CN102838544A - Crystalline form II of celecoxib, preparation method and purpose thereof - Google Patents
Crystalline form II of celecoxib, preparation method and purpose thereof Download PDFInfo
- Publication number
- CN102838544A CN102838544A CN2011101648662A CN201110164866A CN102838544A CN 102838544 A CN102838544 A CN 102838544A CN 2011101648662 A CN2011101648662 A CN 2011101648662A CN 201110164866 A CN201110164866 A CN 201110164866A CN 102838544 A CN102838544 A CN 102838544A
- Authority
- CN
- China
- Prior art keywords
- celecoxib
- crystal form
- preparation
- crystal
- celecoxib crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 title description 53
- 229960000590 celecoxib Drugs 0.000 title description 53
- 238000002360 preparation method Methods 0.000 title description 22
- 239000013078 crystal Substances 0.000 description 55
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000005755 formation reaction Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002775 capsule Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 3
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 201000003068 rheumatic fever Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- -1 sanitas Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007948 fast release tablet Substances 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a crystalline form II of celecoxib and a preparation method thereof, and further relates to a pharmaceutical composition prepared by using the crystalline form II of celecoxib obtained by the invention, and an application of the pharmaceutical composition. The crystalline form II 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 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, be used for treatment of arthritis.
Another object of the present invention is to provide the preparation method of the celecoxib crystal form II that is fit to suitability for industrialized production.
A further object of the present invention is to provide the pharmaceutical composition that contains the celecoxib crystal form II.
A further object of the invention is to disclose the application of pharmaceutical composition aspect preparation treatment rheumatic arthritis medicine that contains the celecoxib crystal form II.
The disclosed celecoxib crystal form II of the present invention has good fusing point and quality, and its quality purity is at least 99.5%.The celecoxib crystal form II 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 of the present invention is methanol solvate shape, and it has the peak with the use Cu-Ka radiating X-ray powder diffraction spectrum (" XRD ") of spending 2 θ and representing 5.24,10.76,16.14 and 21.56.Infrared absorption spectrum is 3338.26,3231.82,3098.28,1347.60 and 1163.95cm
-1Characteristic spectrum belt is arranged, and its DSC endothermic transition is at 157-162 ℃.
Celecoxib crystal form II 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
Its DSC endothermic transition of celecoxib crystal form II is at 157-162 ℃.
3. ir spectra (IR):
Instrument: PE-983G IR
Specimen preparation: KBr compressing tablet
The ir spectra wave number of celecoxib crystal form II (pressing potassium bromide troche) is (cm
-1) be: 3338.26,3231.82,3098.28,1347.60 and 1163.95cm
-1Characteristic spectrum belt is arranged,
4. fusing point:
Instrument: YTR-3 type fusing point appearance (Precision Instrument Factory, Tianjin Univ.)
The fusing point of celecoxib crystal form II is 157-162 ℃.
The present invention prepares the method for celecoxib crystal form II, 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 methyl alcohol.
Crystal habit celecoxib physico-chemical property and pharmacodynamic study thereof
One, the stability of celecoxib crystal form II
Get the celecoxib crystal form II 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 stability influence factor is measured the result
Conclusion: the celecoxib crystal form II 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/ml) 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 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 and pharmaceutically acceptable carrier.
Celecoxib crystal form II 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;
Fig. 2 is the infrared spectrogram of celecoxib crystal form II;
Fig. 3 is the thermogram of celecoxib crystal form II.
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:
The preparation of celecoxib crystal form II: get celecoxib 10 grams and insert in 250 milliliters of round-bottomed flasks, add 70-75 milliliter analytical pure acetonitrile and gac, heating, backflow, filtration; The filtrating room temperature was placed 24 hours, filtered filter cake washing; 50-60 ℃ of drying under reduced pressure gets 9.5 gram celecoxib crystal form IIs.Fusing point 157-162 ℃.
The XRD figure of celecoxib crystal form II has the peak 5.24,10.76,16.14 and 21.56.Infrared absorption spectrum is 3338.26,3231.82,3098.28,1347.60 and 1163.95cm
-1Characteristic spectrum belt is arranged, and its DSC endothermic transition is at 157-162 ℃.See Fig. 1 a, Fig. 1 b, Fig. 2, Fig. 3.
The 100mg capsule preparation of celecoxib crystal form II
Preparation has the capsule of combination thing:
The 200mg capsule preparation of celecoxib crystal form II
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 (%)
| |
5 |
10 |
20 |
30 |
45 minutes | 60 minutes |
| Crystal form II | 79.75 | 92.42 | 98.23 | 100.3 | 101.1 | 101.1 |
| Conventional capsule | 76.22 | 95.12 | 99.69 | 100.1 | 100.1 | 101.8 |
Claims (6)
1. a celecoxib crystal form II is characterized in that, described celecoxib crystal form II uses the Cu-Ka radiation, 5.24,10.76,16.14 and 21.56 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent.
