CN104418799A - Etoricoxib crystal as well as preparation method and application thereof - Google Patents

Etoricoxib crystal as well as preparation method and application thereof Download PDF

Info

Publication number
CN104418799A
CN104418799A CN201310423071.8A CN201310423071A CN104418799A CN 104418799 A CN104418799 A CN 104418799A CN 201310423071 A CN201310423071 A CN 201310423071A CN 104418799 A CN104418799 A CN 104418799A
Authority
CN
China
Prior art keywords
crystal formation
etoricoxib
tablet
capsule
pharmaceutical composition
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
Application number
CN201310423071.8A
Other languages
Chinese (zh)
Inventor
梅林雨
郑志超
王杏林
高晶
罗振福
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Institute of Pharmaceutical Research Co Ltd
Original Assignee
Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tianjin Institute of Pharmaceutical Research Co Ltd filed Critical Tianjin Institute of Pharmaceutical Research Co Ltd
Priority to CN201310423071.8A priority Critical patent/CN104418799A/en
Publication of CN104418799A publication Critical patent/CN104418799A/en
Pending legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/61Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides an etoricoxib crystal. The etoricoxib crystal is irradiated with Cu-Ka, and the X-ray powder diffraction pattern expressed with an angel of 2theta shows that the etoricoxib crystal has diffraction peaks at the diffraction intensities of 8.30, 8.56, 15.14, 17.00, 17.14, 17.78, 18.82, 21.62, 22.34, 22.78, 23.38, 23.64, 27.02, 27.48, 28.58 and 30.18. The invention further provides a preparation method of the etoricoxib crystal, a medicinal composition which contains the etoricoxib crystal and takes the etoricoxib crystal as an active component and an application of the etoricoxib crystal in the preparation of medicines for treating acute or chronic osteoarthritis or acute gouty arthritis.

