation are accounting for sizable ratio.Solid pharmaceutical preparation only has stripping to be absorbed by body, and what of stripping quantity then can be used as one of reference index of drug effect.Therefore, pharmacopoeia of each country has all been stipulated the dissolution determination project to many pharmaceutical preparations.In recent years, the quality standard of the pharmaceutical solid preparation of the new reply of China has all been formulated the dissolution test project as much as possible.
Patent WO2010072166 discloses the tyrosine protein kinase inhibitor of a brand-new generation: the dihydroindene amides compound, instructions embodiment 16 discloses (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, this patent to quality of preparation, preparation etc. without any research.
Summary of the invention
For these reasons, the applicant has determined contains active component (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2, the pharmaceutical preparation of 3-dihydroindene-5 an acid amides sesquisulfate and measure the dissolution rate method of this pharmaceutical preparation, the method is determined by scientific experiment, take water as dissolution medium, rotating speed is 75 rpms, adopt ultraviolet spectrophotometry, measure absorbance log at 257nm.
The present invention is achieved through the following technical solutions.
A kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound,
In its dissolution determination method take water as dissolution medium.
Wherein dissolution determination method medium speed per minute 75 turns.
Dissolution determination method described above is: according to two appendix of Chinese Pharmacopoeia version in 2010
C the second method dissolution method, take 1000ml distilled water as dissolution medium, rotating speed is that per minute 75 turns, in the time of 30 minutes, get solution, filter, get subsequent filtrate and be need testing solution or accurate measure subsequent filtrate with distilled water quantitatively dilution to make the solution that contains formula I compound 2-20 μ g among every 1ml be need testing solution, according to two appendix of Chinese Pharmacopoeia version in 2010
The A UV-VIS spectrophotometry is measured absorbance log at the wavelength place of 257nm; Modus ponens I compound reference substance is an amount of, accurately weighed in addition, makes the solution that contains 2-20 μ g among every 1ml with dissolved in distilled water and quantitative dilution, measures with method, calculates the stripping quantity of preparation.
Pharmaceutical preparation described above comprises tablet or capsule.
Dissolution rate is more than or equal to 80% and less than or equal to 100% during tablet described above or capsule 30 minutes.
Dissolution rate is more than or equal to 90% and less than or equal to 100% during tablet described above or capsule 30 minutes.
Tablet described above consists of wherein tablet consists of (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 1-5 weight portion, filling agent 6-30 weight portion, disintegrant 0.3-2 weight portion adds or does not add lubricant 0.07-0.5 weight portion.
Filling agent is one or more in lactose, microcrystalline cellulose, cornstarch, pregelatinized starch, sweet mellow wine, sorbierite, calcium monohydrogen phosphate, the calcium sulphate in the tablet described above.
Disintegrant is one or more in low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, Ac-Di-Sol, sodium carboxymethyl starch, the calcium carboxymethylcellulose in the tablet described above.
Lubricant is one or more in dolomol, talcum powder, superfine silica gel powder, Macrogol 4000, the Macrogol 6000 in the tablet described above.
The preparation method of tablet described above is: get (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2, the disintegrant of 3-dihydroindene-5 an acid amides sesquisulfate, filling agent, 80%-90% weight mixes, water softwood processed, granulate, add the residue disintegrant, add lubricant, mix, compressing tablet, and get final product.
One, dissolution rate methodological study
1, the selection of dissolution medium
Test method: respectively take the water of 1000ml, 0.1M aqueous hydrochloric acid solution, pH6.8 phosphate buffer as dissolution medium, be 75rpm according to dissolution method (2010 editions appendix XC the second methods of Chinese Pharmacopoeia) rotating speed, in accordance with the law operation, respectively at 5,10,15,20,30,45,60min gets solution 10ml, 0.45 μ m filtering with microporous membrane, and replenish simultaneously the fresh dissolution medium of equal-volume, (40mg specification sample is measured respectively in 2.5ml to the 10ml measuring bottle to get subsequent filtrate, distilled water is settled to scale, shakes up) be need testing solution; Precision takes by weighing the about 10mg of chemical compounds I reference substance in addition, and is accurately weighed, puts in the 100ml measuring bottle, is settled to scale with water, and precision is measured in 5ml to the 50ml measuring bottle, is settled to scale with distilled water, is reference substance solution.According to ultraviolet-visible spectrophotometry, measure the absorbance log of need testing solution and reference substance solution in the 257nm place, external standard method is calculated the stripping quantity of different time points, draws the accumulation stripping curve.
