CN102988326B - A kind of febuxostat tablet and preparation method thereof and detection method - Google Patents

A kind of febuxostat tablet and preparation method thereof and detection method Download PDF

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CN102988326B
CN102988326B CN201210544090.1A CN201210544090A CN102988326B CN 102988326 B CN102988326 B CN 102988326B CN 201210544090 A CN201210544090 A CN 201210544090A CN 102988326 B CN102988326 B CN 102988326B
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febuxostat
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CN102988326A (en
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张观福
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Guizhou Xinbang Pharmaceutical Co Ltd
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Abstract

The invention provides a kind of febuxostat tablet and preparation method thereof and detection method, described tablet calculates by weight, is made up of 40 ~ 120 parts of Febuxostats, 95 ~ 165 parts of microcrystalline Cellulose, 20 ~ 60 parts of lactose, 10 ~ 27 parts of cross-linking sodium carboxymethyl celluloses and 1 ~ 3 part of magnesium stearate.The present invention is directed to the deficiencies in the prior art, the prescription of febuxostat tablet and preparation technology are optimized, make it more remarkable to the curative effect of disease such as treatment hyperuricemia and gout etc., and establish system, complete, effective composition differentiates and content assaying method, effectively can control the quality of this medicine, thus guarantee its clinical efficacy.

Description

A kind of febuxostat tablet and preparation method thereof and detection method
Technical field
The present invention relates to a kind of febuxostat tablet and preparation method thereof and detection method, belong to technical field of western medicines.
Background technology
Gout one group of different substantiality disease that blood uric acid increases caused by purine metabolic disturbance and (or) sour acatharsia.After World War II, along with the raising of various countries' economic level, the change of dietary structure, population aging, life, hyperuricemia has become the height morbidity of old people.
Gout is exactly the commonly encountered diseases of the developed countries such as America and Europe from ancient times.Over nearly 20 years, the prevalence of Asia hyperuricemia and gout has the trend significantly increased.
Allopurinol be clinically unique one for suppressing the medicine of uricopoiesis, and be widely used in clinical as the gold medicine of gout, but because allopurinol only has inhibitory action to the XOR of reduced form, need to repeat heavy dose of administration to maintain higher levels of drugs.Many patients maybe can not tolerate allopurinol is irritated, invalid.Febuxostat (febuxostat) is then a species specificity xanthine oxidase inhibitor.Compared with allopurinol, Febuxostat stops the incidence rate of the curative effect of gout outbreak and adverse effect similar, but suppresses uricopoiesis intensity higher.Existing European Union and FDA all ratify its application for quotation, for the treatment of the too high disease gout of chronic uric acid.Clinical study results shows: Clinical efficacy and the safety of Febuxostat all have satisfactory result.
But, because Febuxostat is purine analogue, inevitably cause the impact relating to purine and other enzymatic activitys of pyridine metabolism, therefore in allopurinol treatment, need to repeat heavy dose of administration to maintain higher levels of drugs, have impact on the treatment curative effect of Febuxostat.
In addition, at present a set of strict quality inspection standard reliably also be there is no to Febuxostat medicine.If do not have strict quality standard, the product obtained can not guarantee its quality, and result will affect the clinical efficacy of this medicine; Think the therapeutical effect improving Febuxostat medicine, guarantee medication safe, effectively and product quality stable, formulating a strict reliable quality standard becomes the basic demand of ensuring drug quality.Along with the development of Modern Instrument Analytical Technique, the analytical methods such as high performance liquid chromatography obtain and apply more and more widely in the quality control of medicine.
Summary of the invention
The object of the invention is to, a kind of febuxostat tablet and preparation method thereof and detection method are provided.The present invention is directed to the deficiencies in the prior art, the prescription of febuxostat tablet and preparation technology are optimized, make it more remarkable to the curative effect of the disease such as hyperuricemia and gout, and establish system, complete, effective composition differentiates and content assaying method, effectively can control the quality of this medicine, thus guarantee its clinical efficacy.
Technical scheme of the present invention: a kind of febuxostat tablet, calculates by weight, is made up of 40 ~ 120 parts of Febuxostats, 95 ~ 165 parts of microcrystalline Cellulose, 20 ~ 60 parts of lactose, 10 ~ 27 parts of cross-linking sodium carboxymethyl celluloses and 1 ~ 3 part of magnesium stearate.
Preferred febuxostat tablet is made up of 80g Febuxostat, 110g microcrystalline Cellulose, 40g lactose, 18g cross-linking sodium carboxymethyl cellulose and 2g magnesium stearate.
The preparation method of aforementioned febuxostat tablet comprises the following steps:
(1) preparation of label:
1. get Febuxostat, lactose, cross 80 eye mesh screens respectively, for subsequent use;
2. mixed homogeneously with microcrystalline Cellulose, lactose, partial cross-linked sodium carboxymethyl cellulose by Febuxostat, add appropriate purified water soft material, 18 eye mesh screens are granulated, 70 DEG C of dryings, 18 mesh sieve granulate, add surplus cross-linked carboxymethyl fiber sodium and magnesium stearate, mix homogeneously;
3. intermediate detects, and qualified rear tabletting, obtains plain sheet;
(2) film coating:
1. getting ethanol, purified water is placed in agitator, adding premix coating powder when constantly stirring, continue stirring 1 hour, coating solution 100 eye mesh screens filter, for subsequent use;
2. plain sheet is placed in coating pan, opens coating pan and start air draft and dust exhaust apparatus, using 40 DEG C ~ 45 DEG C hot-air pre-heatings simultaneously, plain sheet is heated evenly, and sops up the fine powder be adsorbed on plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the Coating Solution prepared is sparged on the label of rotation equably; After coating, continue to use cold air drying 10 minutes, coating weight gain 3%-5%.
In the preparation method of aforementioned febuxostat tablet, in mixing and tabletting filling process, ambient humidity controls below 50%.
