CN102349875A - Preparation method of methylsulfonic acid imatinib tablet - Google Patents
Preparation method of methylsulfonic acid imatinib tablet Download PDFInfo
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- CN102349875A CN102349875A CN2011103167262A CN201110316726A CN102349875A CN 102349875 A CN102349875 A CN 102349875A CN 2011103167262 A CN2011103167262 A CN 2011103167262A CN 201110316726 A CN201110316726 A CN 201110316726A CN 102349875 A CN102349875 A CN 102349875A
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Abstract
The invention discloses a preparation method of methylsulfonic acid imatinib tablet. The invention takes organic solvent or organic solution with volume concentration bigger than 70% as pelletization solution, and the weight of water-insoluble filling agent in the tablet accounts for less than 20% of the total weight of the tablet. The invention has advantages of simple technical process, high yield and good dissolution of a product.
Description
Technical field
The present invention relates to a kind of method for preparing that contains the imatinib mesylate tablet.
Background technology
Imatinib mesylate is the inhibitor of first tumor generation coherent signal that gets the Green Light conduction of the whole world by the exploitation of Novartis company.Its chemistry is by name: 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-aniline mesylate.
Molecular formula: C
29H
31N
7OCH
4SO
3
Molecular weight: 589.7
Skeleton symbol is:
WO2009/042803 discloses the technology that adopts dry granulation explained hereafter imatinib mesylate sheet, and the ratio of its crude drug is 23-29%.
EP1762230B1 has protected the technology of producing coated tablet, mainly is dry granulation technology, and the API amount is between 25-80%.
Adopt dry granulation to carry out the production of imatinib mesylate sheet; Certain defective is arranged in commercially producing; Comparatively speaking; The dust generation is greater than wet granulation technology in the dry granulation technology, and this is the health protection that is unfavorable for Producer for this antineoplastic agent of imatinib mesylate.Therefore adopting wet granulation technology is more suitable for the production of this product.
CN200910142577.5 discloses the technology with the water wet granulation.But the inventor finds that it is not too suitable in wet-granulation process, adopting water; Imatinib mesylate runs into water can produce very big viscosity; Water is granulated as binding agent; Produce bigger agglomerate in pelletization easily, and then influence the difficulty and the yield of follow-up granulate technology, and further influence drying efficiency.
Also find to exist the stripping problem of lower in addition.This possibly be cause raw material to be difficult to due to the stripping because insoluble adjuvant is piled up such as microcrystalline Cellulose.
These problems all need solve.Particularly, need in technological design, simplify technical process more, enhance productivity, and pay close attention to labourer's protection this antineoplastic agent of imatinib mesylate.
Summary of the invention
Therefore, the invention provides a kind of method for preparing of imatinib mesylate ordinary tablet, the inventor finds under study for action; If in prescription, use insoluble bulking agent, such as microcrystalline Cellulose, Powderd cellulose; Filleies such as calcium hydrogen phosphate; Can cause the product dissolution to reduce, even unqualified, this may have a negative impact to the clinical effectiveness of product.
The present invention discloses a kind of method for preparing of imatinib mesylate conventional tablet, comprises following steps:
(1) imatinib mesylate is mixed in high-speed mixing granulating machine with pharmaceutic adjuvant;
(2) adopt organic solvent or volumetric concentration greater than 70% aqueous solutions of organic solvent granulate, drying obtains granule;
(3) granule is mixed with extra pharmaceutic adjuvant, and be pressed into tablet;
The used imatinib mesylate of said method is an alpha-crystal form, and in the pharmaceutic adjuvant, the water-insoluble filler accounts for the ratio of tablet total weight amount less than 10%.
The inventor finds, if the ratio of insoluble bulking agent in prescription is less than 10%, preferably less than 5% in the tablet formulation.Its dissolution is good.
Insoluble bulking agent, including, but not limited to microcrystalline Cellulose, Powderd cellulose, calcium hydrogen phosphate is optimized microcrystalline Cellulose, wherein one or more such as starch.
Among the present invention, the imatinib mesylate crude drug of employing is a crystal form, is preferably the imatinib mesylate of alpha-crystal form, and α, beta crystal have following characteristic:
Fusing point is 217 ℃ among the dsc analysis figure of beta crystal, and the fusing point of alpha-crystal form is 226 ℃ (beginning fusions).
In the x-ray diffraction pattern, beta crystal does not have marker peak (1), and alpha-crystal form has marker peak (1), specifically sees Appendix 1.