Description

Crystal formation of a kind of Etoricoxib and its preparation method and application
Technical field
The invention belongs to autoimmunization regulating drug technical field, relate to a kind of crystal formation of Etoricoxib.Particularly, the present invention relates to a kind of crystal formation of Etoricoxib, prepare the method for this crystal formation, containing the pharmaceutical composition of described crystal formation as activeconstituents, and this crystal formation for the preparation for the treatment of acute phase or chronic phase osteoarthritis or acute gouty arthritis medicine in application.
Background technology
The arthritis that urarthritis is disorders of purine metabolism, blood uric acid increases caused recurrent exerbation.Uric Acid is that the purine in the nucleic acid and other purine compounds and food decomposed by cellular metabolism decomposes.The generation of uric acid increases and the minimizing of draining all can make uric acid accumulate and produce hyperuricemia.Urate deposition in joint, periarticular tissue and subcutis, cause arthritic recurrent exerbation, have acute red, swollen, severe pain, produce that B&J destroys, deformity, ankylosis and dysfunction gradually.Gout can have primary and Secondary cases two class.Primary gout can be relevant with inherited genetic factors.Secondary gout can betide renal hypofunction, underexcretion patient; Also leukemia, myelomatosis and the malignant tumour patient that nucleic acid decomposition increases after chemotherapy, radiotherapy can be betided.
Clinical manifestation:
1, primary gout is multiple is born in more than the 40 years old male sex, and women is rare, accounts for 5%.Some patients has family history.
2, asymptomatic stage, only has high blood uric acid.Blood uric acid increases to joint symptoms duration of seizure can reach the several years.
3, acute attack stage: often break out night, first betide Metatarsophalangeal joint, severe pain, culminate within a few hours, obvious tumefaction is rubescent, tenderness is obvious, dysfunction.Can with heating, up to 38 ~ 39 DEG C.The symptoms such as weak, apocleisis, headache.Remission after 1 ~ 2 week, recurred after the interval several months to several years.Other joint toe, thumb, metacarpophalangeal joint, ankle, wrist, knee, shoulders etc. also can occur.Drink, gluttony, fatigue, wound or direct stimulation etc. all can bring out sacroiliitis outbreak.
4, the chronic arthritis phase: sacroiliitis is frequently shown effect, the intermittent phase shortens, arthroncus, joint epiphysis destroy and hyperplasia and teratogenesis shape.Uratoma is there is in auricle or joint part.Be positioned at subcutaneous, in faint yellow tubercle.Can flow out lime shape thing during uratoma ulceration, sinus is difficult to healing, can secondary pyogenic infection.There is urate calculi in about 10 ~ 20% patients, and can cause blood urine, renal colic symptom.The complication such as hypertension, coronary heart disease can be there is.
Osteoarthritis (osteoarthritis) is because old or the birth defect, joint deformity etc. of other reasons as wound, joint cause the non-inflammation degeneration of joint cartilage and joint margins spur to be formed, and clinically produces the symptoms such as arthralgia, limitation of activity and joint deformity.Conventional synonym is a lot, as osteoarthropathy, and osteoarthritis, senile arthritis, hypertrophiarthritis etc.Namely the degeneration of cartilage may start from 20 years old later stage, and more than 50 years old in crowd, large multipotency shows the performance of osteoarthritis on X-ray film.Often comparatively the male sex is more outstanding in women for pathology, involves finger-joint, knee, hip, backbone etc. more, is the most common cause affecting the elderly's activity.
Etoricoxib, English Etoricoxib by name, its chemical structural formula is as follows:
Be used for the treatment of acute phase and chronic phase osteoarthritis sings and symptoms, and treatment acute gouty arthritis.Still wishing by seeking new Etoricoxib crystal formation at present, there is excellent physico-chemical property and the crystal formation being applicable to extensive synthesis production, simultaneously also for the diseases such as treatment of arthritis provide more material choice to obtain.
Summary of the invention
The object of the invention is to make up blank of the prior art, provide a kind of good stability, Etoricoxib crystal formation that pharmacokinetic property is good, and prepare the method for this crystal formation, containing the pharmaceutical composition of described crystal formation as activeconstituents, and this crystal formation for the preparation for the treatment of acute phase or chronic phase osteoarthritis or acute gouty arthritis medicine in application.
The present inventor have unexpectedly discovered that the new crystal of Etoricoxib in an experiment, it shows excellent physico-chemical property, and solvent reclaims economical, the relatively stable and preparation that can be directly used in medicine of water content as in tablet, capsule and granule, thus improves the performance of preparation.The present invention is based on above-mentioned discovery to be accomplished.
The X-ray powder diffraction pattern the invention provides a kind of crystal formation of Etoricoxib, described crystal formation uses Cu-Ka radiation, representing with 2 θ angles has diffraction peak at 8.30,8.56,15.14,17.00,17.14,17.78,18.82,21.62,22.34,22.78,23.38,23.64,27.02,27.48,28.58 and 30.18 places.
According to crystal formation of the present invention, wherein, the infrared absorption spectrum that records with KBr pressed disc method of described crystal formation is at 3057cm -1, 3038cm -1, 3007cm -1, 2926cm -1, 1598cm -1, 1563cm -1, 1425cm -1, 1309cm -1, 1188cm -1, 1153cm -1, 1117cm -1, 778cm -1, 770cm -1, 734cm -1and 719cm -1there is characteristic spectrum belt.