The detection method of aforementioned febuxostat tablet comprises character, discriminating, inspection and assay project; Wherein differentiate it is that the Febuxostat in preparation is differentiated; Inspection carries out related substance, dissolution, microbial limit and weight differential to this preparation respectively to check; Assay measures Febuxostat.
Concrete content assaying method is:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase be methanol-with triethylamine adjust pH be 5.0 0.3% acetic acid=70:30, adopt UV detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20, this preparation, accurately weighed, porphyrize, precision takes the fine powder being equivalent to Febuxostat 10mg, put in 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 25mL measuring bottle, add methanol dilution to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 10mg and puts in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, adds methanol to scale, and precision measures 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, in contrast product solution; Precision measures above-mentioned reference substance solution and each 10 μ L of need testing solution, respectively injection liquid chromatography, record chromatogram.
Concrete discrimination method is:
(1) liquid phase is differentiated: under assay item, the retention time of test sample main peak is all consistent with the retention time at reference substance peak;
(2) ultraviolet is differentiated: get this preparation fine powder being equivalent to Febuxostat 6mg, put in 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 50mL measuring bottle, add methanol dilution to scale, shake up, ultraviolet visible spectrophotometry with reference to " Chinese Pharmacopoeia " version in 2010 two annex IV A measures, and has absorption maximum at the wavelength place of 215nm and 315nm.
Particular exam method is:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, with the 1000mL phosphate buffer of pH=6.8 for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in 25mL measuring bottle, add stripping medium to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 16mg, puts in 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, then precision pipettes 2mL and puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution; With reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IVA, measure trap at 317nm wavelength place; Calculate the stripping quantity of every sheet;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase be methanol-with triethylamine adjust pH be 5.0 0.3% acetic acid=70:30, adopt UV detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder be equivalent to containing Febuxostat 10mg, put in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, lets cool, adds methanol dilution to scale, shake up, filter, get subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, becomes 1% own control product solution with methanol dilution; Another precision takes impurity A reference substance 10mg, becomes the amount of the impure A of every 1mL to be 2 μ g, in contrast product solution with methanol dilution, gets above-mentioned need testing solution, each 10 μ L injecting chromatographs of reference substance solution, record chromatogram; In need testing solution chromatogram, if any impurity A peak, calculate with external standard method, should 1% be greater than; Desolventize outside peak and adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, the method with reference to " Chinese Pharmacopoeia " two annex Ⅺ J in 2010 calculates;
(4) weight differential: get this preparation, accurately weighed, calculate average sheet weight, then distinguish the weight of accurately weighed every sheet, the regulation of " Chinese Pharmacopoeia " version in 2010 two annex I A should be met.
Described detection method comprises:
(1) character: this preparation is Film coated tablets, after removing coating, whitening color or off-white color;
(2) assay:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase be methanol-with triethylamine adjust pH be 5.0 0.3% acetic acid=70:30, adopt UV detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20, this preparation, accurately weighed, porphyrize, precision takes the fine powder being equivalent to Febuxostat 10mg, put in 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 25mL measuring bottle, add methanol dilution to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 10mg and puts in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, adds methanol to scale, and precision measures 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, in contrast product solution; Precision measures above-mentioned reference substance solution and each 10 μ L of need testing solution, respectively injection liquid chromatography, record chromatogram;
(3) differentiate:
(1) liquid phase is differentiated: under assay item, the retention time of test sample main peak is all consistent with the retention time at reference substance peak;
(2) ultraviolet is differentiated: get this preparation fine powder being equivalent to Febuxostat 6mg, put in 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 50mL measuring bottle, add methanol dilution to scale, shake up, ultraviolet visible spectrophotometry with reference to " Chinese Pharmacopoeia " version in 2010 two annex IV A measures, and has absorption maximum at the wavelength place of 215nm and 315nm;
(4) check:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, with the 1000mL phosphate buffer of pH=6.8 for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in 25mL measuring bottle, add stripping medium to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 16mg, puts in 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, then precision pipettes 2mL and puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution; With reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IV A, measure trap at 317nm wavelength place; Calculate the stripping quantity of every sheet;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase be methanol-with triethylamine adjust pH be 5.0 0.3% acetic acid=70:30, adopt UV detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder be equivalent to containing Febuxostat 10mg, put in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, lets cool, adds methanol dilution to scale, shake up, filter, get subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, becomes 1% own control product solution with methanol dilution; Another precision takes impurity A reference substance 10mg, becomes the amount of the impure A of every 1mL to be 2 μ g, in contrast product solution with methanol dilution, gets above-mentioned need testing solution, each 10 μ L injecting chromatographs of reference substance solution, record chromatogram; In need testing solution chromatogram, if any impurity A peak, calculate with external standard method, should 1% be greater than; Desolventize outside peak and adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, the method with reference to " Chinese Pharmacopoeia " two annex Ⅺ J in 2010 calculates;
(4) weight differential: get this preparation, accurately weighed, calculate average sheet weight, then distinguish the weight of accurately weighed every sheet, the regulation of " Chinese Pharmacopoeia " version in 2010 two annex I A should be met.
In order to ensure the prescription of febuxostat tablet of the present invention and preparation technology's science, reasonable, feasible, applicant carried out series of experimental research and investigation.
One, formulation study:
1, crude drug character
Febuxostat is white or off-white color crystalline powder; Insoluble in water.Therefore, when drafting the prescription of tablet, the dissolution of medicine is an aspect considered emphatically.
2, the character of adjuvant and selection
Known from the relevant information of the ADENURIC of European Union's approval, the adjuvant used in ADENURIC is lactose, microcrystalline Cellulose, magnesium stearate etc.
Lactose compact property is good, and uses lactose unilateral more smooth as filler, and outward appearance is better.
Microcrystalline Cellulose has good mobility and compressibility as filler, and the rapid disintegrate of imbibition, after disintegrate, granule is very thin
Cross-linking sodium carboxymethyl cellulose has extremely strong disintegrate ability.The medicine strong for hydrophobicity is especially applicable.
Magnesium stearate is lubricant, is easy to granule mixing, makes unilateral smooth.
