CN103508958A - Novel celecoxib crystal form C and preparation method thereof - Google Patents
Novel celecoxib crystal form C and preparation method thereof Download PDFInfo
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- CN103508958A CN103508958A CN201310525397.1A CN201310525397A CN103508958A CN 103508958 A CN103508958 A CN 103508958A CN 201310525397 A CN201310525397 A CN 201310525397A CN 103508958 A CN103508958 A CN 103508958A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
Abstract
The invention provides a novel celecoxib crystal form C and a preparation method thereof. The preparation method comprises the steps as follows: dissolving the celecoxib crystal form A with a certain amount of methylbenzene, heating for complete dissolution, adding water, cooling, performing crystallization, filtering and drying under reduced pressure, so that the novel celecoxib crystal form C is obtained. In a powder X-ray diffraction pattern of the crystal form, characteristic diffraction peaks are achieved when the angles between (2 theta+0.2) to (2 theta-0.2) are equal to 5.33 degrees, 10.71 degrees, 16.10 degrees and 21.52 degrees respectively. The novel celecoxib crystal form C has the advantages that the stability is good, the production, transportation and storage are convenient and the crystal form C can meet the requirement of being used as a preparation raw material; moreover, the preparation method for the novel celecoxib crystal form C, provided by the invention, is simple to operate, mild in reaction conditions, easy to control, low in production cost, and suitable for industrialization.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly, relate to celecoxib new crystal C and preparation method thereof.
Background technology
Celecoxib, trade(brand)name celecoxib (Celecoxib), it is II type cyclooxygenase (COX-2) inhibitor of first listing, by U.S. Searle company, developed, the listing of the 1999 Nian U.S., be used for the treatment of the diseases associated with inflammation such as osteoarthritis and rheumatoid arthritis, there is the advantages such as gi tract and Toxicity of Kidney are little.Because it can optionally suppress COX-2, COX-1, without obvious restraining effect, is had to the curative effect of remarkable anti-inflammatory antipyretic-antalgic, but digestive tube damage can not occur, be a kind of good anti-inflammation analgesis medicament.
On the other hand, COX-2 (COX-2) suppresses and promotes the aspects such as vasculogenesis to play an important role at tumorigenesis, transfer, apoptosis, has become the novel targets for the treatment of and prevention of tumour.U.S. FDA approval celecoxibs in 1999 are used for the assisting therapy of familial intestinal cancer polyp, and this indicates that cox 2 inhibitor is formally for tumor prevention.Research shows, and has suitable COX-2 and suppresses active Compound Phase ratio, and the activity of celecoxib inducing apoptosis of tumour cell is stronger.Therefore, celecoxib is carried out to Anticancer Effect and Mechanism is inquired into and the research of composition optimizes is increasing.
Celecoxib chemical name is 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, structural formula is as follows:
Listing preparation only has celecoxib capsule at present, yet celecoxib bulk drug is water-soluble very poor, affects in body and absorbs, and as such medicine with remarkable clinical efficacy, it is also the emphasis that everybody pays close attention to that its crystal formation is studied.
The applicant finds after deliberation, after celecoxib raw material is added and reacted completely in Virahol equal solvent, adds water, heating molten, fast cooling, crystallization, filtration, drying under reduced pressure entirely, makes crystal habit celecoxib crystal form A.This crystal formation shows good physico-chemical property, and solvent reclaims economical, and stable crystal form is convenient to produce, transports and is stored, and can meet the advantages such as requirement of preparation raw material.The present invention is based on above-mentioned discovery is accomplished.
The present invention finds by research, adopts different solvents system, obtains different celecoxib crystal formations.By further research, from celecoxib crystal form A, through recrystallization, can obtain new crystal C.Because different crystal can show different physico-chemical properties, in pharmaceutical preparation process, improving preparation performance provides possibility.
Summary of the invention
The object of this invention is to provide a kind of stable crystal form, be easy to the celecoxib new crystal C of commercial scale production.