According to crystal formation of the present invention, wherein, the DSC endothermic transition of described crystal formation is 135 ~ 140 DEG C.Preferably, the fusing point of described crystal formation is 135 ~ 139 DEG C.
According to crystal formation of the present invention, wherein, described crystal formation use Cu-Ka radiation, the X-ray powder diffraction pattern that represents with 2 θ angles substantially as shown in Figure 1.
According to crystal formation of the present invention, wherein, the infrared absorption spectrum that records with KBr pressed disc method of described crystal formation substantially as shown in Figure 3.Preferably, the differential scanning calorimetric thermogram of described crystal formation substantially as shown in Figure 4.
Present invention also offers a kind of method preparing the crystal formation of above-mentioned Etoricoxib, the method comprises:
(1) Etoricoxib is dissolved in ethyl acetate, heating, backflow, filtration, obtain filtrate;
(2) filtrate under agitation slow cooling to 20 ~ 30 DEG C step (1) obtained, crystallization, filters, obtains described crystal formation.
According to method of the present invention, wherein, in step (1), the weightmeasurement ratio of described Etoricoxib and ethyl acetate is 1:2.5 ~ 3.5.Weightmeasurement ratio described herein can be the ratio of weight (g) and volume (ml).Such as, when Etoricoxib is 1g, when ethyl acetate is 1ml, their weightmeasurement ratio is 1:1.In addition, when Etoricoxib is dissolved in ethyl acetate, also can add appropriate gac for adsorbing contaminant.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition includes crystal formation or the crystal formation of Etoricoxib of preparation according to the method described above of the above-mentioned Etoricoxib of effective amount.
Etoricoxib crystal formation of the present invention can make pharmaceutical composition jointly with one or more pharmaceutically acceptable vehicle.In other words, pharmaceutical composition provided by the invention contains Etoricoxib crystal formation and pharmaceutically acceptable carrier.Described vehicle can comprise thinner, tackiness agent, disintegrating agent, sanitas, dispersion agent, glidant, lubricant etc.Wherein, lactose, starch, Microcrystalline Cellulose can be adopted as thinner; Gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. can be used as tackiness agent; Starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose can be used as disintegrating agent; Talcum powder, micro-part of silica gel, stearin, calcium stearate or magnesium etc. can be used as glidant or lubricant.Those skilled in the art also can use other conventional auxiliary materials to prepare pharmaceutical composition containing Etoricoxib.
According to pharmaceutical composition of the present invention, wherein, described pharmaceutical composition is oral Preparation.Preferably, described oral Preparation is selected from tablet, capsule, granule, oral solution, oral suspensions or syrup.More preferably; described tablet is selected from fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coated tablet; described capsule is selected from hard capsule, soft capsule, slow releasing capsule, controlled release capsule or enteric coated capsule, and described granule is selected from mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules or controlled release granule.When preparing oral solid formulation, the crystal formation of Etoricoxib and suitable pharmaceutical excipient can be made particle pack or load gelatine capsule or tabletted.
According to pharmaceutical composition of the present invention, wherein, described pharmaceutical composition is external preparation.Preferably, described external preparation is selected from gelifying agent, ointment, ointment, paste or patch.Etoricoxib crystal formation in this pharmaceutical composition first can make the form of micro mist.
Etoricoxib crystal formation of the present invention is effective within the scope of quite wide dosage range.Such as, described pharmaceutical composition can contain the Etoricoxib crystal formation of 10 ~ 200mg, can be preferably 30 ~ 120mg.The actual dosage taken should be decided according to interesting cases by doctor, these situations comprise the physical state of patient, the route of administration of patient, the age, body weight, to the individual reaction of medicine and the severity of symptom etc.But as preferably, the optimised form of aforementioned pharmaceutical compositions is tablet, this tablet generally every can be preferably 30 ~ 120mg containing the Etoricoxib crystal formation of 10 ~ 200mg, be more preferably every sheet containing 30,60,90, the Etoricoxib crystal formation of 120mg.
Present invention also offers above-mentioned Etoricoxib crystal formation or according to the method described above and preparation Etoricoxib crystal formation for the preparation for the treatment of acute phase or chronic phase osteoarthritis or acute gouty arthritis medicine in purposes.
More particularly, Etoricoxib crystal formation of the present invention, for ethyl acetate solvent shape, it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum (" XRPD ") represented to spend 2 θ has peak 8.30,8.56,15.14,17.00,17.14,17.78,18.82,21.62,22.34,22.78,23.38,23.64,27.02,27.48,28.58 and 30.18.Infrared absorption spectrum is 3057,3038,3007,2926,1598,1563,1425,1309,1188,1153,1117,778,770,734 and 719cm -1have characteristic spectrum belt, its DSC endothermic transition is at 135 ~ 140 DEG C.
Etoricoxib crystal formation provided by the invention, testing method is as follows:
1.X-ray powder diffraction (XRPD):
Instrument: Rigaku D/MAX-2500.1708X ray polycrystal powder diffractometer
Target: Cu-K а radiation, 2 θ=2 ~ 40 DEG C
Step angle: 0.04 DEG C
Computing time: 0.5 second
Pipe pressure: 40KV
Guan Liu: 100mA
Sweep velocity: 8 DEG C/min
Filter disc: graphite monochromator
2. dsc (DSC):
