CN103694165A - Gimeracil amorphous cured product and preparation method thereof - Google Patents
Gimeracil amorphous cured product and preparation method thereof Download PDFInfo
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- CN103694165A CN103694165A CN201310556111.6A CN201310556111A CN103694165A CN 103694165 A CN103694165 A CN 103694165A CN 201310556111 A CN201310556111 A CN 201310556111A CN 103694165 A CN103694165 A CN 103694165A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/69—Two or more oxygen atoms
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Abstract
The present invention provides a method for preparing a gimeracil amorphous cured product. According to the gimeracil amorphous cured product, gimeracil is dissolved in a suitable solvent to make the gimeracil be cured through a certain method so as to form a powdery solid, and the X-ray diffraction detection result shows that at least 90% of the solid exists in the amorphous form. The gimeracil amorphous cured product has good flowability and good bulk density so as to make manufacturing and preparation of the gimeracil-containing drug be easy, can meet preparation process requirements without crushing operation, and has good bioavailability. In addition, the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to amorphous cured article of a kind of gimeracil and preparation method thereof.
Background technology
Gimeracil is oral anticancer compound medicine for one of main component of lucky capsule difficult to understand, for lucky capsule difficult to understand, by Japanese roc medicine Co., Ltd., developed, be approved for the treatment of the kinds cancers such as cancer of the stomach, non-small cell carcinoma, colorectal carcinoma, mainly by activeconstituents Tegafur and two kinds of biochemical regulator gimeracils, oteracil potassiums, formed.
Gimeracil itself does not have anti-tumor activity, after taking, this medicine retention is in gi tract, by suppressing dihydropyrimidine dehydrogenase DPD, suppress the degraded of 5-Ro 2-9757, the long period has maintained the concentration of 5-Fluracil in blood plasma and tumor tissues, thereby has strengthened anti-tumor activity.
Gimeracil (Gimeracil), has another name called Gimeracil, gimeracil, the chloro-4 hydroxyls-2(1H of chemical name 5-chloro-2,4-dihydroxypyridine or 5-)-pyridone, structural formula is as follows:
About the preparation method of gimeracil, bibliographical information mainly contains two kinds of preparation methods:
(1) synthetic route 1:
Den?Henog?H?J,?Kolder?C?R.Migration?of?halogen?atomsin?halogeno-derivatives?of?2,4-?dihydroxypyridine?[J].Rec?Trav?Chim,?1953,?72:853-858.
This method also can obtain product for raw material through steps such as superchlorination, addition, hydrolysis with 2,4-dihydroxy-pyridine (2).
(2) synthetic route 2:
CONVENIENT?AND?PRACTICAL?SYNTHESIS?OF?5-CHLORO-
4-HYDROXY-2(lH)-PYRIDINON?[J]?HETER℃YCLES.,1993,36：145-148
This method with propane dinitrile, trimethyl orthoacetate and 1,1-dimethoxy Trimethylamine 99 for starting raw material, chloro-2 through the synthetic 5-of condensation, cyclization, chloro and hydrolysis four-step reaction, 4-dihydroxy-pyridine.This route raw material is easy to get, and operational condition is simple, is applicable to suitability for industrialized production.
(3) Hao Linghua etc.The synthetic > > of < < Gimeracil, Shenyang Pharmaceutical University's journal, 22(6), in November, 2005,420-421.
(4) the in addition polymorphous preparation of document < < gimeracil of the work such as Wang Hai Pu and identify > > (Chinese pharmaceutical chemistry magazine, 81[18-1], in February, 2008, 44-47) and application for a patent for invention (application number 200710020907.4, the chloro-4 hydroxyls-2(1H of denomination of invention: 5-)-pyridone crystal form and its preparation method and application, applying date 2007.04.03, publication number CN101033211, open day 2007.09.12) find and obtained two kinds of crystal formations of gimeracil: particulate state P crystal formation and hour hand shape L crystal formation crystal.
