CN104473887A - Method for improving reproducibility of rivaroxaban tablet dissolution curve - Google Patents
Method for improving reproducibility of rivaroxaban tablet dissolution curve Download PDFInfo
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- CN104473887A CN104473887A CN201410635383.XA CN201410635383A CN104473887A CN 104473887 A CN104473887 A CN 104473887A CN 201410635383 A CN201410635383 A CN 201410635383A CN 104473887 A CN104473887 A CN 104473887A
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- dissolution medium
- dissolution
- lauryl sulphate
- sodium lauryl
- razaxaban
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Abstract
The invention provides a method for improving reproducibility of a rivaroxaban tablet dissolution curve; the method comprises that through use of sodium dodecyl sulfate as a surfactant, a dissolution medium stock solution is prepared, wherein the content of sodium dodecyl sulfate in the dissolution medium stock solution is not allowed to be higher than 10%w/v; and micelles formed by sodium dodecyl sulfate in a dissolution medium are broken before use, sodium dodecyl sulfate is homogenized in the dissolution medium, and finally a dissolution rate test on the obtained dissolution medium is carried out. The method can effectively improve the reproducibility of the rivaroxaban tablet dissolution rate curve and provides a guarantee for accurate determination of the rivaroxaban dissolution rate.
Description
Technical field
This area belongs to field of medicine and chemical technology, is specifically related to a kind of reproducible method of raising razaxaban sheet stripping curve.
Background technology
Razaxaban, the chemistry chloro-nitrogen of 5--({ (5S)-2-oxygen-3-[-4-(3-oxygen-4-morpholinyl) phenyl]-1,3-azoles alkane-5-base } methyl)-2-thiophene-carboxylic acid amides by name, structural formula is as follows:
This compound is developed by Bayer Bitterfeld GmbH drugmaker, and to get the Green Light first listing in Canada in 2008 as medicine.At present, at the razaxaban sheet having German import of Discussion on Chinese Listed, visit auspicious appropriate (Xarelto).
Razaxaban is a kind of Xa factor inhibitor.Xa factor is exogenous and joint that is intrinsic coagulation pathway, is the key point in coagulation process.Razaxaban can selectivity, directly suppress Xa factor active, thus the formation of the generation of Trombin inhibiting and thrombosis, therefore razaxaban is a kind of anticoagulation medicine, is mainly used in the formation preventing hip joint and knee prosthesis postoperative patient person deep venous thrombosis (DVT) and pulmonary infarction (PE).
Razaxaban compound is a kind of aqueous solution property hard to tolerate compound, it is about 5 ~ 7 μ g/ml at the dissolubility in water, and it is high osmosis medicine in vivo, and onset is rapid, within after administration 2 ~ 4 hours, can reach peak plasma concentration fast, absolute bioavailability is up to 80 ~ 100%; Within 1 ~ 4 hour, can obtain the effect of maximum suppression Xa factor after taking, Anti-Xa activity is held time length, reaches 24 hours.Therefore grasp razaxaban sheet stripping situation in vivo, for making rational planning for, medication is very important.
Usually, pharmaceutical field be all assess medicinal tablet by measuring the In Vitro Dissolution of medicinal tablet body in release conditions, razaxaban sheet is also like this.For the medicine of low-solubility, when carrying out stripping experiment, usually can add some solubilizing agents in dissolution medium, be all generally some surfactants, as sodium lauryl sulphate or tween.Surfactant can reduce solvent (as water) surface activity tension force to increase the dissolubility of increase-volume matter.Meanwhile, in order to obtain enough dissolubility, more surfactant is added sometimes.Just cause surfactant to form micelle when adding the surfactant of finite concentration (critical micelle concentration).The micelle that surfactant is formed also can the dissolubility of increase solubilizate to a certain degree.In prior art, the people such as ANAND BALAKRISHNAN are at Surfactant-Mediated Dissolution:Contributions ofSolubility Enhancement and Relatively Low Micelle Diffusivity, JOURNAL OF PHARMACEUTICALSCIENCES, VOL.93, the increase-volume contribution research of surfactant is reported in NO.8, AUGUST 2004:2064 ~ 2075..
But in actual experiment, the micelle formation of surfactant is random, does not have uniformity, and more micelle formation uniformities are poorer.Due to randomness, the inhomogeneities of the formation of micelle, in each Dissolution experiments, the repeatability of drug dissolution just can not be guaranteed, and therefore correctly can not reflect the actual dissolution of medicine under specific leaching condition, is particularly carrying out in razaxaban sheet stripping experimentation.