Table 1 stripping curve result (the 0.1M aqueous hydrochloric acid solution is medium)
Table 2 stripping curve result (the pH6.8 phosphate buffer is medium)
Table 3 stripping curve result (water is dissolution medium)
Experimental result: same batch sample (Preparation Example 1 tablet) adopts different dissolution mediums to measure its cumulative leaching rate.The result shows that the dissolution rate of tablet in three kinds of dissolution mediums of chemical compounds I preparation is suitable, therefore selects water as dissolution medium.
2, the selection of rotating speed
Select the slurry method to carry out dissolution determination, and investigate different rotating speeds to the impact of compound stripping.
Test method: rotating speed is selected respectively 100rpm, 75rpm and 50rpm, take 1000ml water as dissolution medium, respectively at 5,10,15,20,30,45, the 60min sampling, measures in accordance with the law, obtains the stripping result.
The comparison of dissolution rate under the table 4 different rotating speeds condition
Test findings: that measures under three kinds of speed conditions of same batch sample (Preparation Example 1 tablet) the results are shown in Table 4.As a result under 50rpm, 75rpm and the 100rpm speed conditions, sample is about respectively 97.18%, 92.23 %, 95.58% through the 30min stripping quantity, stripping is complete, but the result can find out, the homogeneity otherness of each sample is larger under the 50rpm condition, 75rpm and 100rpm condition stripping curve are substantially similar, and be complete for guaranteeing the sample stripping, selection of speed 75rpm.
3, the methodology of dissolution determination checking
(1) detects determining of wavelength
It is an amount of that precision takes by weighing the compound reference substance respectively, prepares the solution into about 0.01mg/ml with water, 0.1mol/l hydrochloric acid solution, pH6.8 phosphate buffer respectively; Respectively at scanning in 200 ~ 400nm wavelength coverage, select maximum absorption wavelength, the preferred later maximum absorption wavelength of 230nm, sample solution should be between 0.5 ~ 0.7 in the absorbance log of maximum absorption wave strong point.The result shows that the ultraviolet absorpting spectrum of main ingredient compound in water, pH6.8 phosphate buffer is basically identical, and maximum absorption wavelength is respectively 257nm, 256nm, and maximum absorption wavelength slightly has violet shift in the 0.1M hydrochloric acid solution.Because of this product dissolution determination take water as dissolution medium, therefore, select the 257nm wavelength as the detection wavelength of dissolution determination.
(2) linearity
Take by weighing an amount of preparation of compound reference substance into about the solution of 0.3mg/ml, as mother liquor, the accurate 0.25ml that draws puts in the 25ml measuring bottle, and thin up is designated as solution a(3 μ g/ml to scale); The accurate mother liquor 0.5ml that draws puts in the 25ml measuring bottle, and thin up is designated as solution b(6 μ g/ml to scale); The accurate mother liquor 0.75ml that draws puts in the 25ml measuring bottle, and thin up is designated as solution c(9 μ g/ml to scale); The accurate mother liquor 1ml that draws puts the 25ml measuring bottle, and thin up is designated as solution d(12 μ g/ml to scale); The accurate absorption in mother liquor 1.25ml to the 25ml measuring bottle, thin up is designated as solution e(15 μ g/ml to scale); The accurate absorption in mother liquor 1.5ml to the 25ml measuring bottle, thin up is designated as solution f(18 μ g/ml to scale).
Press the sequential determination absorbance log of a, b, c, d, e, f, the results are shown in Table 5.Record absorbance log concentration is carried out linear regression, ask regression curve and related coefficient.As seen, compound of the present invention is in concentration is the scope of 3.00-18.00ug/ml, and linear good, regression curve is Y=0.0499X+0.0055, r2=0.9999.
The absorbance log of the compound solution of table 5 variable concentrations under 257nm
| Concentration (μ g/mL) | 3 | 6 | 9 | 12 | 15 | 18 |
| A | 0.154 | 0.308 | 0.457 | 0.601 | 0.753 | 0.908 |
(3) precision
Take by weighing compound reference substance 10mg in the 100ml volumetric flask, be dissolved in water and be settled to scale, shake up; The accurate absorption in 1ml to the 10ml volumetric flask, distilled water is settled to scale, shakes up, and gets the solution that concentration is 10 μ g/ml (100% concentration level).6 its absorbances of METHOD FOR CONTINUOUS DETERMINATION.The results are shown in Table 6, RSD is 0.20%, shows that precision is good.