2. celecoxib crystal form II as claimed in claim 1 is characterized in that, infrared absorption spectrum is 3338.26,3231.82,3098.28,1347.60 and 1163.95cm
-1Characteristic spectrum belt is arranged, and its DSC endothermic transition is at 157-162 ℃.
3. method for preparing the said celecoxib crystal form II of claim 1-2; 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 methyl alcohol.
5. a pharmaceutical composition is characterized in that, said composition contains right and requires the described celecoxib crystal form II of 1-2 and one or more pharmaceutical excipients.
Like the defined celecoxib crystal form II of claim 1-2 as the application of activeconstituents at analgesic, the analgesia of preparation, anti-arthritic object space face.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101648662A CN102838544A (en) | 2011-06-20 | 2011-06-20 | Crystalline form II of celecoxib, preparation method and purpose thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101648662A CN102838544A (en) | 2011-06-20 | 2011-06-20 | Crystalline form II of celecoxib, preparation method and purpose thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102838544A true CN102838544A (en) | 2012-12-26 |
Family
ID=47366305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101648662A Pending CN102838544A (en) | 2011-06-20 | 2011-06-20 | Crystalline form II of celecoxib, preparation method and purpose thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102838544A (en) |
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 |
| JP2017052719A (en) * | 2015-09-09 | 2017-03-16 | 株式会社トクヤマ | Method for producing celecoxib type II crystal |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746231A (en) * | 2011-04-20 | 2012-10-24 | 天津药物研究院 | Celecoxib preparation process |
-
2011
- 2011-06-20 CN CN2011101648662A patent/CN102838544A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746231A (en) * | 2011-04-20 | 2012-10-24 | 天津药物研究院 | Celecoxib preparation process |
Non-Patent Citations (1)
| Title |
|---|
| GARIMA CHAWLA ETAL: "Characterization of solid-state forms of celecoxib", 《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
Cited By (6)
| 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 |
| JP2017052719A (en) * | 2015-09-09 | 2017-03-16 | 株式会社トクヤマ | Method for producing celecoxib type II crystal |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103664958B (en) | A kind of crystal formation of Ticagrelor and preparation method thereof | |
| CN102838543A (en) | Crystalline form III of celecoxib, preparation method and purpose thereof | |
| CN102838542A (en) | Crystalline form I of celecoxib, preparation method and purpose thereof | |
| Gajda et al. | The role of the polymer matrix in solvent-free hot melt extrusion continuous process for mechanochemical synthesis of pharmaceutical cocrystal | |
| CN102838544A (en) | Crystalline form II of celecoxib, preparation method and purpose thereof | |
| CN102464659B (en) | Licopyrinobuter compound crystal forms, preparation method, and use thereof | |
| CN102838545B (en) | Celecoxib crystalline form IV and its production and use | |
| CN101896477B (en) | Form V of nitrosamide compound crystal, its preparation method, its pharmaceutical composition and application | |
| CN101671315B (en) | New crystal form of febuxostat and preparation method thereof | |
| Manchanda et al. | Recent advancements in Pharmaceutical cocrystals, Preparation methods, and their applications | |
| CN105801568B (en) | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition | |
| CN107245054B (en) | Amorphous bulleyaconitine A compound and preparation method thereof | |
| CN1944420B (en) | Iguratimod crystal form and its composition | |
| CN101885717B (en) | Iguratimod crystal habit and composition thereof | |
| CN105198932B (en) | Lobaplatin dihydrate, preparation method and medicinal application | |
| CN105017216A (en) | Dexlansoprazole crystal form III and preparation method and application thereof | |
| CN104418799A (en) | Etoricoxib crystal as well as preparation method and application thereof | |
| CN101885718B (en) | Iguratimod crystal habit and composition thereof | |
| CN105193749A (en) | Medicinal tadalafil composition tablets for treating urological diseases | |
| CN102558051B (en) | A kind of tolvaptan crystal and pharmaceutical composition thereof | |
| CN103709169A (en) | Crystallization morphology of 6-(4-chlorophenyl)-2, 2-dimethyl-7-phenyl-2, 3-dihydro-pyrrolizinone-5-acetate nitric acid butyl ester | |
| CN101891726A (en) | Iguratimod crystalline forms and compositions thereof | |
| CN103709168A (en) | Crystallization morphology of 6-(4-chlorophenyl)-2, 2-dimethyl-7-phenyl-2, 3-dihydro-pyrrolizinone-5-acetate nitric acid butyl ester | |
| CN102702033A (en) | Amorphous peramivir, preparation method thereof and medicinal composition | |
| CN104693192A (en) | Crystal form A of compound as well as preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20121226 |