3, prescription screening
Because Febuxostat is water-soluble hardly, therefore, being mainly paper examines index with the disintegration of tablet, dissolution etc. when carrying out prescription screening, the results are shown in Table 1.
Table 1 prescription screening result
Supplementary material title Prescription 1 Prescription 2 Prescription 3 Prescription 4
Febuxostat 4.0g 4.0g 4.0g 4.0g
Microcrystalline Cellulose 8.1g 6.8g 5.5g 5.5g
Lactose -- 1.0g 2.0g 2.0g
Cross-linking sodium carboxymethyl cellulose 0.3g (outward) 0.6g (outward) 0.9g (outward) 0.5g (outward) 0.4g (interior)
Magnesium stearate 0.1g 0.1g 0.1g 0.1g
Appearance character Unilateral slightly rough Unilateral slightly rough Unilateral bright and clean Unilateral bright and clean attractive in appearance
Disintegration (min) 20 14 8 7
Dissolution surveys (%) ---- ---- 81.3 88.6
Result: design sheet weight average in four prescriptions at 0.25g, do not add lactose in prescription 1, it is unilateral that some is coarse, and the disintegrate of tablet and stripping not ideal; In prescription 2, increase the consumption of lactose and disintegrating agent, disintegration time and stripping make moderate progress, but undesirable; The consumption of disintegrating agent is increased in prescription 3, unilateral bright and clean attractive in appearance after increasing lactose consumption, but the granule of accidental non-disintegrate in disintegrating procedue.So by have in prescription 4 disintegrating agent of half change in add, disintegration and stripping meet the requirements, ideal.
Conclusion: preliminary by the prescription of prescription 4 as study on the stability prescription.
Two, Study of operational conditions
1, the selection of binding agent
Because Febuxostat material is more puckery, its mobility is not good enough, therefore adopts wet granule compression tablet technique, and screens binding agent.
Prepare mixed powder according to prescription 4, adopt 50% alcoholic solution, purified water, 2%PVP-k30 aqueous solution to be that binding agent is granulated respectively, observing effect, row filter of going forward side by side.The results are shown in Table 2.
Table 2 binding agent the selection result
Note: all adopt 18 mesh sieve granulating process above.
Conclusion: adopt 50% ethanol as binding agent, material viscosity is comparatively large, cannot granulate; Adopt water and 2%PVP-k30 aqueous solution as binding agent, uniform particles, complete, good fluidity, tablet weight variation is little, and both consider from simple process and economic angle without obviously difference, directly adopt purified water as binding agent.
2, the mensuration of critical relative humidity
For the preparation of solid preparation, the moisture absorption of preparation process Chinese medicine powder is a link that must pay close attention to.The critical relative humidity of drug powder must be measured, and operating environment is controlled.
Method: prepare CH respectively 3cOOK, MgCl 2, KNO 3, NaBr, NaCl, KCl, KNO 2saturated solution, the saturated solution of preparation is inserted in silica gel drier respectively, in 25 DEG C place 72 hours, obtain the constant humidity solution that relative humidity is 20.0%, 33.0%, 42.8%, 59.7%, 75.3%, 84.3%, 92.5% respectively.
By the medicinal mixture that prepared in phosphorus pentoxide desiccator dry 48 hours, the mixture of about 2g is put into bottom the weighing botle of constant weight, after precision weighing, be placed in the exsiccator filling 7 kinds of different saturated solutions to keep 72 hours, precise weighing, calculate Moisture percentage, the results are shown in Table 3.
The Moisture percentage of medicated powder under the different relative humidity of table 3
Solution RH％（25℃） Moisture percentage (%)
CH 3COOK 20.0 1.98
MgCl 2 33.0 2.22
KNO 3 42.8 2.44
NaBr 59.7 3.82
NaCl 75.3 5.93
KCl 84.3 8.26
KNO 2 92.5 11.14
With hydroscopicity data for vertical coordinate, relative humidity data is abscissa mapping, the results are shown in Figure 1.As seen from Figure 1, more than 50%, moisture absorption obviously strengthens, and therefore, can determine that the critical relative humidity of finished product is 50%.In mixing and tabletting filling process, ambient humidity controls below 50%.
Three, formulation and technology demonstration test
Method: the prescription determined with screening process, (lot number: 080909), and film coating, with plain sheet hardness, coated tablet outward appearance, tablet weight variation, dissolution, related substance and content for inspection target, are evaluated to prepare 200, sample.
1, outward appearance
This preparation is Film coated tablets, and removing film-coat shows off-white color.
2, tablet weight variation inspection
Get coated tablet 20 at random, successively precision weighing sheet weight, record numerical value, sheet average weight 0.2581g, maximum overgauge 3.3%, maximum minus deviation 4.4%, meets pharmacopeia relevant regulations.
3, hardness measurement
The hardness of element sheet has important impact to coating, and General Requirements sheet hardness is at more than 5Kg.Get lower 10 of tablet weight variation item, measure hardness, the results are shown in Table 4.
Table 4 hardness measurement result
Sample number Hardness (Kg)
1 6.25
2 7.23
3 7.56
4 8.22
5 7.56
6 7.88
7 7.33
8 7.96
9 7.14
10 7.37
Average sheet is heavily 7.45Kg, and hardness is moderate, is applicable to coating.
4, assay
Get the sample under tablet weight variation item, measure according to method under assay item, assay result is 100.5%.
5, Dissolution Rate Testing
Get this preparation, measure according to method under quality standard Dissolution Rate Testing item, result is 95.5%.
Conclusion: as can be seen from above-mentioned dissolution test result, the dissolution of preproduction is more than 80%, and drug-eluting is good, conforms with the regulations.
6, determination of related substances
Measure by quality standard determination of related substances method, impurity A result is 0.387%; Other related substance result is 0.059%.
The study on determination method of impurity A (i.e. Febuxostat hydrolyzate), refers to the patent application document that name that the applicant and present specification submit to is on the same day called " a kind of preparation method of febuxostat raw material and detection method ".