Table 6 withinday precision (n=6)
| No | 1 | 2 | 3 | 4 | 5 | 6 | RSD% |
| A | 0.452 | 0.451 | 0.452 | 0.451 | 0.450 | 0.450 | 0.20 |
(4) stability
Get under the precision item solution and measure absorbance log respectively at 0,2,4,6,8,12,24, in the 36h, investigate the RSD% of absorbance log.The results are shown in Table 7, the result shows that sample solution is good at 36 hours internal stabilities.
The stability of table 7 compound solution
(5) recovery
Take by weighing blank prescription 75mg, nominal is got 12 parts, put in the 50ml measuring bottle, numbering is designated as bottle 1 ~ No. 12, respectively at 1 ~ 3 bottle of accurate about 5mg(50% of bulk drug that adds), in 4 ~ No. 6 accurate about 8mg(80% of bulk drug that add of bottle), in 7 ~ No. 9 accurate about 10mg(100% of bulk drug that add of bottle), the accurate about 12mg(120% of bulk drug that adds in the 10-12 bottle).It is an amount of to add water, and shake well adds water and is settled to scale, as need testing solution.It is an amount of that other gets reference substance, and the solution that is configured to 10 μ g/ml is solution in contrast.According to UV-VIS spectrophotometry, measure respectively the absorbance of need testing solution and reference substance solution, external standard method is calculated content and the recovery, the results are shown in Table 8.As seen, the average recovery rate of each level is respectively 99.55%, 99.71%, 99.60% and 101.7%, satisfies the dissolution determination requirement.
The table 8 compound sheet dissolution determination method recovery is investigated the result
Through the methodology checking of system, the linearity of the method, precision, the recovery, stability of solution meet the requirement of dissolution determination, can be used for the dissolution determination of compound tablet.
4, criticize in and batch between the stripping homogeneity investigate
(1) embodiment sample stripping curve is criticized interior homogeneity investigation
Method through system is screened, and quantivative approach has been carried out the methodology checking of system, determines that the dissolution determination method of this product is as follows:
Take 1000ml water as dissolution medium, according to dissolution method (2010 editions appendix of Chinese Pharmacopoeia
C the second method) rotating speed is 75rpm, in accordance with the law operation, respectively at 5,10,15,20,30,45,60min gets solution 10ml, 0.45 μ m filtering with microporous membrane, and replenish simultaneously isopyknic fresh dissolution medium, getting subsequent filtrate (40mg specification sample is measured respectively in 2.5ml to the 10ml measuring bottle, and distilled water is settled to scale, shakes up) is need testing solution; Precision takes by weighing the about 10mg of compound reference substance in addition, and is accurately weighed, puts in the 100ml measuring bottle, adds water and makes dissolving, adds water to scale, shakes up, and precision is measured in 5ml to the 50ml measuring bottle, is settled to scale with water, is reference substance solution.According to ultraviolet-visible spectrophotometry, measure the absorbance log of need testing solution and reference substance solution in the 257nm place, external standard method is calculated the stripping quantity of different time points, draws the curve of accumulation stripping quantity.See Table 9～14.
Table 9 embodiment 2 tablet cumulative leaching rates
Table 10 embodiment 3 tablet cumulative leaching rates
Table 11 embodiment 4 tablet cumulative leaching rates
5 cumulative leaching rates of table 12 embodiment
Table 13 embodiment 6 tablet cumulative leaching rates
Table 14 embodiment 7 tablet cumulative leaching rates
Each three batch sample batch between the stripping homogeneity investigate
Calculate respectively the average stripping curve of each three batch sample of two specifications, and the stripping homogeneity between relatively each batch sample is criticized, the results are shown in Table and see 15.
Table 15 three batch sample strippings batch between homogeneity investigate the result
The dissolution determination of six batch samples
Through the optimization of above condition, finally determine the dissolution determination method of this product:
Take 1000ml water as dissolution medium, according to dissolution method (2010 editions appendix of Chinese Pharmacopoeia
C the second method) rotating speed is 75rpm, and operation is got solution with 0.45 μ m filtering with microporous membrane behind 30min in accordance with the law, and getting subsequent filtrate (40mg specification sample is measured in 12ml to the 50ml measuring bottle, and distilled water is settled to scale, shakes up) is need testing solution; Precision takes by weighing the about 10mg of compound reference substance in addition, and is accurately weighed, puts in the 100ml measuring bottle, adds water and makes dissolving, adds water to scale, shakes up, and precision is measured in 5ml to the 50ml measuring bottle, is settled to scale with water, is reference substance solution.According to ultraviolet-visible spectrophotometry, measure the absorbance log of need testing solution and reference substance solution in the 257nm place, external standard method is calculated every stripping quantity.
