CN102838543A - Crystalline form III of celecoxib, preparation method and purpose thereof - Google Patents
Crystalline form III of celecoxib, preparation method and purpose thereof Download PDFInfo
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- CN102838543A CN102838543A CN2011101648446A CN201110164844A CN102838543A CN 102838543 A CN102838543 A CN 102838543A CN 2011101648446 A CN2011101648446 A CN 2011101648446A CN 201110164844 A CN201110164844 A CN 201110164844A CN 102838543 A CN102838543 A CN 102838543A
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Abstract
The invention relates to a crystalline form III of celecoxib and a preparation method thereof, and further relates to a pharmaceutical composition prepared by using the crystalline form III of celecoxib obtained by the invention, and an application of the pharmaceutical composition. The crystalline form III of celecoxib is characterized by an x-ray powder diffraction pattern spectrum, a differential thermal analysis spectrum and an infra-red spectrogram thereof.
Description
Technical field
The invention belongs to autoimmunization and regulate technical field of pharmaceuticals, more particularly, the present invention relates to celecoxib crystal form II I and preparation method thereof and be used to prepare that treatment is analgesic, the application of analgesia, anti-arthritic object space face.
Background technology
Rheumatic arthritis (rheumatoid arthritis RA) is the stronger systemic autoimmune disorder of a kind of disabling property, like not active and effective treatment, generally in 1 to 2 year, joint aggressiveness pathology will take place.At present, the RA treatment is two big types of medicines, nonsteroidal anti-inflammatory analgetic (NSAIDs) and change course of disease antirheumatic (DMARDs).NSAIDs mainly acts on to be arthralgia, the swelling that alleviates RA patient and to improve function of joint, but it has limited its use to GI serious adverse reaction.The enzymology of reorganization shows that it is to the IC of COX-2 and COX-1
50Be respectively 0.04 μ mol/L and 15 μ mol/L; The selective inhibitory of the selectivity inhibition strength of COX-2 being compared COX-1 is strong 375 times: celecoxib can suppress COX-2 to greatest extent; And COX-1 is suppressed also not obvious; This makes it have than strong solution heat, analgesia, arthritis activity, does not influence barrier of gastric mucosa, thrombocyte and renal function again, thereby has significantly reduced the common untoward reaction of NSAIDs (NSAIDs).
Celecoxib, English name Celecoxib, chemical structural formula is:
Its chemical structure, method of manufacture, purposes have been disclosed at WO 1995/15316.
The inventor is unexpected in experiment to find that celecoxib has multiple crystal habit (ETHYLE ACETATE crystal formation, methyl alcohol crystal formation, ethanol crystal formation; The THF crystal formation); Crystals with different shows good physico-chemical property; Solvent reclaims economical, thereby water cut is relatively stable and can directly be used for preparation such as the capsule of medicine and the performance that granule has improved preparation.The present invention is based on above-mentioned discovery is accomplished.
Summary of the invention
The object of the present invention is to provide a kind of celecoxib crystal form II I, be used for treatment of arthritis.
Another object of the present invention is to provide the preparation method of the celecoxib crystal form II I that is fit to suitability for industrialized production.
A further object of the present invention is to provide the pharmaceutical composition that contains celecoxib crystal form II I.
A further object of the invention is to disclose the application of pharmaceutical composition aspect preparation treatment rheumatic arthritis medicine that contains celecoxib crystal form II I.
The disclosed celecoxib crystal form II of the present invention I has good fusing point and quality, and its quality purity is at least 99.5%.Celecoxib crystal form II I has synthetic on a large scale or is mixed with the required performance of therapeutic preparation, to light, wet, thermally-stabilised, is convenient to produce, store.
For realizing above-mentioned purpose of the present invention, adopt following technical scheme:
Celecoxib crystal form II I of the present invention is alcohol solvent shape, and it has the peak with the use Cu-Ka radiating X-ray powder diffraction spectrum (" XRD ") of spending 2 θ and representing 5.34,10.70,16.08 and 21.52.Infrared absorption spectrum is 3339.15,3232.86,3099,1347.69 and 1164.43cm
-1Characteristic spectrum belt is arranged, and its DSC endothermic transition is at 160-163 ℃.
Celecoxib crystal form II I provided by the invention, testing method is following:
1.X-ray powder diffraction:
Instrument: Japanese D/MAX-2500.1708X ray polycrystalline powder diffractometer of science
Target: Cu-K a radiation, 2 θ=2-40 ℃
Step angle: 0.04 ℃
Computing time: 0.5 second
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 ℃/min
Filter disc: graphite monochromator
2. dsc (DSC):
Instrument: Japanese standard type TG-DTA analyser of science
TR: room temperature～300 ℃
Heat-up rate: 10 ℃/minute
The DSC endothermic transition of celecoxib crystal form II I is at 160-163 ℃.