7, the investigation of influence factor
(1) exposure experiments to light:
Get this preparation, putting illumination is that 4500LX ± 500LX irradiates 10 days, by sampling in 0,5,10 day, measures indices, the results are shown in Table 5.
Table 5 febuxostat tablet exposure experiments to light result
Result of the test shows, this preparation illumination 5,10 days, indices compared with 0 day, and indices has no significant change.
(2) hot test
Get this preparation, place 10 days under putting 60 DEG C of temperature, by sampling in 0,5,10 day, measure indices, the results are shown in Table 6.
Table 6 febuxostat tablet hot test result
Result of the test shows, places 5,10 days for 60 DEG C, indices with within 0 day, compare indices and have no significant change.
(3) high humility test
Get this preparation, put in constant-temperature enclosed vessel, 25 DEG C respectively at relative humidity 92.5% and 75% ± 1% condition under place 10 days, by sampling in 0,5,10 day, during relative humidity 92.5% condition, respectively moisture absorption 13.2% and 14.4% in 5,10 days; During relative humidity 75% ± 1% condition, moisture absorption 1.8% and 2.1% respectively in 5,10 days; So sample when getting relative humidity 75% ± 1% condition, measure indices, the results are shown in Table 7.
Table 7 febuxostat tablet high humility result of the test
Result of the test shows, relative humidity 75% ± 1% is placed 5,10 days, and indices compared with 0 day, and indices has no significant change.
In addition, in order to ensure detection method science, reasonable, feasible, applicant carried out series of experimental research and investigation.
One, character: measure four batch samples and be Film coated tablets, except off-white color aobvious after coating, the results are shown in Table 8.
Table 8 measurement result
Two, differentiate
1, in the chromatogram recorded under assay item, the retention time of need testing solution main peak should consistent with reference substance solution main peak.Identification result is in table 9.
2, intend adopting x powder diffraction to measure Febuxostat crystal formation characteristic peak, after using raw material and adjuvant to measure respectively, discovery adjuvant measures crystal formation impact, does not therefore adopt.
3, ultraviolet is differentiated: get this preparation fine powder appropriate (being about equivalent to Febuxostat 6mg), put in 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 50mL measuring bottle, add methanol dilution to scale, shake up, ultraviolet visible spectrophotometry with reference to " Chinese Pharmacopoeia " version in 2010 two annex IV A measures, and has absorption maximum at the wavelength place of 215nm and 315nm.The results are shown in Table 9.
Measurement result differentiated by table 9
Three, check
1, weight differential: get febuxostat tablet 20, accurately weighed, calculate average sheet weight, then distinguish the weight of accurately weighed every sheet.Comparatively, limit test of weight variation is ± 7.5% for the weight of every sheet and average sheet anharmonic ratio, measures four batches, the results are shown in Table 10.
Table 10 check result
2, limit test of microbe: get febuxostat tablet, with reference to the method for " Chinese Pharmacopoeia " two annex Ⅺ J in 2010, measures four batches, the results are shown in Table 11.
Table 11 limit test of microbe result
3, the methodological study of dissolution and mensuration
3.1 instruments: ZRS-8G type medicament dissolution instrument; Agilent 6010 ultraviolet-visible spectrophotometer.
The determination of 3.2 mensuration concentration: get febuxostat raw material medicine and be about 8mg, put in 100mL measuring bottle, add methanol ultrasonic dissolution and be diluted to scale, shake up, then measure 1mL, 2mL, 3mL, 5mL respectively and respectively put in 25mL measuring bottle, be diluted with water to scale, shake up, with reference to the UV, visible light-spectrophotography of " Chinese Pharmacopoeia " version in 2010 two annex IV A, measure trap at 317nm wavelength place, result measures 2mL, and to put the trap of the solution of 25mL measuring bottle comparatively suitable.
3.3 febuxostat tablet of the present invention (adopt novel crystal forms, its crystal formation preparation method refers to the patent application document that name that the applicant and present specification submit to is on the same day called " a kind of preparation method of febuxostat raw material and detection method ") stripping situation in various medium and the comparative study of sheet prepared with Febuxostat (patent crystal formation, its patent publication No. is CN1275126A).
Sample thief, with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, respectively with the water of 1000mL, 0.1mol/L hydrochloric acid solution, buffer salt (the 9.15g citric acid of pH=5.5, 40.43g dipotassium hydrogen phosphate, add water to 1000mL) and phosphate buffer (pH=6.8) be dissolution medium, rotating speed is set to 100 turns per minute, operate in accordance with the law, through 5, 10, 20, 30, 45, when 60 minutes, sample 10mL(fluid infusion simultaneously 10mL respectively), filter, precision pipettes subsequent filtrate 2mL, put in 25mL measuring bottle, add stripping medium to scale, shake up, as need testing solution.Precision takes at Febuxostat reference substance 16mg, puts in 50mL measuring bottle, add dissolve with methanol and be diluted to scale, shaking up, then precision pipettes 2mL, puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution.Get above-mentioned two kinds of solution, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two annex IV A, measure trap at 317nm wavelength place, calculate the stripping quantity of every sheet.The results are shown in Table 12 and Fig. 2.
Measurement result in table 12 two kinds of each media of crystal formation
From data and the stripping curve of the different dissolution medium of two kinds of crystal formations, the In Vitro Dissolution behavior of novel crystal forms prepared by the present invention and sample prepared by patent crystal formation is basically identical.
3.4 adjuvant interference tests
The blank auxiliary appropriate (being about equivalent to containing Febuxostat 16mg) of getting this preparation is put in 50mL measuring bottle, add dissolve with methanol and be diluted to scale, shake up, then precision pipettes 2mL, put in 100mL measuring bottle, be diluted with water to scale, shake up, get above-mentioned solution, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two annex IV A, trap is measured, result adjuvant not interference measurement at 317nm wavelength place.