Although there is the relative alpha-crystal of bibliographical information beta crystal that better flowability and stability are arranged; But the inventor finds, adopts technology of the present invention, also can obtain the preparation of better stability with alpha-crystal; Through 6 months study on the stability, find having good stability of product.
The dissolubility of imatinib mesylate in water is good, and the inventor finds, makes an experiment at the medicine that uses raw material particle size D (v, 0.9) to be respectively 101um and 340um, and the dissolution rate of the tablet of its preparation is more or less the same.
In addition among the present invention; Having studied employing water and concentration is the contrast test that 70% (V/V) ethanol carries out wet granulation, finds that adopting water is that binding agent carries out wet granulation, and medicated powder is clamminess agglomerating easily; Cause subsequently granulate process difficulty carry out; Even if the granule of crossing through granulate simultaneously also because granule has excessively slightly caused drying efficiency not high, also can be crossed and slightly causes problems such as the slice, thin piece stripping is on the low side owing to the granule of preparation.And use 70% (V/V) ethanol to granulate, and can effectively alleviate the phenomenon that is clamminess of medicated powder, material can be not agglomerating yet, all carries out comparatively smoothly in subsequently granulate and dry run, and this explanation adopts alcohol granulation to be fit to the wet granulation technology of imatinib mesylate sheet.According to the present invention, find to adopt 80% (V/V) ethanol or 90% (V/V) ethanol or dehydrated alcohol can produce better effect.
Find that further adopt isopropyl alcohol, acetone and other organic solvent also can reach the effect identical with ethanol.
Description of drawings:
Accompanying drawing 1 is the X-ray diffracting spectrum of alpha-crystal form imatinib mesylate;
Accompanying drawing 2 is the X-ray diffracting spectrum of beta crystal imatinib mesylate.
Specific embodiment
Embodiment 1-3
Table 1
Preparation technology:
1, with her horse of alpha-crystal form methanesulfonic acid for and pharmaceutic adjuvant in the wet granulation pot, mix,
2, alcoholic solution (or water) is joined in the pot of granulating granulate, the preparation granule,
3, the granule with step " 2 " gained carries out drying, granulate,
4, add pharmaceutic adjuvant, and carry out tabletting,
5, adopt the coating powder of commodity Opadry by name that slice, thin piece is carried out coating.
To embodiment 1,2, the slice, thin piece of 3 preparations carries out the detection of stripping curve, and detection method is: dissolution medium volume: 1000ml, dissolution medium are the hydrochloric acid solution of pH1.2, and rotating speed is 50rpm, the oar method.The stripping curve result sees table 2.
Table 2
To embodiment 1,2,3 produce, and carrying out batch is 10; 000/batch production, the technology of embodiment 3 is adopted in discovery, and its back yield of granulating has only 80%, and reason is that embodiment 3 adopts the water granulation; Behind its wet granulation, have agglomerating material to cause its yield to descend, and embodiment 1 adopt alcohol granulation, after the granulation through screen cloth; Do not have agglomerating phenomenon, through screen cloth, its yield can reach more than 95% material easily.
And embodiment 2 is excessive owing to the ratio of microcrystalline Cellulose, and its ratio in prescription is 23.6%, adopts the slice, thin piece stripping of this prescription preparation slow partially.
Embodiment 4-7
Preparation technology:
1, with her horse of alpha-crystal form methanesulfonic acid for and pharmaceutic adjuvant in the wet granulation pot, mix,
2, dehydrated alcohol (or isopropyl alcohol, acetone) is joined in the pot of granulating granulate, the preparation granule,
3, the granule with step " 2 " gained carries out drying, granulate,
4, add pharmaceutic adjuvant, and carry out tabletting,
5, adopt the coating powder of commodity Opadry by name that slice, thin piece is carried out coating.
To embodiment 4,5, the slice, thin piece of 6,7 preparations carries out the detection of stripping curve, and detection method is: dissolution medium volume: 1000ml, dissolution medium are the hydrochloric acid solution of pH1.2, and rotating speed is 50rpm, the oar method.
Embodiment 4 and 5 contrasts among the embodiment 4, do not contain insoluble bulking agent, and among the embodiment 5, the ratio of microcrystalline Cellulose is 7.76%, and its both strippings do not have too big-difference.
Embodiment 6,7 adopts isopropyl alcohol respectively, and acetone is granulated, and the sample of its result of extraction and embodiment 4,5 is similar.
