CN107417599A - A kind of preparation method of Etoricoxib crystal formation - Google Patents
A kind of preparation method of Etoricoxib crystal formation Download PDFInfo
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- CN107417599A CN107417599A CN201710474500.2A CN201710474500A CN107417599A CN 107417599 A CN107417599 A CN 107417599A CN 201710474500 A CN201710474500 A CN 201710474500A CN 107417599 A CN107417599 A CN 107417599A
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- acid
- etoricoxib
- crystal seed
- crystal formation
- acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention discloses a kind of preparation method of Etoricoxib crystal formation, this method includes Etoricoxib adding specific crystal seed induction crystallization in suitable solvent, filter, be drying to obtain Etoricoxib polymorphic highly finished product, this method is simple to operate, favorable reproducibility, high income, suitable industrialized production, gained crystal formation are adapted to prepare Etoricoxib preparation.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to the polymorphous preparation method of Etoricoxib, pharmaceutical composition and
Medical usage.
Background technology
The selective depressant that it is cyclooxygenase-2 that Etoricoxib, which is, there is anti-inflammatory, bring down a fever acts on analgesic, its chemistry
Structure is as follows.
At present, Etoricoxib in the form of film coating piece in multiple states such as Britain, Spain, Australia, China
Family's listing, is mainly clinically used as NSAIDs.
The crystal formation of Etoricoxib has large effect to the property of medicine, and patent WO2001092230A1 discloses support
Examine the property and preparation method of eight kinds of crystal formations of former times, including crystal formation I, crystal formation II, crystal formation III, crystal formation IV, crystal formation V, semihydrate,
Times semihydrate and amorphous state, and (DSC) and X- diffraction powders collection of illustrative plates (XRPD) are composed by differential scanning calorimetric thermogram
Confirmed.However, preparation narration of this patent for crystal formation V is more simple, the present inventor is iteratively repeated the preparation of crystal formation V
Method, discovery are difficult to reappear.
Patent WO2001037833 disclose the preparation method of Etoricoxib crystal formation I, crystal formation II, crystal formation III and crystal formation IV with
And related XRPD collection of illustrative plates, but the preparation method of crystal formation V is not referred to.
In addition, patent WO2005085199A1 discloses Etoricoxib crystal formation Ⅸ, crystal formation Ⅹ, crystal formation Ⅺ, crystal formation Ⅻ, crystal formation
XIII, crystal formation XIV, crystal formation XV, crystal formation XVI preparation method, and its XRD property is confirmed.But for crystal formation V
Preparation method do not refer to.
Above-mentioned existing literature has carried out more research to the crystal formation of Etoricoxib, but for making available for pharmaceutical preparation
The preparation of crystal formation V refers to less, the simple preparation method of only WO2001092230A1 announcements, and by the present inventor's
Repeatedly attempt experiment, it is difficult to reappear and obtain crystal formation V.Therefore, the present inventor is by substantial amounts of research, it was found that a kind of Etoricoxib
Specific crystal seed, the specific crystal seed are made by adding acid in Etoricoxib lysate, and by Etoricoxib crystal formation V's
Specific crystal seed is added in preparation process, Etoricoxib crystal formation V is prepared so as to simple and quick.The preparation method is simple to operate, repeats
The good, high income of property, suitable industrialized production, the crystal formation of preparation this also comply with medicinal demand.
The content of the invention
The invention provides a kind of method for preparing Etoricoxib crystal formation V, this method makes preparation by adding specific crystal seed
Technological operation is simple, favorable reproducibility, high income, suitable industrialized production.Particularly the present inventor by substantial amounts of research and visits
Rope, a kind of specific crystal seed is found, make Etoricoxib crystal formation V become to be very easy to preparation, and crystal formation V purity using the crystal seed
Height, it is especially suitable for medicinal requirement.