Instrument: Rigaku standard type TG-DTA analyser
Temperature range: room temperature ~ 300 DEG C
Heat-up rate: 10 DEG C/min
3. infrared spectra (IR):
Instrument: PE-983G infrared spectrometer
Sample preparation: KBr compressing tablet
4. fusing point:
Instrument: YTR-3 type melting point apparatus (Precision Instrument Factory, Tianjin Univ.)
The method preparing Etoricoxib crystal formation of the present invention comprises and adds in crystallization solvent by Etoricoxib raw material, heating, backflow, crystallization, filtration, obtained crystalline Etoricoxib.Wherein said crystallization solvent is ethyl acetate.Such as, filtrate at room temperature or in refrigerator can be placed 18 ~ 24 hours, filter, washing leaching cake, drying under reduced pressure at 50 ~ 60 DEG C, obtained crystalline Etoricoxib.
Etoricoxib crystal formation of the present invention has good fusing point and quality, its quality purity is at least 99.5%, and there is the performance synthesized on a large scale or be mixed with needed for therapeutic preparation, to light, wet, thermally-stabilised, be convenient to produce, store, thus its physico-chemical property is good, has good medicinal characteristic.
In addition, the preparation manipulation of Etoricoxib crystal formation of the present invention is comparatively simple, and process costs is cheap, is conducive to production quality control, is applicable to scale operation and technology popularization.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 shows the X-ray Powder Diffraction pattern (XRPD) of the Etoricoxib crystal formation of embodiment 1;
Fig. 2 shows the result data X-ray Powder Diffraction pattern of the Etoricoxib crystal formation of embodiment 1 being carried out to peak value retrieval;
Fig. 3 shows the infrared spectrogram of the Etoricoxib crystal formation of embodiment 1;
Fig. 4 shows the differential scanning calorimetric analysis figure of the Etoricoxib crystal formation of embodiment 1.
Embodiment
Further illustrate the present invention below by specific embodiment, but should be understood to, these embodiments are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
General description is carried out to the material used in the present invention's test and test method in this part.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and working method are well known in the art.
Except as otherwise noted, in this article, temperature refers to centigradetemperature (DEG C); Room temperature generally refers to about 18 ~ 23 DEG C.
Except as otherwise noted, the Etoricoxib (or the former crystal formation of Etoricoxib) used in following examples is according to Ian W.Davies, et al., J.Org.Chem., (2000), vol.65, obtained by the method recorded in No.25, pp.8415-8420 document.
embodiment 1
The present embodiment is for illustration of the crystal formation and preparation method thereof of Etoricoxib of the present invention.
Get Etoricoxib 10g to insert in 250ml round-bottomed flask, but add 25ml analytical pure ethyl acetate, and appropriate gac, heating, backflow are dissolved, and filter.Get filtrate, under agitation slow cooling to 20 ~ 30 DEG C, filtrate is at room temperature placed 18h, filter, obtain the crystal of 9.8g.
XRPD figure (see Fig. 1 and Fig. 2) of above-mentioned Etoricoxib crystal formation has peak 8.30,8.56,15.14,17.00,17.14,17.78,18.82,21.62,22.34,22.78,23.38,23.64,27.02,27.48,28.58 and 30.18.
Infrared absorption spectrum (see figure 3) is 3057,3038,3007,2926,1598,1563,1425,1309,1188,1153,1117,778,770,734 and 719cm -1there is characteristic spectrum belt.
Its DSC endothermic transition is 135 ~ 140 DEG C of (see figure 4)s, and fusing point is 135 ~ 140 DEG C.
embodiment 2
The present embodiment is for illustration of the crystal formation and preparation method thereof of Etoricoxib of the present invention.
Get Etoricoxib 10g to insert in 250ml round-bottomed flask, but add 35ml analytical pure ethyl acetate, and appropriate gac, heating, backflow, filtration.Get filtrate, under agitation slow cooling to 20 ~ 30 DEG C, crystallization, filter, obtain the crystal of 9g.
The XRPD figure of above-mentioned Etoricoxib crystal formation has peak 8.30,8.56,15.14,17.00,17.14,17.78,18.82,21.62,22.34,22.78,23.38,23.64,27.02,27.48,28.58 and 30.18.
Infrared absorption spectrum is 3057,3038,3007,2926,1598,1563,1425,1309,1188,1153,1117,778,770,734 and 719cm -1there is characteristic spectrum belt.
Recording its DSC endothermic transition is 135 ~ 140 DEG C, and fusing point is 135 ~ 140 DEG C.
embodiment 3
The present embodiment is for illustration of the preparation of the tablet containing Etoricoxib crystal formation of the present invention.
Prescription: (every sheet is about 120mg containing Etoricoxib crystal formation)
Technique:
Feed intake by formula preparation 1000 amounts in batch for having in the wet granulator of high shear force of kilogram levels; micronized Etoricoxib crystal formation is placed in wet granulator and adds lactose, Microcrystalline Cellulose, 2/3 croscarmellose sodium successively, stir and mix for 5 minutes.With 3%HPMC aqueous solution softwood; granulate in oscillating granulator 24 mesh sieve; and by obtained wet granular in 60 DEG C of baking ovens dry 4 hours, with adding Magnesium Stearate after the whole grain of 24 orders concussion sieve, residue croscarmellose sodium mixed, the granulation that then will mix.
Prepare tablet coating suspension: by solid content 12%, weightening finish 3%, takes coating powder, slowly adds (liquid level just has whirlpool) in the pure water in stirring, and dispersed with stirring is even, continues stirring 45 minutes, and 100 eye mesh screens filter.
Coating pan is with rotating speed 35 revs/min, and temperature 45 ~ 50 DEG C adds label preheating 5 ~ 10 minutes; Regulate pressurized air that ejection liquid is well atomized, start dressing, dry 30 ~ 40 minutes of the complete continuation of dressing, obtains the tablet containing Etoricoxib crystal formation.