The selection of 3.5 rotating speeds
Get febuxostat tablet, with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, with 1000mL phosphate buffer (pH=6.8) for dissolution medium, rotating speed is for be set to 50,75,100 turns per minute respectively, operate in accordance with the law, through 5,10,20,30,45,60 minutes time, sample 10mL respectively, (and the 10mL of fluid infusion simultaneously) filters, precision pipettes subsequent filtrate 2mL, puts in 25mL measuring bottle, adds stripping medium to scale, shake up, as need testing solution.Precision takes at Febuxostat reference substance 16mg, puts in 50mL measuring bottle, add dissolve with methanol and be diluted to scale, shaking up, then precision pipettes 2mL, puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution.Get above-mentioned two kinds of solution, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two annex IV A, measure trap at 317nm wavelength place.Calculate the stripping quantity of every sheet.The results are shown in Table 13.
The mensuration of table 13 selection of speed
This preparation rotating speed be 50 revs/min, 75 revs/min and 100 revs/min time, the dissolution of 45 minutes these preparations is all about 90%, consider the situation of the mensuration of dissolution to quality of the pharmaceutical preparations resolution capability, select the comparatively slow-speed of revolution, the rotating speed of this preparation dissolution determination is decided to be 50 turns per minute, and sample time is 30 minutes.
3.6 dissolution method
The Dissolution Rate Testing condition of this preparation and method, test with reference to " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C.The dissolution medium of this preparation selects 1000mL phosphate buffer (pH=6.8); Adopt " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, rotating speed is 50 revs/min, and sampling in 30 minutes, adopts the dissolution of UV method working sample.
3.7 linear relationship
Precision takes febuxostat raw material medicine 12.8mg, put in 100mL measuring bottle, add dissolve with methanol and be diluted to scale, shake up, precision measures 1,3,5,7,10mL puts in 100mL measuring bottle respectively, add stripping medium to scale, shake up, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IV A, measure trap at 317nm wavelength place.The results are shown in Table 14 and Fig. 3.
The mensuration of table 14 working curve
Concentration (μ g/mL) 1.287 3.861 6.435 9.009 12.870
Trap (A) 0.094 0.281 0.457 0.653 0.912
As shown in Figure 3, linear equation is Y=0.0708X+0.0054, R 2=0.9996 shows in 1.287-12.870 μ g/mL concentration range in good linear.
3.8 stability test
Precision takes this preparation sheet powder appropriate (about containing Febuxostat 16mg), puts in 50mL measuring bottle, adds dissolve with methanol and be diluted to scale, shaking up, filter, get subsequent filtrate 2mL and put in 100mL measuring bottle, add stripping medium to scale, shake up, as need testing solution.Get above-mentioned solution respectively at 0,1,2,3,4 hour, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IV A, measure trap at 317nm wavelength place.The results are shown in Table 15.
The mensuration of table 15 stability test
Time (h) 0 1 2 3 4 On average Rsd％
Trap (A) 0.437 0.429 0.433 0.435 0.430 0.433 0.77
3.9 recovery test
Precision takes each three parts of febuxostat raw material medicine 9.6mg, 16mg, 19.2mg, put in 50mL measuring bottle respectively, and add various adjuvant in prescription ratio, add dissolve with methanol and be diluted to scale, shaking up, filtering, getting subsequent filtrate 2mL puts in 100mL measuring bottle, add stripping medium to scale, shake up, as need testing solution.Another precision takes Febuxostat reference substance 16mg, puts in 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, then precision pipettes 2mL and puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution.Get above-mentioned solution respectively, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two annex IV A, measure trap at 317nm wavelength place.The results are shown in Table 9.
Table 16 determination of recovery rates result
The mensuration of 3.10 stripping curves
Get this preparation (four batches), with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, with 1000mL phosphate buffer (pH=6.8) for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, and sampled 10mL(respectively in 5,10,20,30,45,60 minutes and the 10mL of fluid infusion simultaneously), filter, get subsequent filtrate 2mL, put in 25mL measuring bottle, add stripping medium to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 16mg, puts in 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, then precision pipettes 2mL and puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution.Get above-mentioned solution respectively, with reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IV A, measure trap at 317nm wavelength place.The results are shown in Table 17.
The mensuration of table 17 stripping curve
The mensuration of 3.11 dissolutions
Get this preparation (four batches), with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex XC second methods, with 1000mL phosphate buffer (pH=6.8) for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, and sampled 10mL(respectively in 30 minutes and the 10mL of fluid infusion simultaneously), filter, get subsequent filtrate 2mL, put in 25mL measuring bottle, add stripping medium to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 16mg, puts in 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, then precision pipettes 2mL and puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution.With reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IV A, measure trap at 317nm wavelength place.The results are shown in Table 18.
Table 18 dissolution determination result
Lot number 080909 081007 081008 081009
Dissolution (%) 95.5 96.9 98.1 98.7
4, Related substances separation
4.1 chromatographic condition
INSTRUMENT MODEL: Japanese Shimadzu LC-10ATvp, SPD-10Avp detector;
Chromatographic column: take octadecylsilane chemically bonded silica as filler;
Mobile phase: methanol-0.3% acetic acid (triethylamine adjusts pH to be 5.0) (70:30);
Flow velocity is 1.0mL/min, and column temperature is room temperature, and wavelength is 317nm, and sample size is 10 μ L.
The preparation of 4.2 need testing solutions
Get this preparation sheet powder appropriate (being about equivalent to containing Febuxostat 10mg), put in 50mL measuring bottle, add methanol appropriate, ultrasonicly make dissolving, let cool, add methanol dilution to scale, shake up, filter, get subsequent filtrate as need testing solution.
The blank interference test of 4.3 adjuvants
The preparation of adjuvant blank solution: according to prescription, gets this pharmaceutical adjunct blank appropriate (being about equivalent to containing Febuxostat 10mg), puts in 50mL measuring bottle, add methanol appropriate, ultrasonicly make dissolving, let cool, add methanol dilution to scale, shake up, filter, get subsequent filtrate as adjuvant blank solution.
Measure blank solution 10 μ L sample introduction, the display of result spectrogram is blank noiseless.