A kind of Etoricoxib crystal formation V of present invention preparation method, including:Etoricoxib is added in organic solvent,
Etoricoxib dissolving is heated to, maintains the temperature at 55~70 DEG C, adds the specific crystal seed of Etoricoxib, is stirred, then slow cooling
Crystallization, filter, dry, produce Etoricoxib crystal formation, the X- diffraction powders collection of illustrative plates of gained crystal formation 2 θ values be 6.49,12.37,
12.98、17.85、19.74、19.98、21.00、21.86、22.96、23.54、24.11、26.39、27.10、28.95、31.34
+0.2oThere is characteristic absorption peak at place.
The method of the invention described above, the specific crystal seed are made by following methods, and this method includes:Etoricoxib is added
Into the organic solvent of 5~10 times of volumes, it is heated to dissolving, maintains the temperature at 50~70 DEG C, addition is sour, stirring 0.4~
0.6h, preferably from about 0.5h, then slow cooling crystallization, is filtered, and is dried, is produced the specific crystal seed of Etoricoxib, wherein, the acid choosing
From lower fatty acid, inorganic acid and sulfonic acid.
The method of the invention described above, the inorganic acid are hydrochloric acid, sulfuric acid or phosphoric acid, and the lower fatty acid is formic acid, second
Acid, propionic acid, butyric acid or isobutyric acid, the sulfonic acid are methanesulfonic acid or p-methyl benzenesulfonic acid.Preferably, it is described acid selected from hydrochloric acid, acetic acid,
Propionic acid and p-methyl benzenesulfonic acid.
The method of the invention described above, the solvent are selected from benzene,toluene,xylene, methyl acetate, ethyl acetate, acetic acid third
Ester, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, pentyl acetate, acetone, methyl are different
One or more in butyl ketone and butanone, it is preferred that the solvent is toluene, ethyl acetate, isopropyl acetate or acetone.
The method of an above-mentioned invention, the molal weight ratio of the acid and Etoricoxib is (0.01~0.9)：1, preferably
(0.01~0.5)：1, more preferably (0.01~0.1)：1.
The method of the invention described above, it is 55~70 DEG C to dissolve by heating temperature, and the temperature for adding crystal seed is maintained at 60~70 DEG C,
The lower fatty acid is acetic acid or propionic acid.
In one embodiment, the specific crystal seed of a kind of Etoricoxib of the invention, is made, this method by following methods
Including:Etoricoxib is added in the organic solvent of 5~10 times of volumes, is heated to temperature as 55~70 DEG C of dissolvings, keeps
Temperature adds a little acid between 50~70 DEG C, 0.4~0.6h of stir about, preferably from about 0.5h, slow cooling crystallization, filters, and does
It is dry, the specific crystal seed of Etoricoxib is produced, wherein, the organic solvent is toluene, ethyl acetate, isopropyl acetate or acetone, institute
State acid and be selected from hydrochloric acid, acetic acid, propionic acid and p-methyl benzenesulfonic acid, the molal weight ratio of the acid and Etoricoxib is (0.01~0.5)：
1, preferably (0.01~0.1)：1.
Present invention also offers a kind of pharmaceutical composition, and it contains the Etoricoxib crystal formation that the method for the invention described above obtains
V and pharmaceutically acceptable carrier.
Purposes of the Etoricoxib crystal formation that the method for the present invention obtains in treatment inflammation and pain medication is prepared.
One kind of the present invention prepares the special polymorphous method of Etoricoxib, and this method includes：Etoricoxib crude product is added
Into the organic solvent of 5~10 times of volumes, Etoricoxib dissolving is heated to, adds and relies between maintaining the temperature at 55~70 DEG C
Former times specific crystal seed is examined, 0.4~0.6h of stir about, then slow cooling crystallization, is filtered, and is dried, is produced Etoricoxib crystal formation V.
Term, " volume " refer to that the volume of solvent is the multiple of the quality of solute, and such as 5~20 times of volumes refer to molten
The volume (L or ml) of agent is 5~20 times of the quality (kg or g) of solute Etoricoxib, such as 5~20L/KG.
In the above-described embodiment, the amount of the solvent is preferably 5 times of volumes.