embodiment 4
The present embodiment is for illustration of the preparation of the tablet containing Etoricoxib crystal formation of the present invention.
Prescription: (every sheet is about 60mg containing Etoricoxib crystal formation)
Technique:
Feed intake by formula preparation 1000 amounts in batch for having in the wet granulator of high shear force of kilogram levels; micronized Etoricoxib crystal formation is placed in wet granulator and adds lactose, Microcrystalline Cellulose, 2/3 croscarmellose sodium successively, stir and mix for 5 minutes.With 3%HPMC aqueous solution softwood; granulate in oscillating granulator 24 mesh sieve; and by obtained wet granular in 60 DEG C of baking ovens dry 4 hours, with adding Magnesium Stearate after the whole grain of 24 orders concussion sieve, residue croscarmellose sodium mixed, the granulation that then will mix.
Prepare tablet coating suspension: by solid content 12%, weightening finish 3%, takes coating powder, slowly adds (liquid level just has whirlpool) in the pure water in stirring, and dispersed with stirring is even, continues stirring 45 minutes, and 100 eye mesh screens filter.
Coating pan is with rotating speed 35 revs/min, and temperature 45 ~ 50 DEG C adds label preheating 5 ~ 10 minutes; Regulate pressurized air that ejection liquid is well atomized, start dressing, dry 30 ~ 40 minutes of the complete continuation of dressing, obtains the tablet containing Etoricoxib crystal formation.
test example 1 stability test
The Etoricoxib crystal formation that Example 1 obtains is placed in weighing bottle, respectively at 60 DEG C, 4500 ± 500LX illumination, and place under 92.5% relative humidity, in sampling in 5 days, 10 days, by the characteristic peak examination Etoricoxib stability of crystal form of x-ray powder diffraction, result is as shown in table 1.
The factors affecting stability measurement result of table 1 Etoricoxib crystal formation
Note: the representative peak (or claiming characteristic peak) of the former crystal formation of above-mentioned Etoricoxib is 13.75, usually used as the key character distinguishing this crystal formation.
Conclusion: Etoricoxib crystal formation 60 DEG C, place 10 days under 4500 ± 500LX illumination and 92.5% relative humidity, two kinds of crystal formation characteristic peaks have no change, illustrate that it has good stability.
test example 2 pharmacokinetic studies
Test materials and method:
1. tested raw material:
The Etoricoxib new crystal that embodiment 1 is obtained.
2. grouping administration
Select Wistar rat 20, be divided into 2 groups at random by body weight, often organize 10, male and female dual-purpose, fasting is after 16 hours, and each group former crystal formation of oral administration gavage Etoricoxib and Etoricoxib new crystal respectively, dosage is respectively 20mg/kg.Get blood, separation of serum respectively at 0.17,0.5,1,2,3,4,6,8,12,18 and 24 hour eye socket after administration ,-20 DEG C of preservations are to be measured.
3. chromatographic condition
Stationary phase: DiamonsilTM C18 post, 10 μm, 250 × 4.6mm(I.D.), column temperature 30 DEG C.
Moving phase: methyl alcohol: water=70:30, flow velocity: 1ml/min.
Determined wavelength: 215nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
4. blood sample treatments
Get rat blood serum 200 μ l, add interior mark (Etoricoxib intermediate 200 μ g/ml) 10 μ l, after mixing, add DMF(N, dinethylformamide) 200 μ l, vibration 10min, places 30 minutes, with the centrifugation 10min of 10000 turns/min, get supernatant liquor 20 μ l sample introduction.
5. determination of plasma concentration
After bioassay standard curve, draw linear regression equation (y=ax+b).After the administration of mensuration rat, the ratio of blood sample gained peak area, calculates Plasma Concentration according to linear regression equation, and through 3P97 medicine for computation program meter
6. instrument
HPLC test macro: Shimadzu SPD-10A Uv detector, Hi-Tech P4000 high-pressure pump, LabAlliance AS1000 automatic sampler, ANASTAR chromatographic working station.
HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai manufactures.
The miniature vortex mixed instrument of WX-80A: Shanghai Hu Xi analytical instrument factory produces.
7. result of study (see table 2)
Table 2 pharmacokinetic parameter
Note: in table, data are mean number ± standard deviation (n=6).
Conclusion: from medicine for parameter, the Etoricoxib new crystal of Oral Administration in Rats gavage 20mg/kg and the former crystal formation of Etoricoxib, medicine between the two does not demonstrate difference for parameter, absorption in animal body, eliminate basically identical.
In addition, Etoricoxib new crystal of the present invention treatment acute phase or chronic phase osteoarthritis or acute gouty arthritis medicine in show higher biological activity.
test example 3 dissolution determination
Sample: Etoricoxib wafer agent prepared by embodiment 3
Contrast product: according to J.ORG.Chem.2000,65,8415-8420 literature method prepares the tablet that the former crystal formation of Etoricoxib is made.
Operate according to " Chinese Pharmacopoeia " 2010 editions two requirements in accordance with the law, with phosphate buffered saline buffer (0.05mol/LpH8) 1000ml for solvent, adjustment rotating speed is per minute 100 turns, in sampling in 5,10,15,20,30,45 minutes, liquid chromatography for measuring, the dissolution results of sample and contrast product is in table 3:
Table 3 Etoricoxib Dissolution of Tablet measurement result (%)
Although present invention has been description to a certain degree, significantly, under the condition not departing from the spirit and scope of the present invention, can carry out the suitable change of each condition.Be appreciated that and the invention is not restricted to described embodiment, and be attributed to the scope of claim, it comprises the equivalent replacement of described each factor.