In the prior art, Chinese patent application CN201310732239 discloses a kind of preparation method of rivaroxaban solid composition, its description discloses described rivaroxaban solid composition Dissolution experiments method: Chinese Pharmacopoeia 2010 editions annex, XC second method, 50 turns/min, pH4.5 acetate buffer+0.05%SDS mixed liquor 1000ml.A kind of test method of dissolution of razaxaban oral formulations is disclosed: get this product in Chinese patent application CN201410255331, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), (2.99g sodium acetate is got with acetate buffer, put in 1000ml water, add the 10%SDS solution of 1.66mL glacial acetic acid and 20mL, with sodium hydroxide solution or glacial acetic acid adjust ph to 4.50 ± 0.1) 900ml is dissolution medium, rotating speed is 75 turns per minute, operate in accordance with the law, through 30 minutes time, get solution, filter, get subsequent filtrate as need testing solution.
In these prior aries, be not all concerned about surfactant form micelle to the impact of razaxaban sheet Dissolution experiments, certainly just do not provide the technical scheme overcoming relevant art problem yet.
In order to the good repeatability of razaxaban sheet stripping experiment can be obtained, Accurate Determining razaxaban sheet dissolution in vitro, the present invention is proposed.
Summary of the invention
Summary of the invention
The present inventor, by many experiments, researchs and analyses repeatedly razaxaban sheet stripping situation, has found that one can improve the reproducible method of razaxaban sheet stripping curve.The method is by adopting sodium lauryl sulphate as surfactant, and preparation dissolution medium storing solution, wherein in dissolution medium storing solution, the content of sodium lauryl sulphate must not higher than 10%, w/v.Then at the dissolution medium before use the dissolution medium storing solution containing sodium lauryl sulphate being diluted to desired concn, adjust ph, break the micelle that in dissolution medium, sodium lauryl sulphate is formed again, make sodium lauryl sulphate homogenization in dissolution medium, finally carry out Dissolution experiments.By described method, effectively raise the repeatability of razaxaban sheet dissolution, provide guarantee to Accurate Determining razaxaban dissolution.
One provided by the invention improves the reproducible method of razaxaban sheet stripping curve, simple, convenient, is applicable to daily razaxaban sheet dissolution and detects.
Term definition
Term " about " refer in the present invention described numerical value ± 10% within.
Term " w/v " refers to the grams of dissolving solute in every 100ml solution in the present invention, i.e. g/100ml.
Term " rpm " is Speed unit in the present invention, refers to rev/min.
Term " AVE " refers to meansigma methods in the present invention, and " SD " refers to standard deviation.
Detailed Description Of The Invention
The invention provides a kind of reproducible method of raising razaxaban sheet stripping curve, said method comprising the steps of:
A) the dissolution medium storing solution of preparation containing sodium lauryl sulphate, wherein Sodium Dodecyl Sulfate is about 0.2% ~ 10%, w/v;
B) before use the dissolution medium storing solution purified water in a) is diluted to the dissolution medium of required concentration, regulates pH;
C) razaxaban sheet is carried out stripping experiment at the dissolution medium of b) gained, and detect dissolution;
It is characterized in that: carry out Homogenization Treatments to facing with by described dissolution medium b), the gel strands that sodium lauryl sulphate in storing solution is formed is broken, to ensure that in each dissolution medium prepared, sodium lauryl sulphate is evenly distributed, and is consistent substantially.
Of the present invention being comprised by dissolution medium Homogenization Treatments allly can make the gel strands that in storing solution, sodium lauryl sulphate is formed be broken, and makes sodium lauryl sulphate finely dispersed mode of operation in dissolution medium.
Wherein, dissolution medium storing solution of the present invention can be the Acetate Solution containing sodium lauryl sulphate, and wherein Sodium Dodecyl Sulfate is about 0.2% ~ 10%, w/v.More preferably, described acetate can be sodium acetate.
Wherein, adjustment pH of the present invention can adopt glacial acetic acid solution to regulate.
In certain embodiments, the mode of operation of described dissolution medium Homogenization Treatments carries out vacuum outgas to dissolution medium, and wherein the temperature of degasser is about 38 DEG C ~ 42 DEG C; Preferably, degasser is distek degasser.
In certain embodiments, the mode of operation of described dissolution medium Homogenization Treatments dissolution medium is placed in the digestion instrument being heated to 37 DEG C, and paddle method stirs more than at least 2 hours, and wherein oar speed is 50rpm.
In certain embodiments, described dissolution medium storing solution is the sodium-acetate buffer containing sodium lauryl sulphate; And be about 0.05mol/L being diluted to sodium acetate concentration by purified water before use, sodium lauryl sulphate concentration is about 0.2%, w/v, dissolution medium, pH regulator is 4.5.
In certain embodiments, the reproducible method of raising razaxaban stripping curve of the present invention, the condition of wherein carrying out Dissolution experiments is: adopt paddle method, dissolution medium volume is 900mL, and temperature is 37.0 DEG C, and oar speed is 75rpm, then in experiment start rear 45min time point on blade top the mid point to liquid level, be no less than 10mm place apart from stripping rotor inwall to sample, sample volume is 10mL, measures dissolution.