3. ir spectra (IR):
Instrument: PE-983G IR
Specimen preparation: KBr compressing tablet
The ir spectra wave number of celecoxib crystal form II I (pressing potassium bromide troche) is (cm
-1) be: 3339.15,3232.86,3099,1347.69 and 1164.43cm
-1Characteristic spectrum belt is arranged.
4. fusing point:
Instrument: YTR-3 type fusing point appearance (Precision Instrument Factory, Tianjin Univ.)
The fusing point 160-163 of celecoxib crystal form II I ℃.
The present invention prepares the method for celecoxib crystal form II I, comprises the celecoxib raw material is added in the crystallization solvent, and heating, backflow, filtration, the filtrating room temperature was placed refrigerator 18-24 hour, filters, filter cake washing, 50-60 ℃ of drying under reduced pressure makes crystalline celecoxib.Wherein said crystallization solvent is selected from ethanol.
Crystal habit celecoxib physico-chemical property and pharmacodynamic study thereof
One, the stability of celecoxib crystal form II I
Get celecoxib crystal form II I in weighing bottle, respectively at 60 ℃, 4500 ± 500LX illumination and 75% relative humidity held, in sampling in 5 days, 10 days, the HPLC method was measured related substance, result such as table 1.
Table 1 celecoxib crystal form II I stability influence factor is measured the result
Conclusion: celecoxib crystal form II I was 60 ℃, 4500 ± 500LX illumination and 92.5% relative humidity held 10 days, and related substance is not all seen obvious increase.
Two, the pharmacokinetics behind 4 kinds of crystal formation raw materials of the oral celecoxib of rat
Test materials and method
1. tried raw material:
Tianjin Inst. of Materia Medica synthetic celecoxib ETHYLE ACETATE crystal formation, methyl alcohol crystal formation, ethanol crystal formation, the THF crystal formation.
2 grouping administrations
Select 40 of Wistar rats for use, be divided into 4 groups at random, 10 every group by body weight; Male and female dual-purpose, fasting are after 16 hours, and each group is 4 kinds of crystal formations of oral administration gavage celecoxib (ETHYLE ACETATE crystal formation, methyl alcohol crystal formation, ethanol crystal formation respectively; The THF crystal formation), dosage respectively is 20mg/kg.Get blood respectively at 0.17,0.5,1,2,3,4,6,8,12,18 and 24 hour eye socket after the administration, separation of serum ,-20 ℃ of preservations are to be measured.
3 chromatographic conditions
Stationary phase: Diamonsil
TMC
18Post, 10 μ m, 250 * 4.6mm (I.D.), 30 ℃ of column temperatures.
Moving phase: methyl alcohol: water=70: 30, flow velocity: 1ml/min.
Detect wavelength: 215nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
4 blood samples are handled
Get rat blood serum 200 μ l, mark (celecoxib midbody 200 μ g/m1) 10 μ l add DMF (N, dinethylformamide) 200 μ l in adding behind the mixing; Vibration 10min; Placed 30 minutes, and, got supernatant 20 μ l sample introductions with the centrifugal 10min of the speed of 10000 commentaries on classics/min.
5 determination of plasma concentration
Behind the bioassay standard curve, draw linear regression equation (y=ax+b).The ratio of blood sample gained peak area calculates Plasma Concentration according to linear regression equation after the administration of mensuration rat, and calculates medicine for parameter through the 3P97 medicine for computation program.
6 instruments
HPLC test macro: Tianjin, island SPD-10AUv detector, Hi-Tech P4000 HPP, LabAlliance AS1000 automatic sampler, ANASTAR chromatographic working station.
The HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
The TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai makes.
The miniature vortex mixed instrument of WX-80A: Shanghai Hu Xi analytical instrument factory produces.
7. result of study
Annotate: data are mean number ± standard deviation (n=6) in the table.
Conclusion: the pharmacokinetic behind 4 kinds of crystal formation raw materials of the oral celecoxib of rat shows; 4 kinds of crystal formations of the celecoxib of rat oral administration gavage 20mg/kg, visible for parameter from medicine, there is some difference between the different parameters of 4 kinds of crystal formations; But basically all in same order of magnitude scope; 4 kinds of crystal formations all can be developed to new medicine, the Stability Analysis of Structures of 4 kinds of crystal formations, absorption in animal body, elimination basically identical.