Claims (11)

1. the crystal formation of an Etoricoxib, the X-ray powder diffraction pattern it is characterized in that, described crystal formation uses Cu-Ka radiation, representing with 2 θ angles has diffraction peak at 8.30,8.56,15.14,17.00,17.14,17.78,18.82,21.62,22.34,22.78,23.38,23.64,27.02,27.48,28.58 and 30.18 places.
2. crystal formation according to claim 1, is characterized in that, the infrared absorption spectrum that described crystal formation records with KBr pressed disc method is at 3057cm -1, 3038cm -1, 3007cm -1, 2926cm -1, 1598cm -1, 1563cm -1, 1425cm -1, 1309cm -1, 1188cm -1, 1153cm -1, 1117cm -1, 778cm -1, 770cm -1, 734cm -1and 719cm -1there is characteristic spectrum belt.
3. crystal formation according to claim 1 and 2, is characterized in that, the DSC endothermic transition of described crystal formation is 135 ~ 140 DEG C; Preferably, the fusing point of described crystal formation is 135 ~ 139 DEG C.
4. crystal formation according to any one of claim 1 to 3, is characterized in that, described crystal formation uses Cu-Ka radiation, the X-ray powder diffraction pattern that represents with 2 θ angles substantially as shown in Figure 1.
5. crystal formation according to any one of claim 1 to 4, is characterized in that, the infrared absorption spectrum that described crystal formation records with KBr pressed disc method substantially as shown in Figure 3; Preferably, the differential scanning calorimetric thermogram of described crystal formation substantially as shown in Figure 4.
6. prepare a method for the crystal formation of the Etoricoxib according to any one of claim 1 to 5, it is characterized in that, the method comprises:
(1) Etoricoxib is dissolved in ethyl acetate, heating, backflow, filtration, obtain filtrate;
(2) filtrate under agitation slow cooling to 20 ~ 30 DEG C step (1) obtained, crystallization, filters, obtains described crystal formation.
7. method according to claim 6, is characterized in that, in step (1), the weightmeasurement ratio of described Etoricoxib and ethyl acetate is 1:2.5 ~ 3.5.
8. a pharmaceutical composition, is characterized in that, the crystal formation that described pharmaceutical composition includes the Etoricoxib according to any one of the claim 1 to 5 of effective amount or the crystal formation of Etoricoxib prepared according to the method described in claim 6 or 7.
9. pharmaceutical composition according to claim 8, is characterized in that, described pharmaceutical composition is oral Preparation; Preferably, described oral Preparation is selected from tablet, capsule, granule, oral solution, oral suspensions or syrup; More preferably; described tablet is selected from fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coated tablet; described capsule is selected from hard capsule, soft capsule, slow releasing capsule, controlled release capsule or enteric coated capsule, and described granule is selected from mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules or controlled release granule.
10. pharmaceutical composition according to claim 8, is characterized in that, described pharmaceutical composition is external preparation; Preferably, described external preparation is selected from gelifying agent, ointment, ointment, paste or patch.
The crystal formation of the Etoricoxib according to any one of 11. claims 1 to 5 or the crystal formation of Etoricoxib prepared according to the method described in claim 6 or 7 for the preparation for the treatment of acute phase or chronic phase osteoarthritis or acute gouty arthritis medicine in purposes.
CN201310423071.8A 2013-09-03 2013-09-16 Etoricoxib crystal as well as preparation method and application thereof Pending CN104418799A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310423071.8A CN104418799A (en) 2013-09-03 2013-09-16 Etoricoxib crystal as well as preparation method and application thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201310394694 2013-09-03
CN2013103946947 2013-09-03
CN201310423071.8A CN104418799A (en) 2013-09-03 2013-09-16 Etoricoxib crystal as well as preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN104418799A true CN104418799A (en) 2015-03-18