In the above-described embodiment, the solvent is selected from benzene,toluene,xylene, methyl acetate, ethyl acetate, acetic acid third
Ester, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, pentyl acetate, acetone methyl tert-butyl
One or more in base ketone, butanone.It is preferred that the solvent is toluene, ethyl acetate, isopropyl acetate or acetone.
In the above-described embodiment, the heating-up temperature is preferably 50~75 DEG C.
In the above-described embodiment, the temperature for adding crystal seed dissolves for 50~70 DEG C, preferably 60~70 DEG C.
In the above-described embodiment, the acid that adds is selected from the inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, example
Such as methanesulfonic acid or the sulfonic acid of p-methyl benzenesulfonic acid, and such as formic acid, acetic acid, propionic acid, butyric acid or isobutyric organic acid, preferably hydrochloric acid
And acetic acid, more elect acetic acid as.
In the above-described embodiment, the temperature for adding acid dissolves for 50~70 DEG C, preferably 50~65 DEG C.
Present invention also offers a kind of pharmaceutical composition, the Etoricoxib polymorphic prepared comprising the method by the present invention
And pharmaceutic adjuvant.
The polymorphic Etoricoxib prepared using the method for the present invention is made into tablet (to use and commercialized product identical medicine
With auxiliary material) after, the XRD of the tablet and marketed products (ARCOXIA pieces) is determined, compares the XRD of the two, finds both XRDs
Modal data is basically identical, illustrates that the polymorphic Etoricoxib that is obtained according to the preparation method of this patent and marketed products are raw materials used
The crystal formation of medicine is essentially identical.Therefore, the polymorphic Etoricoxib that prepared by the present invention manufactures available for preparation, suitable pharmaceutical preparation
Include tablet, capsule, oral disintegrating tablet, dispersible tablet etc..
Brief description of the drawings
The polymorphous XRD of gained Etoricoxib of Fig. 1 embodiments 1.
The gained Etoricoxib of Fig. 2 embodiments 1 polymorphous DSC and TGA scheme.
Embodiment
Following examples are used for the essence that the present invention is explained further, but do not limit the scope of the present invention with this.
Embodiment 1
50g Etoricoxib crude products are added in the toluene 250mL of 5 times of volumes, are heated to 70 DEG C of dissolvings, are maintained the temperature at
(acetic acid is 0.01 with Etoricoxib molal weight ratio to 68 DEG C of a little acetic acid of addition：1), stir about 0.5h, slow cooling crystallization, mistake
Filter, dry, produce the specific crystal seed 46.4g of Etoricoxib.
500g Etoricoxib crude products are added in the isopropyl acetate 2500mL of 5 times of volumes, are heated to 70 DEG C of dissolvings, are protected
Hold temperature and the specific crystal seed 0.5g of Etoricoxib is added between 65~70 DEG C, stir about 0.5h, slow cooling crystallization, filter, do
It is dry, produce polymorphic Etoricoxib 44.8g.Measure fusing point：134.8~138.4 DEG C.
The X-ray powder diffraction figure (XRD) of gained crystal formation is determined using Cu targets x-ray powder diffraction instrument, sees Fig. 1, its
The 2 θ values and relative intensity I% of characteristic absorption peak are shown in Table 1.
The 2 θ values and relative intensity I% of the XRD determining Etoricoxib polymorphic absworption peak of table 1
Gained crystal formation is entered using TGA and DSC 2LF1100/155 testers (TGADSC40-350 DEG C of 10 DEG C/min)
Row differential scanning calorimetric analysis DSC and thermogravimetric analysis TGA, is as a result shown in Fig. 2.
Embodiment 2
45g Etoricoxib crude products are added in the ethyl acetate 420mL of 7 times of volumes, are heated to 65 DEG C of dissolvings, are kept temperature
Degree adds a little propionic acid at 60 DEG C, and (propionic acid is 0.1 with Etoricoxib molal weight ratio：1), stir about 0.4-0.6h, slow cooling
Crystallization, filter, dry, produce the specific crystal seed 41.3g of Etoricoxib.