The present invention also provides the method for preparing celecoxib new crystal C, comprise the steps: celecoxib crystal form A to join in crystallization solvent, heating entirely molten, add water, cooling, crystallization, filtration, drying under reduced pressure, obtain celecoxib crystal C.
Crystallization solvent is preferably toluene.The consumption of toluene is 3～12 times of volumes of celecoxib crystal form A.
In crystallization reaction, cooling rate is 3～20 ℃ of coolings per hour, is finally cooled to 15～25 ℃.Preferably cooling rate is 5～10 ℃ of coolings per hour.
Conventionally drying under reduced pressure temperature is 40～65 ℃, and be 4～10h time of drying.
Celecoxib crystal C of the present invention is that the crystal form A by recrystallization celecoxib from toluene obtains.Celecoxib crystal form A has:
(1) X-ray powder diffraction pattern, described X-ray powder diffraction pattern contains the peak 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06 and 29.68;
(2) DSC endothermic transition is at 161.3-163.1 ℃.
Patent<201310520234.4 a kind of celecoxib new crystal A that the applicant submits to and preparation method thereof>in, the crystal form A of celecoxib can adopt following method preparation:
(1) Claisen condensation reaction: add alkaline solution and Virahol in p-methyl aceto phenone and trifluoroacetic acid alkyl ester, be warming up to 45～65 ℃, react 2～10h, keep in as reaction solution a;
(2) in another reactor, by Virahol, diazanyl benzsulfamide hydrochloride and trifluoroacetic acid are warming up to 45～55 ℃, add reaction solution a, continue reaction 0.5～2h;
(3) add water, be heated to 60～80 ℃ complete molten, make in reaction solution without solid;
(4) control rate of temperature fall, make system fast cooling, crystallization;
(5) suction filtration, by crystallization drying under reduced pressure 4～10 hours, obtain celecoxib new crystal A.
New crystal C of the present invention has good quality, and purity is at least 99.5%.Have and synthesize on a large scale or be mixed with the required performance of therapeutic preparation, to light, wet, thermally-stabilised, be convenient to produce, store and transport.
The present invention prepares celecoxib crystal C, and it uses Cu-Ka radiation, to spend the X-ray powder diffraction spectrum that 2 θ represent, 5.33,10.71,16.10 and 21.52, has peak.Its DSC endothermic transition is at 159.4-162.5 ℃.
The testing method of crystal C provided by the invention is as follows:
1, X-ray powder diffraction
Data are by methods known in the art, utilize senior powder diffractometer to obtain:
Instrument: German Brukrt AXS D8-FOCUS
Model: D8-FOCUS
Condition determination: CuK alpha-ray, Ni filtering, 40KV, 40mA, LynxEye192 bit array detector, 0.01 ° of 2theta of scanning step (Increment), the every step of speed (scanspeed) 0.05sec/step, 4.0Soller slit
2, dsc (DSC)
Instrument: the resistance to STA449F that speeds of Germany
Instrument parameter: temperature accuracy: ± 0.1 ℃;
Temperature rise rate: 0.1～50 ℃/per minute; Top temperature: 1500 ℃; Hot analytical balance range 0.001mg～50g.
Condition determination: starting temperature: 30 ℃, 10 ℃/per minute of temperature rise rate
The stability of celecoxib crystal C
Get celecoxib crystal C in weighing bottle, respectively at 60 ℃, 4500 ± 500LX illumination, and place under 75% relative humidity, in sampling in 5 days, 10 days, HPLC method was measured related substance, and result is as table 1.