Family

ID=52969004

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310423071.8A Pending CN104418799A (en) 2013-09-03 2013-09-16 Etoricoxib crystal as well as preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN104418799A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105906647A (en) * 2016-05-19 2016-08-31 江苏神龙药业有限公司 Pharmaceutical composition of pramipexole dihydrochloride and application of pharmaceutical composition in biomedicine
CN107982234A (en) * 2017-12-08 2018-05-04 佛山市弘泰药物研发有限公司 A kind of Etoricoxib sustained release tablets and preparation method thereof
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

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1278795A (en) * 1997-09-25 2001-01-03 麦克公司 Process for making diaryl pyridines useful as cox-2 inhibitors
WO2001037833A1 (en) * 1999-11-29 2001-05-31 Merck Frosst Canada & Co. Polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl
CN1306425A (en) * 1998-04-24 2001-08-01 麦克公司 Process for synthesizing Cox-2 inhibitors
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
WO2005085199A1 (en) * 2004-01-14 2005-09-15 Cadila Healthcare Limited Novel polymorphs of etoricoxib
WO2013075732A1 (en) * 2011-11-21 2013-05-30 Synthon Bv Process for making crystalline form i of etoricoxib
CN103204803A (en) * 2012-01-13 2013-07-17 阿尔弗雷德·E·蒂芬巴赫尔有限责任两合公司 Method used for synthesizing etoricoxib