Because its solubleness of different crystal formations, dissolution rate, stability etc. can be variant, therefore different crystal formations produces significant impact for the bioavailability of lucky capsule difficult to understand can to its oral preparations.
Summary of the invention
Technical problem to be solved by this invention is to provide the amorphous cured article of a kind of gimeracil simple to operate, that be easy to get, makes it have good mobility and bulk density, is beneficial to manufacture and the preparation of pharmaceutical composition.
The amorphous cured article of gimeracil disclosed by the invention refers to gimeracil dissolving cured through certain method, forms pulverulent solids, and this solid is to have (as shown in Figure 1) with amorphous form through X-ray diffraction at least 90%.
Another technical problem to be solved by this invention is the preparation method who discloses the amorphous cured article of above-mentioned gimeracil.
The preparation method of the amorphous cured article of above-mentioned gimeracil disclosed by the invention comprises the following steps: to add 5-10 times of dissolution with solvents in gimeracil solid, being cooled to-80 ℃ to-30 ℃ solidifies,-100 ℃ of-0 ℃ of vacuum lyophilization 24-48 hour, then being warming up to-10 ℃-0 ℃ is dried, obtaining, is to exist with amorphous form through X-ray diffraction at least 90%.
A technical problem more to be solved by this invention is the application of the amorphous cured article of open gimeracil in pharmaceutical compositions.
The amorphous cured article of gimeracil of the present invention can be mixed with various medically acceptable oral preparations with certain proportion with pharmaceutical excipient as one of compound preparation principal constituent.Pharmaceutical excipient of the present invention comprises: thinner, disintegrating agent, tackiness agent and lubricant etc., as: lactose, Microcrystalline Cellulose, starch, croscarmellose sodium, polyvinylpyrrolidone, sodium lauryl sulphate, Magnesium Stearate etc.
The unformed cured article of gimeracil disclosed by the invention has good flowing property and bulk density performance, is easy to preparation and produces, and has good bioavailability.
Accompanying drawing explanation: Fig. 1 is X ray diffracting spectrum.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention
.
Embodiment 1:
Gimeracil (5g) adds in freeze-drying bottle, adds medicinal alcohol (30mL) in 25 ℃ of-30 ℃ of dissolvings, is then cooled to-70 ℃ of rotations and solidifies.Maintain-60 ℃ to-50 ℃ of vacuum lyophilizations, final stage can be warming up to-10 ℃ to 0 ℃ and be dried.The amorphous cured article of gained gimeracil, wherein approximately 92% exists with unbodied form.
Embodiment 2:
With Virahol (40mL), replace ethanol (30mL), other are identical with embodiment 1.The amorphous cured article of gained gimeracil, wherein approximately 90% exists with unbodied form.
Embodiment 3:
Gimeracil (5g) adds in freeze-drying bottle, adds ethyl acetate (30mL) in 20 ℃ of-25 ℃ of dissolvings, is then cooled to-20 ℃ of rotations and solidifies.Maintain-10 ℃ to-0 ℃ of vacuum lyophilization, final stage can be warming up to 0 ℃-5 ℃ and be dried.The amorphous cured article of gained gimeracil, wherein approximately 95% exists with unbodied form.
Embodiment 4:
Gimeracil (5g) adds in freeze-drying bottle, adds trichloromethane (40mL) in 25 ℃ of-30 ℃ of dissolvings, is then cooled to-20 ℃ of rotations and solidifies.Maintain-10 ℃ to-0 ℃ of vacuum lyophilization, final stage can be warming up to 0 ℃-5 ℃ and be dried.The amorphous cured article of gained celecoxib, wherein approximately 94% exists with unbodied form.