Table 1 celecoxib crystal C factors affecting stability measurement result
| Placement condition | ? | Celecoxib powder | Crystal C |
| ? | Time | Total impurities (%) | Total impurities (%) |
| ? | 0 day | Do not detect | Do not detect |
| 60℃ | 5 days | 0.06 | 0.07 |
| 60℃ | 10 days | 0.07 | 0.10 |
| Illumination (4500Lux) | 5 days | 0.06 | 0.05 |
| Illumination (4500Lux) | 10 days | 0.10 | 0.10 |
| 75% relative humidity (25 ℃) | 5 days | 0.08 | 0.12 |
| 75% relative humidity (25 ℃) | 10 days | 0.10 | 0.15 |
Can find celecoxib crystal C placement 10 days, related substance is showed no obvious increase.
Pharmaceutical composition provided by the invention contains celecoxib crystal C and pharmaceutically acceptable carrier.
Celecoxib crystal C of the present invention, because it has good quality and stability, is suitable for oral Preparation, as tablet comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc.; Capsule comprises hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.; Granule comprises mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Oral solution; Oral suspensions; Syrup etc.While preparing oral solid formulation, can or pack gelatine capsule into or suppress in flakes celecoxib and the pack of suitable pharmaceutical excipient granulation.
In addition, the method for preparing celecoxib crystal C provided by the invention is simple to operate, and reaction conditions is gentle, easily controls, and low production cost, is applicable to industrialization.
Accompanying drawing explanation
The X-ray powder diffraction spectrogram of Fig. 1 celecoxib crystal C;
The differential thermogram of Fig. 2 celecoxib crystal C;
The collection of illustrative plates of Fig. 3 celecoxib crystal C purity detecting.
Embodiment
Describe embodiments of the invention below in detail, it should be noted that the embodiment the following describes is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.In addition, if do not clearly not stated, all reagent of adopting are in the following embodiments can be buied on market, or can be synthetic according to text or known method, for the reaction conditions of not listing, be also that those skilled in the art easily obtain.
Embodiment 1
Get 10g celecoxib crystal form A and be placed in 250ml there-necked flask, add 30ml toluene, heat up complete molten after, add 30ml water, 5 ℃ of coolings per hour, are cooled to 15 ℃ of suction filtrations, drying under reduced pressure at 40 ℃, dry 10h.Obtain celecoxib crystal C 9.5g, purity 99.1%.
The XRD figure of celecoxib crystal C is at Degree(2 θ) there is charateristic avsorption band on 16.54,12.67,10.00,8.25,8.03,6.79,6.67,5.96,5.78,5.50,5.31.
Embodiment 2
Get 10g celecoxib crystal form A and be placed in 250ml there-necked flask, add 50ml toluene, heat up complete molten after, add 50ml water, 10 ℃ of coolings per hour, are cooled to 15 ℃ of suction filtrations, drying under reduced pressure at 50 ℃, dry 8h.Obtain celecoxib crystal C 8.6g, purity 99.3%.
Embodiment 3
Get 10g celecoxib crystal form A and be placed in 250ml there-necked flask, add 70ml toluene, heat up complete molten after, add 70ml water, 3 ℃ of coolings per hour, are cooled to 25 ℃ of suction filtrations, drying under reduced pressure at 60 ℃, dry 5h.Obtain celecoxib crystal C 7.9g, purity 99.5%.
Embodiment 4
Get 10g celecoxib crystal form A and be placed in 250ml there-necked flask, add 100ml toluene, heat up complete molten after, add 100ml water, 8 ℃ of coolings per hour, are cooled to 25 ℃ of suction filtrations, drying under reduced pressure at 65 ℃, dry 4h.Obtain celecoxib crystal C 6.4g, purity 99.6%.
Embodiment 5
Get 10g celecoxib crystal form A and be placed in 250ml there-necked flask, add 120ml toluene, heat up complete molten after, add 120ml water, 10 ℃ of coolings per hour, are cooled to 25 ℃ of suction filtrations, drying under reduced pressure at 65 ℃, dry 6h.Obtain celecoxib crystal C 5.6g, purity 99.8%.
Although illustrated and described embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention in the situation that not departing from principle of the present invention and aim, modification, replacement and modification.