4.4 failure test
Acid degradation product: get need testing solution 2mL, adds 1mol/L hydrochloric acid 1mL, shakes up, and places half an hour, is adjusted to neutrality, obtains final product with 1mol/L sodium hydroxide.
Alkaline degradation product: get need testing solution 2mL, adds 1mol/L sodium hydroxide 1mL, shakes up, and places half an hour, is adjusted to neutrality, obtains final product with 1mol/L hydrochloric acid.
Oxidative breakdown product: get need testing solution 2mL, adds hydrogen peroxide 2mL, shakes up, and places half an hour, immediately sample introduction.
High temperature: get need testing solution 5mL, puts heating in 80 degree of baking ovens and lets cool after 3 hours, add to 5mL with methanol.
Photo damage: get need testing solution 5mL, places 3 hours, adds to 5mL after taking-up with methanol under 4500 ± 500LX high light.
Get each 10 μ L injecting chromatographs of above-mentioned degraded solutions respectively, record spectrogram, result shows that this formulation soln is comparatively stable to acid, hydrogen peroxide, light and high temperature, more unstable to alkali.
4.5 minimumly detect
Get this preparation need testing solution 1mL to put in 100mL measuring bottle, add methanol dilution to scale, shake up, as 1% solution, then get 1% solution with methanol respectively and be diluted to 0.01%, 0.02% and 0.03% solution.
Get each 10 μ L sample introductions of above-mentioned 0.01%, 0.02% and 0.03% solution respectively, record spectrogram, result shows that the minimum detectable activity of this preparation is 0.20ng, and minimum limit of detection is 0.03%.
4.6 algoscopys:
Get this preparation sheet powder appropriate (being about equivalent to containing Febuxostat 10mg), put in 50mL measuring bottle, add methanol appropriate, ultrasonicly make dissolving, let cool, add methanol dilution to scale, shake up, filter, get subsequent filtrate as need testing solution.Precision pipettes above-mentioned need testing solution 1mL again, becomes 1% own control product solution with methanol dilution; Another precision takes impurity A (retention time is about about 4 minutes) reference substance 10mg, becomes the amount of the impure A of every 1mL to be 2 μ g, in contrast product solution with methanol dilution, gets each 10 μ L injecting chromatographs of above-mentioned solution, record chromatogram.In need testing solution chromatogram, if any impurity A peak, calculate with external standard method, should 1%(1% be greater than); Desolventize outside peak and adjuvant peak, the peak area sum of other impurity should be not more than 1 times (1%) of own control peak area.Measure four batches and the results are shown in Table 19.
Table 19 Related substances separation
Lot number 080909 081007 081008 081009
Impurity A 0.387 0.037 0.391 0.183
Other impurity 0.059 0.048 0.048 0.068
Four, assay
Adopt HPLC method to carry out the methodological study of assay, and determine the content of sample.Specify that the content limit of this preparation is 95.0-105.0%.
1, INSTRUMENT MODEL: Japanese Shimadzu LC-10ATvp; SPD-10Avp detector.
2, chromatographic condition
Be filler with octadecylsilane chemically bonded silica; Methanol-0.3% acetic acid (triethylamine adjusts pH to be 5.0) (70:30), adopt UV to detect, determined wavelength is 317nm.Flow velocity is 1.0mL/L.
3, replica test
Get same batch sample appropriate (about containing Febuxostat 10mg), six parts respectively, accurately weighed, put in 50mL measuring bottle, add methanol appropriate, ultrasonicly make dissolving, add methanol to scale, shake up, filter.Precision measures subsequent filtrate 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, as need testing solution; Another precision takes Febuxostat reference substance 10mg and puts in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, adds methanol to scale, and precision measures 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, in contrast product solution.Precision measures above-mentioned reference substance solution and each 10 μ L of need testing solution injection liquid chromatography respectively, and record chromatogram, calculates the content of working sample, the results are shown in Table 20.
The repeated measurement result of table 20
4, need testing solution stability
Get the lower first part of need testing solution of repeated item, got 10 μ L injection liquid chromatographies respectively at 0,2,4,6,8 hour, record chromatogram, to obtain final product.The results are shown in Table 21.
Table 21 Stability Determination result
Time (hour)) 0 2 4 6 8 On average RSD%
Peak area (A) × 10 3 1158 1165 1156 1161 1159 1159.8 0.29
5, recovery test
Precision take Febuxostat reference substance 8,10,12mg three parts respectively, put in 50mL measuring bottle, add adjuvant in prescription ratio, add methanol in right amount the ultrasonic Febuxostat that makes dissolve, add methanol dilution again to scale, shake up, filter, precision pipettes subsequent filtrate 5mL, put in 25 measuring bottles, add methanol dilution to scale, shake up, as need testing solution.Another precision takes Febuxostat reference substance 10mg and puts in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, adds methanol to scale, and precision measures 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, in contrast product solution.Precision measures above-mentioned reference substance solution and each 10 μ L of need testing solution injection liquid chromatography respectively, and record chromatogram, calculates the response rate.The results are shown in Table 22.
Table 22 determination of recovery rates result
6, assay
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Methanol-0.3% acetic acid (triethylamine adjusts pH to be 5.0) (70:30), adopt UV to detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000.
Get 20, this preparation, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to Febuxostat 10mg), put in 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 25mL measuring bottle, add methanol dilution to scale, shake up, as need testing solution.Another precision takes Febuxostat reference substance 10mg and puts in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, adds methanol to scale, and precision measures 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, in contrast product solution.Precision measures above-mentioned reference substance solution and each 10 μ L of need testing solution injection liquid chromatography respectively, and record chromatogram, result of calculation is in table 23.
Table 23 assay result
Lot number 080909 081007 081008 081009
Labelled amount content (%) 100.5 100.0 100.2 100.1
Five, stability testing method and result
The stability of febuxostat tablet is investigated according to " Chinese Pharmacopoeia " version two-shift system agent medicine stability requirement in 2010.