Embodiment 5:
With several pharmaceutical excipients, the amorphous cured article of gimeracil is made to the lucky capsule difficult to understand that replaces containing Tegafur 20mg as follows
| Supplementary material title | Supplementary material consumption (a g/1000 preparation unit) |
| Gimeracil | 5.8 |
| Tegafur | 20 |
| Oteracil potassium | 19.6 |
| |
10 |
| Magnesium Stearate | 1 |
| |
10 |
| |
20 |
| The 5%SDS aqueous solution | In right amount |
Capsule manufacture method containing the amorphous cured article of gimeracil is that Tegafur, oteracil potassium, the amorphous cured article of gimeracil are mixed with lactose, polyvinylpyrrolidone, Microcrystalline Cellulose, with the aqueous solution of sodium lauryl sulphate, do wetting agent wet granulation, after dry, whole grain, mix rear encapsulated and get final product with Magnesium Stearate.
Embodiment 6:
With several pharmaceutical excipients, the amorphous cured article of gimeracil is made to the lucky capsule difficult to understand that replaces containing Tegafur 25mg as follows
| Supplementary material title | Supplementary material consumption (a g/1000 preparation unit) |
| Gimeracil | 7.25 |
| Tegafur | 25 |
| Oteracil potassium | 24.5 |
| |
10 |
| Magnesium Stearate | 1 |
| |
10 |
| |
20 |
| The 5%SDS aqueous solution | In right amount |
Manufacture method is identical with embodiment 5.
Claims (3)
1. the unformed cured article of gimeracil, is characterized in that it is to exist with amorphous form that this solid detects at least 90% through X-ray diffraction.
2. the preparation method of the unformed cured article of gimeracil as claimed in claim 1, it is characterized in that the method comprises the following steps: to add 5-10 times of dissolution with solvents in gimeracil solid, being cooled to-80 ℃ to-30 ℃ solidifies,-100 ℃ of-0 ℃ of vacuum lyophilization 24-48 hour, then be warming up to-10 ℃-0 ℃ and be dried, obtain.
3. method as claimed in claim 2, solvent for use includes but not limited to methyl alcohol, ethanol, Virahol, propyl carbinol, ethyl acetate, methylene dichloride, acetone, acetonitrile.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106692173A (en) * | 2015-11-18 | 2017-05-24 | 北京诺普德医药科技有限公司 | Anti-tumor compound composition and applications thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003014086A1 (en) * | 2001-08-03 | 2003-02-20 | Ranbaxy Laboratories Limited | Process for the preparation of amorphous form of torsemide |
| CN101033211A (en) * | 2007-04-03 | 2007-09-12 | 江苏省药物研究所 | 5-chloro-4-hydroxy-2(1H)-pyridone and its preparation method and applicaiton |
| CN101607936A (en) * | 2008-06-17 | 2009-12-23 | 杭州民生药业集团有限公司 | A kind of Gimeracil crystal form and preparation method thereof |
| CN102432530A (en) * | 2011-11-17 | 2012-05-02 | 深圳海王药业有限公司 | Method for preparing high-purity gimeracil |
| CN103159673A (en) * | 2011-12-12 | 2013-06-19 | 山东新时代药业有限公司 | Refining method for preparing gimeracil |
-
2013
- 2013-11-12 CN CN201310556111.6A patent/CN103694165B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003014086A1 (en) * | 2001-08-03 | 2003-02-20 | Ranbaxy Laboratories Limited | Process for the preparation of amorphous form of torsemide |
| CN101033211A (en) * | 2007-04-03 | 2007-09-12 | 江苏省药物研究所 | 5-chloro-4-hydroxy-2(1H)-pyridone and its preparation method and applicaiton |
| CN101607936A (en) * | 2008-06-17 | 2009-12-23 | 杭州民生药业集团有限公司 | A kind of Gimeracil crystal form and preparation method thereof |
| CN102432530A (en) * | 2011-11-17 | 2012-05-02 | 深圳海王药业有限公司 | Method for preparing high-purity gimeracil |
| CN103159673A (en) * | 2011-12-12 | 2013-06-19 | 山东新时代药业有限公司 | Refining method for preparing gimeracil |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106692173A (en) * | 2015-11-18 | 2017-05-24 | 北京诺普德医药科技有限公司 | Anti-tumor compound composition and applications thereof |
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