Celecoxib crystal form II I of the present invention is showing higher biological activity aspect the preparation treatment rheumatic arthritis medicine.
Pharmaceutical composition provided by the invention contains celecoxib crystal form II I and pharmaceutically acceptable carrier.
Celecoxib crystal form II I of the present invention is suitable for oral Preparation, comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc. like tablet; 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 or the like.Celecoxib micro mist of the present invention also is suitable for the preparation of external preparation such as gelifying agent, ointment, ointment, paste, patch or the like.Preparation is during oral solid formulation, can celecoxib and suitable pharmaceutical excipient processed the particle pack or pack gelatine capsule or compacting in flakes.
Acceptable carrier comprises one or more pharmaceutical excipients on the pharmacology, for example tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant.Compsn can contain the celecoxib of the crystal habit of 50-500mg (being generally 100-200mg).The peroral administration optimised form of this compsn is a capsule, general every the celecoxib that contains the crystal habit of 50-500mg (being generally 100-200mg) of capsule.Best is every celecoxib that contains the 200mg crystal habit.
Description of drawings
Fig. 1 a and Fig. 1 b are the XRD figures of celecoxib crystal form II I;
Fig. 2 is the infrared spectrogram of celecoxib crystal form II I;
Fig. 3 is the thermogram of celecoxib crystal form II I.
Embodiment
Following embodiment further illustrates of the present invention, rather than limits.
Except as otherwise noted, in this article, temperature be meant centigradetemperature (℃), room temperature is meant about 18-23 ℃.The present inventor has identified several kinds of different crystallization celecoxib forms, has used several method (normally using XRD, DSC and IR) that their characteristic is characterized.
According to the narration of CN 100379727, the preparation celecoxib, reaction formula is following:
Celecoxib crystal form II I preparation: get celecoxib 10 grams and insert in 250 milliliters of round-bottomed flasks; Add 15-20 milliliter analytical pure ethanol and gac, heating, backflow, filtration, the filtrating room temperature was placed refrigerator 18 hours; Filter; Filter cake washing, 50-60 ℃ of drying under reduced pressure gets 9.5 gram celecoxib crystal form II I.Fusing point 160-163 ℃.
The XRD figure of celecoxib crystal form II I has the peak 5.34,10.70,16.08 and 21.52.Infrared absorption spectrum is 3339.15,3232.86,3099,1347.69 and 1164.43cm
-1Characteristic spectrum belt is arranged, and its DSC endothermic transition is at 160-163 ℃.See Fig. 1 a, Fig. 1 b, Fig. 2, Fig. 3.
The preparation of celecoxib crystal form II I100mg capsule
Preparation has the capsule of combination thing:
The preparation of celecoxib crystal form II I200mg capsule
Preparation has the capsule of combination thing:
Embodiment 2-3 is suitable for the preparation process
In in batches for the wet granulator of 1kg, feed intake, place wet granulator to add sodium lauryl sulphate, Vinylpyrrolidone polymer, Sodium Croscarmellose successively, add or do not add sucrose fatty ester micronized celecoxib and stirred 30 minutes by 5000 amounts of prescription preparation with high shear; Add lactose, add or do not add Microcrystalline Cellulose and continue to stir and mixed in 2 minutes with identical method.Water system softwood is granulated in waving nodulizer 24 mesh sieves, and with the wet granular that makes in 60 ℃ of baking ovens dry 4 hours, mixes with the whole grain of 30 orders concussion sieve back adding Magnesium Stearate.Then in particle packing to 1 gelatine capsule with mixing.
Prepare tablet coating suspension-s with following method: press solid content 12%, weightening finish 3%.Take by weighing coating powder, slowly add in the pure water in stirring (liquid level has just had whirlpool), dispersed with stirring is even, continues to stir 45 minutes, and 100 eye mesh screens filter, and get final product.Coating pan is with 35 rev/mins of rotating speeds, and temperature 45-50 ℃ adds label preheating 5-10 minute; Regulate pressurized air ejection liquid is well atomized, beginning dressing, dressing finish and continued dry 30-40 minute.
Dissolution determination:
According to " 2010 editions two requirements of Chinese pharmacopoeia are operated in accordance with the law; 1000ml is a solvent with phosphate buffered saline buffer (0.05mol/L pH8), and the adjustment rotating speed was that PM 100 changes, in sampling in 5,10,20,30,45,60 minutes; Determined by ultraviolet spectrophotometry, the dissulution result of sample is following
Celecoxib preparation dissolution determination result (%)
| Sample | 5 minutes | 10 |
20 |
30 minutes | 45 minutes | 60 minutes |
| Crystal form II I | 78.92 | 83.07 | 98.03 | 98.65 | 99.27 | 99.90 |
| Conventional capsule | 76.22 | 95.12 | 99.69 | 100.1 | 100.1 | 101.8 |
Claims (6)
1. a celecoxib crystal form II I is characterized in that, described celecoxib crystal form II I uses the Cu-Ka radiation, 5.34,10.70,16.08 and 21.52 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent.
