CN104418819A - Stable parecoxib sodium compound - Google Patents
Stable parecoxib sodium compound Download PDFInfo
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- CN104418819A CN104418819A CN201310406393.1A CN201310406393A CN104418819A CN 104418819 A CN104418819 A CN 104418819A CN 201310406393 A CN201310406393 A CN 201310406393A CN 104418819 A CN104418819 A CN 104418819A
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- Prior art keywords
- parecoxib sodium
- semihydrate
- parecoxib
- composition
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and particularly relates to a parecoxib sodium hemihydrate and a preparation method thereof. The obtained parecoxib sodium hemihydrate has hemi-crystal water, has the advantages of high purity and good stability, and is not obvious in moisture-absorption weight gain even under high humidity.
Description
Technical field
The invention belongs to medical art, be specifically related to Parecoxib sodium hydrate and preparation method thereof, the invention still further relates to the application using the composition of this hydrate to treat the illness that Transitional cell carcinomas (COX-2) mediates.
Background technology
Parecoxib is the prodrug of Valdecoxib, and Parecoxib through liver enzyme hydrolysis, is converted into rapidly the material of pharmacological activity after quiet note or intramuscular injection--Valdecoxib.Valdecoxib is selectivity COX-2 (COX-2) inhibitor in clinical dosage scope, and cyclooxygenase participates in prostaglandin(PG) building-up process.Now there are COX-1 and COX-2 two kinds of isomer.Research shows COX-2 as cyclooxygenase isomer by front-inflammatory stimulus inductive formation, thus infers that COX-2 plays main effect in the building-up process of the prostaglandin-like mediator relevant with pain, inflammation and heating.
Parecoxib Sodium (Parecoxib Sodium), be developed by Pfizer first can the specific cox 2 inhibitor of intravenously administrable (IV) and intramuscular injection (IM), with heavily pound medicine celecoxib, imrecoxib are similar drugs, for the short of postoperative pain, go on the market in March, 2002 in Europe.
Parecoxib Sodium structural formula:
Chemical name: N-[[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionamide sodium salt,
Molecular formula: C19H17N2O4SNa
Molecular weight: 392.41
Disclose the method for synthesis Parecoxib Sodium in patent US5932598, but this patent only discloses its fusing point is 271.5-272.7 DEG C, the crystalline texture of Parecoxib Sodium is characterized.
The Parecoxib Sodium hemi-hydrate crystalline that the present invention obtains on the basis of great many of experiments, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Summary of the invention
One object of the present invention, discloses a kind of Parecoxib Sodium semihydrate.
Another object of the present invention, discloses the preparation method of Parecoxib Sodium semihydrate.
Another object of the present invention, discloses the pharmaceutical composition comprising Parecoxib Sodium semihydrate.
The invention also discloses the illness application that Parecoxib Sodium semihydrate mediates in preparation treatment Transitional cell carcinomas (COX-2).
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of Parecoxib Sodium semihydrate (shown in formula I),
(I)
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through multiple batches of mensuration, the moisture that described invention compound contains is between 2.13%-2.35% (weight percent).In Parecoxib Sodium semihydrate, the theoretical content of water is 2.24%, can assert that invention compound contains half crystal water.
Wherein the measurement result of 6 batches is as follows:
This Parecoxib Sodium hemi-hydrate crystalline, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), D value and relative intensity are as follows,
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C first method, the fusing point recorded is 255.6 DEG C-256.3 DEG C.
Another object of the present invention, discloses the preparation method of Parecoxib Sodium hemi-hydrate crystalline, by being dissolved at Virahol-acetic acid-heated in water solution by Parecoxib Sodium, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that Parecoxib Sodium adds in the mixed solution of 4-5 times of (weight or measurement (WM) ratio) Virahol-acetic acid-water=4.5-6:0.1-0.3:5-6.5, be heated to dissolve, filtrate naturally cools to 30 DEG C-35 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
A large amount of experiments proves: the proportioning of mixed solution, standing temperature and time are most important to obtaining Parecoxib Sodium hemi-hydrate crystalline of the present invention.