1, accelerated test: (sample lot number: 081007,081008,081009)
Get this preparation, respectively simulation listing packaging, be placed in 40 DEG C ± 2 DEG C, humidity be 75% ± 5% time place, in 0,1,2,3,6 month sampling, detect.The results are shown in Table 24.
Table 24 accelerated test result
5.2 long term tests: (sample lot number: 081007,081008,081009)
Get this preparation, respectively simulation listing packaging, be placed in 25 DEG C ± 2 DEG C, relative humidity be 60% ± 10% preserve, in 0,3,6,12,18 month sampling, detect.The results are shown in Table 25.
Table 25 long-term test results
Six, conclusion and evaluation
According to chemicals stability study technological guidance principle, stability test is carried out to this preparation.(1) pilot sample is carried out to influence factor's experiments such as illumination, high temperature, high humidity, result shows: every inspection target, without significant change, all meets clinical sample quality draft standard; (2) three batch samples are accelerated test 6 months (40 DEG C, RH75% condition under) under simulation listing packaging, and this preparation is through above-mentioned condition accelerated test after 6 months, and every inspection target, without significant change, all meets clinical sample quality draft standard; (3) three batch sample simulation listing packagings, 25 DEG C ± 2 DEG C, under the condition of relative humidity 60% ± 10%, through keeping sample investigation after 6 months for a long time, every inspection target is without significant change, all meet clinical sample quality draft standard, keep sample for a long time to investigate to test and still carrying out.
Compared with prior art, the present invention improves the prescription of febuxostat tablet and preparation technology, and be stable preparation process, feasible, the Febuxostat tablet quality of preparation is well stablized, and makes it more remarkable to the curative effect of the disease such as hyperuricemia and gout; And, the present invention is directed to the febuxostat tablet after improvement and establish system, complete, effective quality determining method, the specificity of described method is strong, precision is high, favorable reproducibility, the response rate are high, measurement result is accurate, reach the object effectively controlling drug quality, thus ensure that the safe, effective of the stable of product quality and clinical application.Package materials selection is proper, and long-term placement sample stability is good.
Accompanying drawing explanation
Fig. 1 is the Moisture percentage curve chart of medicated powder under different relative humidity;
Fig. 2 is the different dissolution medium comparative graph of two kinds of crystal formations;
Fig. 3 is febuxostat tablet dissolution linear relationship working curve diagram.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1: described febuxostat tablet is made up of 80g Febuxostat, 110g microcrystalline Cellulose, 40g lactose, 18g cross-linking sodium carboxymethyl cellulose and 2g magnesium stearate.Get Febuxostat, lactose, cross 80 eye mesh screens respectively, for subsequent use; Mixed homogeneously with 110g microcrystalline Cellulose, 40g lactose, 8g cross-linking sodium carboxymethyl cellulose by 80g Febuxostat, add appropriate purified water soft material, 18 eye mesh screens are granulated, 70 DEG C of dryings, 18 mesh sieve granulate, add surplus cross-linked carboxymethyl fiber sodium and 2g magnesium stearate, mix homogeneously; Intermediate detects, and qualified rear tabletting, obtains plain sheet; Getting 370g ethanol, 100g purified water is placed in agitator, adding 30g premix coating powder when constantly stirring, continue stirring 1 hour, coating solution 100 eye mesh screens filter, for subsequent use; Plain sheet is placed in coating pan, opens coating pan and start air draft and dust exhaust apparatus, using 40 DEG C ~ 45 DEG C hot-air pre-heatings simultaneously, plain sheet is heated evenly, and sops up the fine powder be adsorbed on plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the Coating Solution prepared is sparged on the label of rotation equably; After coating, continue to use cold air drying 10 minutes, coating weight gain 3%-5%; In mixing and tabletting filling process, ambient humidity controls below 50%.
Embodiment 2: described febuxostat tablet is made up of 120g Febuxostat, 165g microcrystalline Cellulose, 60g lactose, 27g cross-linking sodium carboxymethyl cellulose and 3g magnesium stearate.Get Febuxostat, lactose, cross 80 eye mesh screens respectively, for subsequent use; Mixed homogeneously with 165g microcrystalline Cellulose, 60g lactose, 12g cross-linking sodium carboxymethyl cellulose by 120g Febuxostat, add appropriate purified water soft material, 18 eye mesh screens are granulated, 70 DEG C of dryings, 18 mesh sieve granulate, add surplus cross-linked carboxymethyl fiber sodium and 3g magnesium stearate, mix homogeneously; Intermediate detects, and qualified rear tabletting, obtains plain sheet; Getting 550g ethanol, 150g purified water is placed in agitator, adding 45g premix coating powder when constantly stirring, continue stirring 1 hour, coating solution 100 eye mesh screens filter, for subsequent use; Plain sheet is placed in coating pan, opens coating pan and start air draft and dust exhaust apparatus, using 40 DEG C ~ 45 DEG C hot-air pre-heatings simultaneously, plain sheet is heated evenly, and sops up the fine powder be adsorbed on plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the Coating Solution prepared is sparged on the label of rotation equably; After coating, continue to use cold air drying 10 minutes, coating weight gain 3%-5%; In mixing and tabletting filling process, ambient humidity controls below 50%.
Embodiment 3: described febuxostat tablet is made up of 40g Febuxostat, 95g microcrystalline Cellulose, 20g lactose, 10g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate.Get Febuxostat, lactose, cross 80 eye mesh screens respectively, for subsequent use; Mixed homogeneously with 95g microcrystalline Cellulose, 20g lactose, 4g cross-linking sodium carboxymethyl cellulose by 40g Febuxostat, add appropriate purified water soft material, 18 eye mesh screens are granulated, 70 DEG C of dryings, 18 mesh sieve granulate, add surplus cross-linked carboxymethyl fiber sodium and 1g magnesium stearate, mix homogeneously; Intermediate detects, and qualified rear tabletting, obtains plain sheet; Getting 185g ethanol, 50g purified water is placed in agitator, adding 15g premix coating powder when constantly stirring, continue stirring 1 hour, coating solution 100 eye mesh screens filter, for subsequent use; Plain sheet is placed in coating pan, opens coating pan and start air draft and dust exhaust apparatus, using 40 DEG C ~ 45 DEG C hot-air pre-heatings simultaneously, plain sheet is heated evenly, and sops up the fine powder be adsorbed on plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the Coating Solution prepared is sparged on the label of rotation equably; After coating, continue to use cold air drying 10 minutes, coating weight gain 3%-5%; In mixing and tabletting filling process, ambient humidity controls below 50%.