530g Etoricoxib crude products are added in the ethyl acetate 3180mL of 6 times of volumes, are heated to 70 DEG C of dissolvings, are kept
Temperature adds the specific crystal seed 0.5g of Etoricoxib between 67~69 DEG C, stir about 0.5h, slow cooling crystallization, filters, and dries,
Produce polymorphic Etoricoxib 468.0g.Measure fusing point：135.3~137.2 DEG C.
Embodiment 3
40g Etoricoxib crude products are added in the acetone 400mL of 10 times of volumes, are heated to 55 DEG C of dissolvings, keeping temperature
Hydrochloric acid is added at 50 DEG C, and (hydrochloric acid is 0.03 with Etoricoxib molal weight ratio：1), stir about 0.5h, slow cooling crystallization, mistake
Filter, dry, produce the specific crystal seed 33.2g of Etoricoxib.
550g Etoricoxib crude products are added in the isopropyl acetate 4400mL of 8 times of volumes, are heated to 70 DEG C of dissolvings, are protected
Hold temperature and the specific crystal seed 0.5g of Etoricoxib added between 65~70 DEG C, stir 0.4-0.6h, slow cooling crystallization, filter,
Dry, produce polymorphic Etoricoxib 44.8g.Measure fusing point：134.9~136.8 DEG C.
Embodiment 4
45g Etoricoxib crude products are added in the isopropyl acetate 360mL of 8 times of volumes, are heated to 70 DEG C of dissolvings, are kept
Temperature adds propionic acid between 65~70 DEG C, and (propionic acid is 0.5 with Etoricoxib molal weight ratio：1), stir about 0.5h, slowly drop
Warm crystallization, filter, dry, produce the specific crystal seed 40.7g of Etoricoxib.
480g Etoricoxib crude products are added in the toluene of 10 times of volumes, are heated to 70 DEG C of dissolvings, are maintained the temperature at 68
DEG C or so add Etoricoxib specific crystal seed 0.1g, stir about 0.5h, slow cooling crystallization, filter, dry, produce polymorphic according to
Support examines former times 425.8g.Measure fusing point：135.2~137.7 DEG C.
Embodiment 5
50g Etoricoxib crude products are added in the isopropyl acetate 100mL of 8 times of volumes, are heated to 70 DEG C of dissolvings, are kept
Temperature adds p-methyl benzenesulfonic acid at 68 DEG C, and (p-methyl benzenesulfonic acid is 0.05 with Etoricoxib molal weight ratio：1), stir about 0.5h,
Slow cooling crystallization, filter, dry, produce the specific crystal seed 46.4g of Etoricoxib.
500g Etoricoxib crude products are added in the isopropyl acetate of 5 times of volumes, are heated to 70 DEG C of dissolvings, keeping temperature
The specific crystal seed 0.5g of Etoricoxib is added between 65~70 DEG C, stir about 0.5h, slow cooling crystallization, is filtered, dries, produces
Polymorphic Etoricoxib 44.8g.Measure fusing point：134.8~138.2 DEG C.
The XRPD of the crystal formation of embodiment 2-5 method acquisition is determined as described in Example 1, and its XRPD feature is in error model
Enclose interior substantially identical with Fig. 1.
Claims (18)
1. a kind of polymorphous preparation method of Etoricoxib, including:Etoricoxib is added in organic solvent, is heated to relying on
Former times dissolving to be examined, maintains the temperature at 55~70 DEG C, adds the specific crystal seed of Etoricoxib, stirring, then slow cooling crystallization, is filtered,
Dry, produce Etoricoxib crystal formation, the X- diffraction powders collection of illustrative plates of gained crystal formation 2 θ values be 6.49,12.37,12.98,17.85,
19.74th, there is spy at 19.98,21.00,21.86,22.96,23.54,24.11,26.39,27.10,28.95,31.34 ± 0.2 °
Levy absworption peak.