Another object of the present invention, provides the composition comprising the Parecoxib Sodium semihydrate that Parecoxib Sodium hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology, the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared from injection.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
Present invention also offers Parecoxib Sodium semihydrate and manufacture the application in treatment Transitional cell carcinomas (COX-2) disorder agent that mediates.
stability test
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in Parecoxib Sodium:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), Parecoxib Sodium has moisture absorption to increase weight, to moist lability.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Parecoxib Sodium used in the present invention, the method synthesis that reference WO2003029230 provides, the Parecoxib Sodium of synthesis, purity 98.3% (HPLC normalization method), optical purity 99.1%ee, its chemical structure, through determination of elemental analysis, proves that chemical structure is correct.After being dried to constant weight, the moisture recorded with Karl_Fischer method is 0.24%.
embodiment 1
In the 5l reactor that stirring, thermometer, condenser are housed, add in the mixed solution of 80 grams of Parecoxib Sodium sodium and 400ml Virahol-acetic acid-water=4.5-6:0.1-0.3:5-6.5, start stirring, be heated to dissolve, filtrate naturally cools to 33 DEG C, then leaves standstill insulation 4 hours, crystallization, filter, through indoor seasoning, obtain Parecoxib Sodium hemihydrate crystalline 230.6 grams, fusing point is the fusing point recorded is 255.6 DEG C-256.3 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure through Karl_Fischer method, the moisture containing 2.25% (weight percent).
X-ray diffractometer is adopted to measure this crystal formation, INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°.Result is as follows:
The error of 2 θ diffraction angle is ± 0.2.
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
Claims (6)
1. Parecoxib Sodium semihydrate shown in formula I,
（Ⅰ）
Measure with Karl_Fischer method, described hydrate contains the moisture of weight percent 2.13%-2.35%;
Described Parecoxib Sodium semihydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of Parecoxib Sodium semihydrate described in claim 1, by being dissolved at Virahol-acetic acid-heated in water solution by Parecoxib Sodium, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that Parecoxib Sodium adds in the mixed solution of 4-5 times of (weight or measurement (WM) ratio) Virahol-acetic acid-water=4.5-6:0.1-0.3:5-6.5, be heated to dissolve, filtrate naturally cools to 30 DEG C-35 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
4. the composition of the Parecoxib sodium hydrate formed containing Parecoxib Sodium semihydrate according to claim 1 and one or more pharmaceutically acceptable carriers.
5. the composition of Parecoxib Sodium semihydrate according to claim 4, is characterized in that said composition is for the preparation of injection.
6. the application of Parecoxib Sodium semihydrate described in claim 1 in the medicine manufacturing the illness that treatment Transitional cell carcinomas (COX-2) mediates.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310406393.1A CN104418819A (en) | 2013-09-10 | 2013-09-10 | Stable parecoxib sodium compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310406393.1A CN104418819A (en) | 2013-09-10 | 2013-09-10 | Stable parecoxib sodium compound |
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| CN104418819A true CN104418819A (en) | 2015-03-18 |
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|---|---|---|---|
| CN201310406393.1A Withdrawn CN104418819A (en) | 2013-09-10 | 2013-09-10 | Stable parecoxib sodium compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056721A (en) * | 2017-04-12 | 2017-08-18 | 山东裕欣药业有限公司 | A kind of Parecoxib Sodium crystalline compounds and preparation method thereof |
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2013
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056721A (en) * | 2017-04-12 | 2017-08-18 | 山东裕欣药业有限公司 | A kind of Parecoxib Sodium crystalline compounds and preparation method thereof |
| CN107056721B (en) * | 2017-04-12 | 2019-09-06 | 山东裕欣药业有限公司 | A kind of Parecoxib Sodium crystalline compounds and preparation method thereof |
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Application publication date: 20150318 |