Embodiment 4: the complete detection method of febuxostat tablet of the present invention is:
(1) character: this preparation is Film coated tablets, after removing coating, whitening color or off-white color;
(2) assay:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase be methanol-with triethylamine adjust pH be 5.0 0.3% acetic acid=70:30, adopt UV detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get 20, this preparation, accurately weighed, porphyrize, precision takes the fine powder being equivalent to Febuxostat 10mg, put in 50mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 25mL measuring bottle, add methanol dilution to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 10mg and puts in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, adds methanol to scale, and precision measures 5mL and puts in 25mL measuring bottle respectively, adds methanol dilution to scale, shakes up, in contrast product solution; Precision measures above-mentioned reference substance solution and each 10 μ L of need testing solution, respectively injection liquid chromatography, record chromatogram;
(3) differentiate:
(1) liquid phase is differentiated: under assay item, the retention time of test sample main peak is all consistent with the retention time at reference substance peak;
(2) ultraviolet is differentiated: get this preparation fine powder being equivalent to Febuxostat 6mg, put in 100mL measuring bottle, add that methanol is ultrasonic to be made Febuxostat dissolve and be diluted to scale, shake up, filter, get subsequent filtrate 5mL, put in 50mL measuring bottle, add methanol dilution to scale, shake up, ultraviolet visible spectrophotometry with reference to " Chinese Pharmacopoeia " version in 2010 two annex IV A measures, and has absorption maximum at the wavelength place of 215nm and 315nm;
(4) check:
(1) dissolution: concrete operations are as follows: get this preparation, with reference to the dissolution method of " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, with the 1000mL phosphate buffer of pH=6.8 for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, and in 30 minutes sampling 10mL, filter, get subsequent filtrate 2mL, put in 25mL measuring bottle, add stripping medium to scale, shake up, as need testing solution; Another precision takes Febuxostat reference substance 16mg, puts in 50mL measuring bottle, adds dissolve with methanol and is diluted to scale, shaking up, then precision pipettes 2mL and puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution; With reference to the spectrophotography of " Chinese Pharmacopoeia " version in 2010 two record IVA, measure trap at 317nm wavelength place; Calculate the stripping quantity of every sheet;
(2) related substance:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Mobile phase be methanol-with triethylamine adjust pH be 5.0 0.3% acetic acid=70:30, adopt UV detect, determined wavelength is 317nm, and flow velocity is 1.0mL/min; Number of theoretical plate is pressed Febuxostat peak and is calculated, and should be not less than 2000;
Algoscopy: get this preparation sheet powder be equivalent to containing Febuxostat 10mg, put in 50mL measuring bottle, adds methanol appropriate, ultrasonicly makes dissolving, lets cool, adds methanol dilution to scale, shake up, filter, get subsequent filtrate as need testing solution; Precision pipettes above-mentioned need testing solution 1mL again, becomes 1% own control product solution with methanol dilution; Another precision takes impurity A reference substance 10mg, becomes the amount of the impure A of every 1mL to be 2 μ g, in contrast product solution with methanol dilution, gets above-mentioned need testing solution, each 10 μ L injecting chromatographs of reference substance solution, record chromatogram; In need testing solution chromatogram, if any impurity A peak, calculate with external standard method, should 1% be greater than; Desolventize outside peak and adjuvant peak, the peak area sum of other impurity should be not more than 1 times of own control peak area;
(3) microbial limit: get this preparation, the method with reference to " Chinese Pharmacopoeia " two annex Ⅺ J in 2010 calculates;
(4) weight differential: get this preparation, accurately weighed, calculate average sheet weight, then distinguish the weight of accurately weighed every sheet, the regulation of " Chinese Pharmacopoeia " version in 2010 two annex I A should be met.

Claims (2)

1. a febuxostat tablet, is characterized in that: calculate by weight, and label is made up of 40 ~ 120 parts of Febuxostats, 95 ~ 165 parts of microcrystalline Cellulose, 20 ~ 60 parts of lactose, 10 ~ 27 parts of cross-linking sodium carboxymethyl celluloses and 1 ~ 3 part of magnesium stearate;
The preparation method of described tablet comprises the following steps:
(1) preparation of label:
1. get Febuxostat, lactose, cross 80 eye mesh screens respectively, for subsequent use;
2. mixed homogeneously with microcrystalline Cellulose, lactose, partial cross-linked sodium carboxymethyl cellulose by Febuxostat, add appropriate purified water soft material, 18 eye mesh screens are granulated, 70 DEG C of dryings, 18 mesh sieve granulate, add surplus cross-linked carboxymethyl fiber sodium and magnesium stearate, mix homogeneously;
3. intermediate detects, and qualified rear tabletting, obtains plain sheet;
(2) film coating:
1. getting ethanol, purified water is placed in agitator, adding premix coating powder when constantly stirring, continue stirring 1 hour, coating solution 100 eye mesh screens filter, for subsequent use;
2. plain sheet is placed in coating pan, opens coating pan and start air draft and dust exhaust apparatus, using 40 DEG C ~ 45 DEG C hot-air pre-heatings simultaneously, plain sheet is heated evenly, and sops up the fine powder be adsorbed on plain sheet; Start coating pan, regulate coating solution granularity of spray and spray velocity, the Coating Solution prepared is sparged on the label of rotation equably; After coating, continue to use cold air drying 10 minutes, coating weight gain 3%-5%.
2. febuxostat tablet according to claim 1, is characterized in that: in mixing and tableting processes, ambient humidity controls below 50%.
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