2. celecoxib crystal form II I as claimed in claim 1 is characterized in that, infrared absorption spectrum is 3339.15,3232.86,3099,1347.69 and 1164.43cm
-1Characteristic spectrum belt is arranged, and its DSC endothermic transition is at 160-163 ℃.
3. method for preparing the said celecoxib crystal form II of claim 1-2 I; It is characterized in that: the celecoxib raw material is joined in the crystallization solvent, heating, backflow, filtration, the filtrating room temperature is placed or freezing 18-24 hour; Filter; Filter cake washing, 50-60 ℃ of drying under reduced pressure makes the crystal habit celecoxib.
4. preparation method as claimed in claim 3 is characterized in that, described crystallization solvent is selected from ethanol.
5. a pharmaceutical composition is characterized in that, said composition contains right and requires the described celecoxib crystal form II of 1-2 I and one or more pharmaceutical excipients.
Like the defined celecoxib crystal form II of claim 1-2 I as the application of activeconstituents at analgesic, the analgesia of preparation, anti-arthritic object space face.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101648446A CN102838543A (en) | 2011-06-20 | 2011-06-20 | Crystalline form III of celecoxib, preparation method and purpose thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103508958A (en) * | 2013-10-30 | 2014-01-15 | 中美华世通生物医药科技（武汉）有限公司 | Novel celecoxib crystal form C and preparation method thereof |
| CN103524416A (en) * | 2013-10-29 | 2014-01-22 | 中美华世通生物医药科技（武汉）有限公司 | Novel crystal form A of celecoxib and preparation method thereof |
| CN103539739A (en) * | 2013-10-30 | 2014-01-29 | 中美华世通生物医药科技（武汉）有限公司 | Novel celecoxib crystal form B and preparation method thereof |
| CN113402463A (en) * | 2021-07-08 | 2021-09-17 | 江南大学 | Celecoxib microcrystal, temperature-sensitive gel loaded with celecoxib microcrystal and preparation method of gel |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011055233A2 (en) * | 2009-11-03 | 2011-05-12 | Actavis Group Ptc Ehf | Improved process for preparing celecoxib polymorph |
| CN102746231A (en) * | 2011-04-20 | 2012-10-24 | 天津药物研究院 | Celecoxib preparation process |
-
2011
- 2011-06-20 CN CN2011101648446A patent/CN102838543A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011055233A2 (en) * | 2009-11-03 | 2011-05-12 | Actavis Group Ptc Ehf | Improved process for preparing celecoxib polymorph |
| CN102746231A (en) * | 2011-04-20 | 2012-10-24 | 天津药物研究院 | Celecoxib preparation process |
Non-Patent Citations (1)
| Title |
|---|
| GUANG WEI LU ET AL: "Characterization of a Novel Polymorphic Form of Celecoxib", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524416A (en) * | 2013-10-29 | 2014-01-22 | 中美华世通生物医药科技（武汉）有限公司 | Novel crystal form A of celecoxib and preparation method thereof |
| CN103524416B (en) * | 2013-10-29 | 2016-08-17 | 湖北华世通生物医药科技有限公司 | A kind of Novel celecoxib crystal form A and preparation method thereof |
| CN103508958A (en) * | 2013-10-30 | 2014-01-15 | 中美华世通生物医药科技（武汉）有限公司 | Novel celecoxib crystal form C and preparation method thereof |
| CN103539739A (en) * | 2013-10-30 | 2014-01-29 | 中美华世通生物医药科技（武汉）有限公司 | Novel celecoxib crystal form B and preparation method thereof |
| CN103539739B (en) * | 2013-10-30 | 2016-02-10 | 中美华世通生物医药科技（武汉）有限公司 | A kind of Novel celecoxib crystal form B and preparation method thereof |
| CN113402463A (en) * | 2021-07-08 | 2021-09-17 | 江南大学 | Celecoxib microcrystal, temperature-sensitive gel loaded with celecoxib microcrystal and preparation method of gel |
| CN113402463B (en) * | 2021-07-08 | 2023-12-26 | 江南大学 | Celecoxib microcrystal, temperature-sensitive gel loaded with celecoxib microcrystal and preparation method of temperature-sensitive gel |
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Application publication date: 20121226 |