2. according to the method for claim 1, the specific crystal seed is made by following methods, this method includes:Support is examined
Former times is added in organic solvent, is heated to dissolving, and maintains the temperature at 50~70 DEG C, adds acid, stirs 0.4~0.6h, Ran Houhuan
Slow cooling crystallization, filters, dries, produce the specific crystal seed of Etoricoxib, wherein, the acid selected from lower fatty acid, inorganic acid and
Sulfonic acid, the molal weight ratio of the acid and Etoricoxib is (0.01~0.9)：1.
3. method according to claim 1 or 2：The dosage of organic solvent is 5~10 times of volumes of Etoricoxib.
4. according to the method for claim 3, the solvent is selected from benzene,toluene,xylene, methyl acetate, ethyl acetate, second
Propyl propionate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, pentyl acetate, acetone, first
One or more in base isobutyl ketone and butanone.
5. according to the method for claim 4, the solvent is toluene, ethyl acetate, isopropyl acetate or acetone.
6. method according to claim 1 or 2, the heating for dissolving temperature is 55~70 DEG C.
7. the temperature for according to the method for claim 1, adding crystal seed is 60~70 DEG C.
8. according to the method for claim 2, the inorganic acid be hydrochloric acid, sulfuric acid or phosphoric acid, the sulfonic acid for methanesulfonic acid or
P-methyl benzenesulfonic acid.
9. according to the method for claim 2, the lower fatty acid is formic acid, acetic acid, propionic acid, butyric acid or isobutyric acid.
10. according to the method for claim 2, the molal weight ratio of the acid and Etoricoxib is (0.01~0.1)：1.
11. a kind of specific crystal seed, is made, this method includes by following methods:Etoricoxib is added to 5-10 times of volume
In organic solvent, temperature is heated to as 55~70 DEG C of dissolvings, addition acid between maintaining the temperature at 50~70 DEG C, stir about 0.4~
0.6h, slow cooling crystallization, filter, dry, produce the specific crystal seed of Etoricoxib, the molal weight ratio of the acid and Etoricoxib
For (0.01~0.9)：1.
12. specific crystal seed according to claim 11, the molal weight ratio of the acid and Etoricoxib is (0.01~0.5)：1,
It is preferred that (0.01~0.1)：1.
13. specific crystal seed according to claim 1, state acid and be selected from lower fatty acid, inorganic acid and sulfonic acid.
14. crystal seed according to claim 11, the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid, and the lower fatty acid is
Formic acid, acetic acid, propionic acid, butyric acid or isobutyric acid, the sulfonic acid are methanesulfonic acid or p-methyl benzenesulfonic acid.
15. crystal seed according to claim 14, the acid is selected from hydrochloric acid, acetic acid, propionic acid and p-methyl benzenesulfonic acid.
16. crystal seed according to claim 11, the organic solvent is toluene, ethyl acetate, isopropyl acetate or acetone.
17. a kind of pharmaceutical composition, it contains the Etoricoxib crystal formation that method as claimed in claim 1 obtains and pharmaceutically acceptable
Carrier.
18. purposes of the Etoricoxib crystal formation that the method for claim 1 obtains in treatment inflammation and pain medication is prepared.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002096877A1 (en) * | 2001-05-25 | 2002-12-05 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl in pure crystalline form and process for synthesis |
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| CN108069896A (en) * | 2016-11-11 | 2018-05-25 | 昆明积大制药股份有限公司 | A kind of preparation method of Etoricoxib crystal form |
-
2017
- 2017-06-21 CN CN201710474500.2A patent/CN107417599B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| WO2002096877A1 (en) * | 2001-05-25 | 2002-12-05 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl in pure crystalline form and process for synthesis |
| CN108069896A (en) * | 2016-11-11 | 2018-05-25 | 昆明积大制药股份有限公司 | A kind of preparation method of Etoricoxib crystal form |
Non-Patent Citations (1)
| Title |
|---|
| 何志成，等: "《化工原理》", 31 August 2015, 中国医药科技出版社 * |
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