Embodiment 4 is carried out study on the stability, and the result sees the following form:
Claims (4)
1. the method for preparing of an imatinib mesylate conventional tablet is characterized in that comprising following steps:
(1) imatinib mesylate is mixed in high-speed mixing granulating machine with pharmaceutic adjuvant;
(2) adopt organic solvent or volumetric concentration to granulate greater than 70% aqueous solutions of organic solvent, drying obtains granule;
(3) granule is mixed with extra pharmaceutic adjuvant, and be pressed into tablet;
Described imatinib mesylate is an alpha-crystal form, and organic solvent is selected from ethanol, acetone, and one or more in the isopropyl alcohol, and in the pharmaceutic adjuvant, the water-insoluble filler accounts for the ratio of tablet total weight amount less than 10%.
2. method for preparing as claimed in claim 1 is characterized in that the water-insoluble filler is selected from microcrystalline Cellulose, optimizes microcrystalline Cellulose, Powderd cellulose, starch, one or more in the calcium hydrogen phosphate etc.
3. method for preparing as claimed in claim 1 is characterized in that ratio that the water-insoluble filler accounts for the tablet total weight amount is less than 5%.
4. method for preparing as claimed in claim 1 is characterized in that adopting organic solvent or volumetric concentration to granulate greater than 80% aqueous solutions of organic solvent.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011103167262A CN102349875A (en) | 2011-10-11 | 2011-10-11 | Preparation method of methylsulfonic acid imatinib tablet |
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| CN2011103167262A CN102349875A (en) | 2011-10-11 | 2011-10-11 | Preparation method of methylsulfonic acid imatinib tablet |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013017100A1 (en) * | 2011-08-04 | 2013-02-07 | 上海创诺制药有限公司 | Imatinib mesylate tablet |
| CN104288115A (en) * | 2014-10-30 | 2015-01-21 | 江苏豪森药业股份有限公司 | Medicinal preparation containing imatinib mesylate, and preparation method thereof |
| CN104739785A (en) * | 2013-12-25 | 2015-07-01 | 辰欣药业股份有限公司 | Imatinib mesylate tablet with high dissolution behavior and preparation method thereof |
Citations (4)
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| CN1646103A (en) * | 2002-04-23 | 2005-07-27 | 诺瓦提斯公司 | High drug load tablet |
| CN101032496A (en) * | 2007-04-25 | 2007-09-12 | 北京市科益丰生物技术发展有限公司 | Stabled desogestrel medical combination and the preparing method |
| CN101851247A (en) * | 2010-06-04 | 2010-10-06 | 浙江华海药业股份有限公司 | Composition containing clopidogrel bisulfate crystal particles |
| WO2011121593A1 (en) * | 2010-03-29 | 2011-10-06 | Hetero Research Foundation | Stable pharmaceutical composition of imatinib |
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2011
- 2011-10-11 CN CN2011103167262A patent/CN102349875A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646103A (en) * | 2002-04-23 | 2005-07-27 | 诺瓦提斯公司 | High drug load tablet |
| CN101032496A (en) * | 2007-04-25 | 2007-09-12 | 北京市科益丰生物技术发展有限公司 | Stabled desogestrel medical combination and the preparing method |
| WO2011121593A1 (en) * | 2010-03-29 | 2011-10-06 | Hetero Research Foundation | Stable pharmaceutical composition of imatinib |
| CN101851247A (en) * | 2010-06-04 | 2010-10-06 | 浙江华海药业股份有限公司 | Composition containing clopidogrel bisulfate crystal particles |
Non-Patent Citations (3)
| Title |
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| 何耀良，廖小新等: "微晶纤维素的研究进展", 《化工技术与开发》 * |
| 吕立华 等: "《药剂学》", 31 March 2009 * |
| 罗明生，高天惠: "《药剂辅料大全》", 31 March 1993 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013017100A1 (en) * | 2011-08-04 | 2013-02-07 | 上海创诺制药有限公司 | Imatinib mesylate tablet |
| CN104739785A (en) * | 2013-12-25 | 2015-07-01 | 辰欣药业股份有限公司 | Imatinib mesylate tablet with high dissolution behavior and preparation method thereof |
| CN104288115A (en) * | 2014-10-30 | 2015-01-21 | 江苏豪森药业股份有限公司 | Medicinal preparation containing imatinib mesylate, and preparation method thereof |
| CN104288115B (en) * | 2014-10-30 | 2016-02-24 | 江苏豪森药业股份有限公司 | Pharmaceutical preparation containing imatinib mesylate and preparation method thereof |
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Application publication date: 20120215 |