CN103524416B - A kind of Novel celecoxib crystal form A and preparation method thereof - Google Patents
A kind of Novel celecoxib crystal form A and preparation method thereof Download PDFInfo
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- CN103524416B CN103524416B CN201310520234.4A CN201310520234A CN103524416B CN 103524416 B CN103524416 B CN 103524416B CN 201310520234 A CN201310520234 A CN 201310520234A CN 103524416 B CN103524416 B CN 103524416B
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- melilotal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
A kind of celecoxib crystal formation A and preparation method thereof, is that to use isopropanol be dicyandiamide solution, by reactant liquor fast cooling, crystallize, filters and be dried to obtain a kind of new celecoxib crystal formation.The X-ray powder diffraction pattern of this crystal formation demonstrates characteristic diffraction peak at 2 θ (° ± 0.2) 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06 and 29.68.Crystal formation A has good stability, it is simple to produces, transport and stores, and can meet as advantages such as preparation raw material requirements.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, in particular it relates to Novel celecoxib crystal form A and preparation method thereof.
Background technology
Celecoxib, trade name celecoxib (Celecoxib), is II type cyclooxygenase (COX-2) suppression of first listing
Agent, is developed by Searle company of the U.S., within 1999, lists in the U.S., is used for treating the inflammation such as osteoarthritis and rheumatoid arthritis
Disease property disease, has gastrointestinal tract and the advantage such as Toxicity of Kidney is little.Because it can optionally suppress COX-2, to COX-1 without bright
Aobvious inhibitory action, has the curative effect of notable antiinflammatory antipyretic-antalgic, but injury to alimentary tract will not occur, be a kind of excellent antiinflammatory
Analgesic.
On the other hand, COX-2 (COX-2) at tumorigenesis, transfer, Apoptosis inhibitor and promotes that blood vessel is raw
The aspects such as one-tenth play an important role, it has also become the novel targets for the treatment of and prevention of tumour.Within 1999, U.S. FDA approval celecoxib is used for
The auxiliary treatment of familial intestinal cancer polyp, this indicates that cox 2 inhibitor is formally for tumor prevention.Research shows, and has
The quite compound of COX-2 inhibitory activity is compared, and the activity of celecoxib inducing apoptosis of tumour cell is higher.Therefore, plug is come
Former times cloth carries out Anticancer Effect and Mechanism and inquires into increasing with the research of structure optimization.
Celecoxib chemical name is 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, structural formula
As follows:
Listing preparation only has Celebret at present, but celecoxib crude drug water solublity is very poor, affects body absorption,
For such a medicine with notable clinical efficacy, studying its crystal formation is also everybody emphasis of paying close attention to.
The earliest report celecoxib crystal formation grind drug company application for former world patent WO2001042222 <
POLYMORPHIC CRYSTALLINE FORMS OF CELECOXIB >, it prepares celecoxib polycrystalline, wherein, first
Use ethyl acetate-heptane solvent, then use DMA, DMF solvent compound, conversion of milling to obtain crystal formation III；Tianjin medicine grinds
Study carefully institute celecoxib crystal formation is studied, apply for 4 Chinese patent CN102838542, CN102838543,
CN102838544, CN102838545, open 4 kinds of crystal formations of celecoxib I, II, III, IV, be respectively adopted ethyl acetate,
Ethanol, methanol, oxolane are as dicyandiamide solution.
The present invention is found by research, uses different solvents system and method for crystallising, and the plug obtaining being different from prior art carrys out former times
Cloth novel crystal forms A, this crystal formation shows excellent physicochemical property, and solvent reclaims economy, stable crystal form, it is simple to produce, transport and
Store, the advantage such as requirement of preparation raw material can be met.
Summary of the invention
It is an object of the invention to provide a kind of stable crystal form, be prone to the novel crystal forms A of the celecoxib of industrial-scale production.
The method that present invention also offers preparation Novel celecoxib crystal form A.
The novel crystal forms A of celecoxib of the present invention can use following method to prepare, but this product is by no means limited to this preparation method:
(1) Claisen condensation reaction: add aqueous slkali and isopropanol in melilotal and alkyl trifluoroacetate, rise
Temperature, to 45～65 DEG C, is reacted 2～10h, is kept in as reactant liquor a；
(2), in another reactor, isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride and trifluoroacetic acid are warming up to 45～55 DEG C,
Add reactant liquor a, continue reaction 0.5～2h；
(3) add water, be heated to 60～80 DEG C complete molten, make in reactant liquor without solid；
(4) control rate of temperature fall, make system fast cooling, crystallize；
(5) sucking filtration, general's crystallization drying under reduced pressure 4～10h, obtain Novel celecoxib crystal form A.
Wherein, the alkali in described aqueous slkali is at least one in Feldalat NM, Sodium ethylate, normal propyl alcohol sodium, sodium isopropylate,
Solvent required for preparing this solution includes but not limited to methanol, ethanol, normal propyl alcohol, isopropanol, the preferred methanol of described aqueous slkali
Sodium/methanol solution.
The mass concentration of described aqueous slkali is 25～35%, preferably 28～30%.
According to embodiments of the invention, Claisen condensation reaction in step (1), melilotal and trifluoroacetic acid alkyl
Ester is with mol ratio as 1:1.0～1:1.4 feeds intake, and the amount adding isopropanol can be 2～6 volumes (in terms of melilotal),
Temperature reaction temperature is 45～70 DEG C, and the response time is 2～10h.According to a particular embodiment of the invention, in above-mentioned step (1)
In, the alkyl in described alkyl trifluoroacetate is selected from C1-C4 alkyl, is preferably selected from least one in methyl or ethyl.