Accompanying drawing explanation
Fig. 1 shows the stripping curve collection of illustrative plates with the preliminary survey of a collection of razaxaban sheet and repetition measurement in embodiment 1 contrast experiment
Fig. 2 show embodiment 2 first, the stripping curve collection of illustrative plates of the razaxaban sheet of second batch and the 3rd batch
Fig. 3 shows the stripping curve collection of illustrative plates of the razaxaban sheet of embodiment 3 first and second batch
Detailed description of the invention
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
Analytical reagent used by the embodiment of the present invention meets the requirement to analytical reagent in Chinese Pharmacopoeia 2010 editions second annex.
Embodiment 1 contrast experiment
Dissolution medium is prepared:
Take sodium acetate trihydrate and be about 2.99g, add purified water 1L, stirring and dissolving, regulate pH to 4.5 with glacial acetic acid, get appropriate above-mentioned solution heating for dissolving and be about 2g sodium lauryl sulphate (SDS), obtain sodium lauryl sulphate storing solution, mix with remaining pH4.5 acetate buffer again, stir evenly, regulate pH to 4.5, to obtain final product.Volume can be adjusted according to practical situation.Parallel preparation 6 parts of dissolution mediums as stated above.
Dissolution Rate Testing condition:
Get and in above-mentioned acquisition dissolution medium, carry out 6 parts of parallel stripping experiments with a collection of razaxaban sheet, actual conditions is as follows:
Method: paddle method
Medium volume: 900mL
Temperature: 37.0 DEG C
Rotating speed: 75rpm
Sample volume: 10mL
Sample position: on blade top to the mid point of liquid level, is no less than 10mm place apart from stripping rotor inwall.
Sampling time point: sample respectively at 5min, 10min, 15min, 20min and 45min time point after Dissolution experiments starts.Then according to Chinese Pharmacopoeia 2010 editions second annex VD high performance liquid chromatography, dissolution detection is carried out to above-mentioned sampling.
After completing first determination experiment, same razaxaban sheet is tested by above-mentioned dissolution medium compound method and Dissolution Rate Testing method at not same date.
Analyze and detect chromatographic condition:
With a collection of razaxaban sheet dissolution preliminary survey result and repetition measurement result as table 1.And experimentally result draws stripping curve figure, as Fig. 1.
Table 1
Embodiment 2
Dissolution medium is prepared:
Take sodium acetate trihydrate and be about 2.99g, add purified water 1L, stirring and dissolving, regulate pH to 4.5 with glacial acetic acid, get appropriate above-mentioned solution heating for dissolving and be about 2g sodium lauryl sulphate (SDS), obtain sodium lauryl sulphate storing solution, mix with remaining pH4.5 acetate buffer again, stir evenly, regulate pH to 4.5, to obtain final product.Volume can be adjusted according to practical situation.With distek degasser, vacuum outgas is carried out to dissolution medium before use, wherein the temperature of degasser is about 40 DEG C, obtains dissolution medium stand-by.Parallel preparation 6 parts of dissolution mediums as stated above.
Dissolution Rate Testing:
Get first razaxaban sheet in above-mentioned acquisition dissolution medium, carry out 6 parts of parallel stripping experiments, concrete leaching condition and analysis testing conditions are as described in example 1 above.
Second batch and the 3rd batch of razaxaban sheet are tested by above-mentioned dissolution medium compound method and Dissolution Rate Testing method at not same date.
First, the razaxaban sheet Dissolution experiments result of second batch and the 3rd batch is as table 2.And experimentally result draws stripping curve figure, as Fig. 2.
Table 2
Embodiment 3
Dissolution medium is prepared:
Take sodium acetate trihydrate and be about 2.99g, add purified water 1L, stirring and dissolving, regulate pH to 4.5 with glacial acetic acid, get appropriate above-mentioned solution heating for dissolving and be about 2g sodium lauryl sulphate (SDS), obtain sodium lauryl sulphate storing solution, mix with remaining pH4.5 acetate buffer again, stir evenly, regulate pH to 4.5, to obtain final product.Volume can be adjusted according to practical situation.Be taken in stripping rotor by the dissolution medium graduated cylinder correct amount prepared, arranging digestion instrument temperature is 37 DEG C, and oar rotating speed is that 75rpm, more than preheating 2h obtain dissolution medium.Parallel preparation 6 parts of dissolution mediums as stated above.
Get first razaxaban sheet in above-mentioned acquisition dissolution medium, carry out 6 parts of parallel stripping experiments, concrete leaching condition and analysis testing conditions are as described in example 1 above.
Second batch razaxaban sheet is tested by above-mentioned dissolution medium compound method and Dissolution Rate Testing method at not same date.