Test findings: the dissolution determination of six batch samples the results are shown in Table 16, and the result shows, the dissolution rate of each three batch sample 30min of different embodiment is about 89% ~ 96%, all above 80%, is not less than 80% of labelled amount so the standard limit ordered as the 30min stripping quantity.
The dissolution test result of six batches of compound tablet of table 16
| The sample lot number | Dissolution rate |
| Embodiment 2 | 99.87±1.74 |
| Embodiment 3 | 94.14±1.48 |
| Embodiment 4 | 100.93±1.17 |
| Embodiment 5 | 96.32±4.16 |
| Embodiment 6 | 98.12±4.04 |
| Embodiment 7 | 96.59±4.43 |
Two, Preparation Example
Embodiment 1
Tablet formulation (1000 preparation unit quantity): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 10g, filling agent pregelatinized starch 25g, microcrystalline cellulose 35g, Ac-Di-Sol 3.5g, lubricant talcum powder 0.75g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, pregelatinized starch, microcrystalline cellulose, 2.8g Ac-Di-Sol, water softwood processed is granulated, and adds the 0.7g Ac-Di-Sol, add the lubricant talcum powder, mix, compressing tablet, and get final product.
Embodiment 2
Tablet formulation (1000 preparation unit quantity): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 45g, filling agent pregelatinized starch 150g, microcrystalline cellulose 140g, low-substituted hydroxypropyl cellulose 19g, lubricant Macrogol 6000 4.77g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, pregelatinized starch, microcrystalline cellulose, 17.1g low-substituted hydroxypropyl cellulose mixes, water softwood processed is granulated, and adds the 1.9g low-substituted hydroxypropyl cellulose, add the lubricant Macrogol 6000, mix, compressing tablet, and get final product.
Embodiment 3
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 25g, filling agent lactose 50g, microcrystalline cellulose 100g, disintegrant polyvinylpolypyrrolidone 12.5g, lubricant superfine silica gel powder 2.3g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, 10.6g polyvinylpolypyrrolidone mixes, water softwood processed is granulated, and adds the 1.9g polyvinylpolypyrrolidone, add the lubricant superfine silica gel powder, mix, compressing tablet, and get final product.
Embodiment 4
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 10g, filling agent lactose 17g, microcrystalline cellulose 41g, pregelatinized starch 3.7g, disintegrating agent carboxymethyl base Starch Sodium 3.4g, magnesium stearate lubricant 0.75g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, pregelatinized starch, the 3g sodium carboxymethyl starch mixes, water softwood processed is granulated, and adds the 0.4g sodium carboxymethyl starch, add magnesium stearate lubricant, mix, compressing tablet, and get final product.
Embodiment 5
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 40g, filling agent lactose 68g, microcrystalline cellulose 163g, pregelatinized starch 15g, disintegrating agent carboxymethyl base Starch Sodium 13.5g, magnesium stearate lubricant 4.4g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, pregelatinized starch, the 12g sodium carboxymethyl starch mixes, water softwood processed is granulated, and adds the 1.5g sodium carboxymethyl starch, add magnesium stearate lubricant, mix, compressing tablet, and get final product.
Embodiment 6
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 20g, filling agent lactose 35g, microcrystalline cellulose 80g, pregelatinized starch 7.5g, disintegrating agent carboxymethyl base Starch Sodium 7g, magnesium stearate lubricant 1.6g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, pregelatinized starch, the 6g sodium carboxymethyl starch mixes, water softwood processed is granulated, and adds the 1g sodium carboxymethyl starch, add magnesium stearate lubricant, mix, compressing tablet, and get final product.
Embodiment 7
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 30g, filling agent lactose 50g, microcrystalline cellulose 125g, pregelatinized starch 12g, disintegrating agent carboxymethyl base Starch Sodium 10.5g, magnesium stearate lubricant 2.30g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, pregelatinized starch, the 9g sodium carboxymethyl starch mixes, water softwood processed is granulated, and adds the 1.5g sodium carboxymethyl starch, add magnesium stearate lubricant, mix, compressing tablet, and get final product.
Embodiment 8
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 25g, filling agent lactose 42g, microcrystalline cellulose 103g, pregelatinized starch 10g, disintegrating agent carboxymethyl base Starch Sodium 8.7g, magnesium stearate lubricant 1.9g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, pregelatinized starch, 7.4g sodium carboxymethyl starch mixes, water softwood processed is granulated, and adds the 1.3g sodium carboxymethyl starch, add magnesium stearate lubricant, mix, compressing tablet, and get final product.