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1278795A (en) * 1997-09-25 2001-01-03 麦克公司 Process for making diaryl pyridines useful as cox-2 inhibitors
CN1306425A (en) * 1998-04-24 2001-08-01 麦克公司 Process for synthesizing Cox-2 inhibitors
WO2001037833A1 (en) * 1999-11-29 2001-05-31 Merck Frosst Canada & Co. Polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl
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
WO2005085199A1 (en) * 2004-01-14 2005-09-15 Cadila Healthcare Limited Novel polymorphs of etoricoxib
WO2013075732A1 (en) * 2011-11-21 2013-05-30 Synthon Bv Process for making crystalline form i of etoricoxib
CN103204803A (en) * 2012-01-13 2013-07-17 阿尔弗雷德·E·蒂芬巴赫尔有限责任两合公司 Method used for synthesizing etoricoxib

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105906647A (en) * 2016-05-19 2016-08-31 江苏神龙药业有限公司 Pharmaceutical composition of pramipexole dihydrochloride and application of pharmaceutical composition in biomedicine
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
CN108069896B (en) * 2016-11-11 2022-08-12 昆明积大制药股份有限公司 Preparation method of etoricoxib crystal form
CN107982234A (en) * 2017-12-08 2018-05-04 佛山市弘泰药物研发有限公司 A kind of Etoricoxib sustained release tablets and preparation method thereof

Similar Documents

Publication Publication Date Title
DK2870163T3 (en) PHARMACEUTICAL COMPOSITIONS CONTAINING RIFAXIMIN AND AMINO ACIDS, METHOD OF PREPARING AND USING THEREOF
CN104603123B (en) Solid-state form of bent Ge Lieting and its production and use
CN106255498A (en) The pharmaceutical composition of therapeutical active compound
CN108779126A (en) Crystalline forms of 2- [ (2S) -1-azabicyclo [2.2.2] oct-2-yl ] -6- (3-methyl-1H-pyrazol-4-yl) thieno [3,2-D ] pyrimidin-4 (3H) -one hemihydrate
CN105980389B (en) A kind of crystal form of disulfate of jak kinase inhibitor and preparation method thereof
CN106163507A (en) The medical composition and its use of therapeutical active compound
CN106795159B (en) A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor
CN106866702A (en) Crystal formation of De Luogewei sodium salts and preparation method thereof
CN105980390B (en) A kind of crystal form of disulfate of jak kinase inhibitor and preparation method thereof
CN104098570A (en) Crystal form of Ticagrelor Brilinta and preparation method and purpose thereof
CN104418799A (en) Etoricoxib crystal as well as preparation method and application thereof
JP2012509909A (en) Five crystal forms of nicosamide compound, its production method and its drug combination and use
CN105801568B (en) One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition
CN104918937A (en) Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof
CN107245054B (en) Amorphous bulleyaconitine A compound and preparation method thereof
JP2022522395A (en) New Salts of Selective Estrogen Receptor Degradants
CN106543124A (en) dapagliflozin compound
CN102838542A (en) Crystalline form I of celecoxib, preparation method and purpose thereof
CN102838545B (en) Celecoxib crystalline form IV and its production and use
CN102838544A (en) Crystalline form II of celecoxib, preparation method and purpose thereof
CN115463133A (en) Pharmaceutical composition, preparation method and application thereof
CN109963565A (en) A kind of pharmaceutical composition and preparation method thereof
TWI436988B (en) Polymorphs of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo [c,f][1,2]thiazepin-11-yl)amino]heptanoic acid s,s-dioxide and methods of making and using the same
CN108299412A (en) The addition salts and its crystal form and pharmaceutical composition of a kind of S1P1 receptor stimulating agents
CN103524424A (en) Crystal form VI of ambrisentan 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
RJ01 Rejection of invention patent application after publication

Application publication date: 20150318

RJ01 Rejection of invention patent application after publication