Claims (10)
1. a celecoxib crystal C, is characterized in that: described celecoxib crystal C is used Cu-Ka radiation, to spend the X-ray powder diffraction spectrum that 2 θ represent, 5.33,10.71,16.10 and 21.52, has peak.
2. celecoxib crystal C as claimed in claim 1, is characterized in that, its DSC endothermic transition is at 159.4-162.5 ℃.
3. a method of preparing the celecoxib crystal C described in claim 1 or 2, is characterized in that, celecoxib crystal form A is joined in crystallization solvent, heating entirely molten, add water, cooling, crystallization, filtration, drying under reduced pressure, obtain celecoxib crystal C.
4. the preparation method of celecoxib crystal C as claimed in claim 3, is characterized in that, described crystallization solvent is toluene.
5. the preparation method of celecoxib crystal C as claimed in claim 4, is characterized in that, described toluene is 3～12 times of volumes of celecoxib crystal form A.
6. the preparation method of celecoxib crystal C as claimed in claim 3, is characterized in that, the speed of described cooling is 3～20 ℃ of coolings per hour, is finally cooled to 15～25 ℃.
7. the preparation method of celecoxib crystal C as claimed in claim 6, is characterized in that, the speed of described cooling is 5～10 ℃ of coolings per hour.
8. the preparation method of celecoxib crystal C as claimed in claim 5, is characterized in that, the temperature of described drying under reduced pressure is 40～65 ℃, and be 4～10h time of drying.
9. celecoxib crystal C as claimed in claim 1 or 2, is characterized in that: described celecoxib crystal C is that the crystal form A by recrystallization celecoxib from toluene obtains, and described celecoxib crystal form A has:
(1) X-ray powder diffraction pattern, described X-ray powder diffraction pattern contains the peak 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06 and 29.68;
(2) DSC endothermic transition is at 161.3-163.1 ℃.
10. the preparation method of celecoxib crystal C as claimed in claim 3, it is characterized in that: the preparation method of described crystal form A is, after celecoxib raw material is joined and is reacted completely in Virahol equal solvent, add water, heating molten, fast cooling, crystallization, filtration, 50-65 ℃ drying under reduced pressure entirely, make crystal habit celecoxib crystal form A.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002000627A1 (en) * | 2000-06-26 | 2002-01-03 | Fako Ilaclari A.S. | A crystalline form of celecoxib |
| CN1411447A (en) * | 1999-12-08 | 2003-04-16 | 药品公司 | Polymorphic crystalline forms of celecoxib |
| WO2011055233A2 (en) * | 2009-11-03 | 2011-05-12 | Actavis Group Ptc Ehf | Improved process for preparing celecoxib polymorph |
| CN102838542A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form I of celecoxib, preparation method and purpose thereof |
| CN102838544A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form II of celecoxib, preparation method and purpose thereof |
| CN102838545A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form IV of celecoxib, preparation method and purpose thereof |
| CN102838543A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form III of celecoxib, preparation method and purpose thereof |
-
2013
- 2013-10-30 CN CN201310525397.1A patent/CN103508958A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1411447A (en) * | 1999-12-08 | 2003-04-16 | 药品公司 | Polymorphic crystalline forms of celecoxib |
| WO2002000627A1 (en) * | 2000-06-26 | 2002-01-03 | Fako Ilaclari A.S. | A crystalline form of celecoxib |
| WO2011055233A2 (en) * | 2009-11-03 | 2011-05-12 | Actavis Group Ptc Ehf | Improved process for preparing celecoxib polymorph |
| CN102838542A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form I of celecoxib, preparation method and purpose thereof |
| CN102838544A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form II of celecoxib, preparation method and purpose thereof |
| CN102838545A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form IV of celecoxib, preparation method and purpose thereof |
| CN102838543A (en) * | 2011-06-20 | 2012-12-26 | 天津药物研究院 | Crystalline form III of celecoxib, preparation method and purpose thereof |
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Application publication date: 20140115 |