Embodiment 9
Tablet formulation (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 50g, filling agent lactose 75g, microcrystalline cellulose 205g, pregelatinized starch 18g, disintegrating agent carboxymethyl base Starch Sodium 19.4g, magnesium stearate lubricant 4.90g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, pregelatinized starch, 16.7g sodium carboxymethyl starch mixes, water softwood processed is granulated, and adds the 2.7g sodium carboxymethyl starch, add magnesium stearate lubricant, mix, compressing tablet, and get final product.
Embodiment 10
Capsule prescription (1000 preparation unit quantity): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 40g, filling agent pregelatinized starch 248g, disintegrant low-substituted hydroxypropyl cellulose 13.3g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, pregelatinized starch, low-substituted hydroxypropyl cellulose mix, water softwood processed, granulate, incapsulate, and get final product.
Embodiment 11
Capsule prescription (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 80g, filling agent lactose 211g, microcrystalline cellulose 358g, disintegrant low-substituted hydroxypropyl cellulose 34.7g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose mix, water softwood processed, granulate, incapsulate, and get final product.
Embodiment 12
Capsule prescription (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 80g, filling agent lactose 208g, microcrystalline cellulose 370g, disintegrant Ac-Di-Sol 39g.
The preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate, lactose, microcrystalline cellulose, Ac-Di-Sol mix, water softwood processed, granulate, incapsulate, and get final product.
Described embodiment includes but not limited to above-mentioned.
Claims (11)
1. dissolution determination method that contains the pharmaceutical preparation of formula I compound,
It is characterized in that in the dissolution determination method take water as dissolution medium.
2. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 1, wherein dissolution determination method medium speed per minute 75 turns.
3. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 1 and 2, wherein dissolution determination method is: according to two appendix of Chinese Pharmacopoeia version in 2010
C the second method dissolution method, take 1000ml distilled water as dissolution medium, rotating speed is that per minute 75 turns, in the time of 30 minutes, get solution, filter, get subsequent filtrate and be need testing solution or accurate measure subsequent filtrate with distilled water quantitatively dilution to make the solution that contains formula I compound 2-20 μ g among every 1ml be need testing solution, according to two appendix of Chinese Pharmacopoeia version in 2010
The A UV-VIS spectrophotometry is measured absorbance log at the wavelength place of 257nm; Modus ponens I compound reference substance is an amount of, accurately weighed in addition, makes the solution that contains 2-20 μ g among every 1ml with dissolved in distilled water and quantitative dilution, measures with method, calculates the stripping quantity of preparation.
4. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 1 and 2, wherein pharmaceutical preparation comprises tablet or capsule.
5. according to right 4 described a kind of dissolution determination methods that contain the pharmaceutical preparation of formula I compound, wherein 30 of tablet or capsule minutes the time dissolution rate more than or equal to 80% and less than or equal to 100%.
6. according to right 4 described a kind of dissolution determination methods that contain the pharmaceutical preparation of formula I, wherein 30 of tablet or capsule minutes the time dissolution rate more than or equal to 90% and less than or equal to 100%.
7. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 4, wherein tablet consists of (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an acid amides sesquisulfate 1-5 weight portion, filling agent 6-30 weight portion, disintegrant 0.3-2 weight portion adds or does not add lubricant 0.07-0.5 weight portion.
8. a kind of dissolution determination method that the formula kind contains the pharmaceutical preparation of formula I compound that contains according to claim 7, wherein filling agent is one or more in lactose, microcrystalline cellulose, cornstarch, pregelatinized starch, sweet mellow wine, sorbierite, calcium monohydrogen phosphate, the calcium sulphate.
9. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 7, wherein disintegrant is one or more in low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, Ac-Di-Sol, sodium carboxymethyl starch, the calcium carboxymethylcellulose.
10. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 7, wherein lubricant is one or more in dolomol, talcum powder, superfine silica gel powder, Macrogol 4000, the Macrogol 6000.
11. a kind of dissolution determination method that contains the pharmaceutical preparation of formula I compound according to claim 7, wherein the preparation method of tablet is: get (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2, the disintegrant of 3-dihydroindene-5 an acid amides sesquisulfate, filling agent, 80%-90% weight mixes, water softwood processed, granulate, add the residue disintegrant, add lubricant, mix, compressing tablet, and get final product.
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