The razaxaban sheet Dissolution experiments result of first and second batch is as table 3.And experimentally result draws stripping curve figure, as Fig. 3.
Table 3
In sum,
There is the contrast of what stripping curve known by the experimental result of embodiment 2 or 3 and the experimental result of stripping curve and embodiment 1, through by the Dissolution experiments method belonging to the present invention, effectively can improve the repeatability of razaxaban stripping curve.Therefore razaxaban dissolution results more accurately can be obtained.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (7)
1. improve the reproducible method of razaxaban sheet stripping curve, said method comprising the steps of:
A) the dissolution medium storing solution of preparation containing sodium lauryl sulphate, wherein Sodium Dodecyl Sulfate is about 0.2% ~ 10%, w/v;
B) before use the dissolution medium storing solution purified water in a) is diluted to the dissolution medium of required concentration, regulates pH;
C) razaxaban sheet is carried out stripping experiment at the dissolution medium of b) gained, and detect dissolution;
It is characterized in that before use the gel strands that described dissolution medium b) makes sodium lauryl sulphate in storing solution be formed being broken, with the Homogenization Treatments ensureing that in each dissolution medium prepared, sodium lauryl sulphate is evenly distributed.
2. method according to claim 1, wherein said dissolution medium storing solution is the Acetate Solution containing sodium lauryl sulphate, and wherein Sodium Dodecyl Sulfate is about 0.2% ~ 10%.
3. method according to claim 1, wherein said dissolution medium is the sodium-acetate buffer containing sodium lauryl sulphate; And be about 0.05mol/L being diluted to sodium acetate concentration by purified water before use, sodium lauryl sulphate concentration is about 0.2%, w/v, and pH regulator is 4.5.
4. the method according to claim 1,2 or 3, wherein said dissolution medium Homogenization Treatments adopts distek degasser to carry out vacuum outgas to dissolution medium, and wherein the temperature of degasser is about 38 DEG C ~ 42 DEG C.
5. the method according to claim 1,2 or 3, wherein said dissolution medium Homogenization Treatments dissolution medium is placed in the digestion instrument being heated to 37 DEG C, and paddle method stirs more than at least 2 hours, and wherein oar speed is 50rpm.
6. method according to claim 4, the condition of wherein carrying out Dissolution experiments is: adopt paddle method, dissolution medium volume is 900mL, temperature is 37.0 DEG C, oar speed is 75rpm, and then after experiment starts, 5min, 10min, 15min, 20min and 45min time point is on blade top to the mid point of liquid level, and distance stripping rotor inwall is no less than 10mm place and samples, sample volume is 10mL, measures dissolution.
7. method according to claim 5, the condition of wherein carrying out Dissolution experiments is: adopt paddle method, dissolution medium volume is 900mL, temperature is 37.0 DEG C, oar speed is 75rpm, and then after experiment starts, 5min, 10min, 15min, 20min and 45min time point is on blade top to the mid point of liquid level, and distance stripping rotor inwall is no less than 10mm place and samples, sample volume is 10mL, measures dissolution.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101424677A (en) * | 2008-05-05 | 2009-05-06 | 王雷波 | Medicament dissolution instrument capable of on-line degassing |
| CN101460151A (en) * | 2006-04-05 | 2009-06-17 | 先灵公司 | Pharmaceutical formulations: salts of 8-[{1-(3,5-bis (trifluoromethy1)pheny1)-e thoxy}-methy1]-8-pheny1-1,7-diaza-spiro[4.5] decan-2-one and treatment methods using the same |
| CN101474175A (en) * | 2009-01-20 | 2009-07-08 | 重庆医药工业研究院有限责任公司 | Oral solid preparation of Febuxostat with high-bioavailability and preparation method thereof |
| CN104055743A (en) * | 2014-06-10 | 2014-09-24 | 吉林省博大制药有限责任公司 | Preparation method of oral preparation containing rivaroxaban |
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- 2014-11-12 CN CN201410635383.XA patent/CN104473887A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101460151A (en) * | 2006-04-05 | 2009-06-17 | 先灵公司 | Pharmaceutical formulations: salts of 8-[{1-(3,5-bis (trifluoromethy1)pheny1)-e thoxy}-methy1]-8-pheny1-1,7-diaza-spiro[4.5] decan-2-one and treatment methods using the same |
| CN101424677A (en) * | 2008-05-05 | 2009-05-06 | 王雷波 | Medicament dissolution instrument capable of on-line degassing |
| CN101474175A (en) * | 2009-01-20 | 2009-07-08 | 重庆医药工业研究院有限责任公司 | Oral solid preparation of Febuxostat with high-bioavailability and preparation method thereof |
| CN104055743A (en) * | 2014-06-10 | 2014-09-24 | 吉林省博大制药有限责任公司 | Preparation method of oral preparation containing rivaroxaban |
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Application publication date: 20150401 |