According to embodiments of the invention, in step (2), 4-hydrazinobenzene-1-sulfonamide hydrochloride and melilotal mole
Ratio can be 1:0.8～1:1.2, and the mol ratio of trifluoroacetic acid and melilotal can be 1:0.02～1:0.07, be warming up to 45～
55 DEG C, after adding reactant liquor a, continue reaction 0.5～2h.Recrystallisation solvent isopropanol is added, in an amount of to methylbenzene during this
5～12 times of ethyl ketone volume.
According to a particular embodiment of the invention, depending on the amount added water in step (3) is according to reaction system state, system is made to exist
Be heated to 60～80 DEG C complete molten.
According to embodiments of the invention, in step (4), quick crystallize can be controlled by temperature, and reaction system is with often
Hour cooling speed of 5～20 DEG C, is finally cooled to 15～25 DEG C, is preferably cooling 6～10 DEG C the most per hour.Additionally, pass through
Experiment finds, uses cooling about 0.5～1 DEG C per hour to carry out slow crystallize, it is possible to obtain former to grind celecoxib III crystal form.
According to embodiments of the invention, in step (5), drying under reduced pressure temperature can be 45～65 DEG C, drying time be 4～
10 hours, available Novel celecoxib crystal form A.
The novel crystal forms A of the present invention has good quality, and purity is at least 99.5%.Have and synthesize on a large scale or be configured to control
Performance needed for treatment preparation, to light, wet, thermally-stabilised, it is simple to produce, store and transport.
Gained celecoxib crystal formation A of the present invention, its recrystallisation solvent is isopropanol, and it uses Cu-Ka radiation, to spend 2 θ tables
The X-ray powder diffraction spectrum shown is 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06
Peak is had with 29.68.Its DSC endothermic transition is at 161.3-163.1 DEG C.
The method of testing of the crystal formation A that the present invention provides is as follows:
1, X-ray powder diffraction
Data are by methods known in the art, utilize Advanced Powder diffractometer to obtain:
Instrument: Germany Brukrt AXS D8-FOCUS
Model: D8-FOCUS
Condition determination: CuK alpha ray, Ni filters, 40KV, 40mA, LynxEye192 bit array detector, scanning step
Long (Increment) 0.01 ° of 2theta, speed degree per step (scanspeed) 0.05sec/step, 4.0Soller slit
2, differential scanning calorimetry (DSC)
Instrument: the resistance to STA449F that speeds of Germany
Instrument parameter: temperature accuracy: ± 0.1 DEG C；
Heating rate: 0.1～50 DEG C/per minute；Maximum temperature: 1500 DEG C；Hot analytical balance range 0.001mg～50g.
Condition determination: initial temperature: 30 DEG C, heating rate 10 DEG C/per minute.
The stability of celecoxib crystal formation A
Take celecoxib crystal formation A in weighing botle, respectively at 60 DEG C, under 4500 ± 500LX illumination, and 75% relative humidity
Placing, in 5 days, sampling in 10 days, HPLC method measures related substance, result such as table 1.
Table 1 celecoxib crystal formation A factors affecting stability measurement result
| Placement condition | Celecoxib powder | Crystal formation A | |
| Time | Total impurities (%) | Total impurities (%) | |
| 0 day | Do not detect | Do not detect | |
| 60℃ | 5 days | 0.06 | 0.05 |
| 60℃ | 10 days | 0.07 | 0.05 |
| Illumination (4500Lux) | 5 days | 0.06 | 0.04 |
| Illumination (4500Lux) | 10 days | 0.10 | 0.06 |
| 75% relative humidity (25 DEG C) | 5 days | 0.08 | 0.06 |
| 75% relative humidity (25 DEG C) | 10 days | 0.10 | 0.07 |
It appeared that Novel celecoxib crystal form A is placed 10 days, related substance is had to be showed no substantially increase.
The pharmaceutical composition that the present invention provides contains celecoxib crystal formation A and pharmaceutically acceptable carrier.
Celecoxib crystal formation A of the present invention, owing to it has good quality and stability, is suitable to oral Preparation, such as tablet
Including fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coatel tablets etc.；Capsule include hard capsule,
Soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.；Granule include mix suspension grain, effervescent granule, enteric coated particles,
Slow-releasing granules, controlled release granule etc.；Oral solution；Oral suspensions；Syrup etc..When preparing oral solid formulation, can
Celecoxib and suitable pharmaceutic adjuvant are made granule pack or loads gelatine capsule or tabletted.
Accompanying drawing explanation
The X-ray powder diffraction spectrogram of Fig. 1 celecoxib crystal formation A；
The differential thermogram of Fig. 2 celecoxib crystal formation A；
The collection of illustrative plates of Fig. 3 celecoxib crystal formation A purity detecting；
The X-ray powder diffraction spectrogram of Fig. 4 crystalline form III of celecoxib.
Detailed description of the invention
Embodiments of the invention are described below in detail, it should be noted that the embodiments described below is exemplary, be only used for
Explain the present invention, and be not considered as limiting the invention.It addition, without clearly stating, in the following embodiments
The all reagent used are on market commercially available, or can synthesize according to text or known method, for not having
There is the reaction condition listed, be also what those skilled in the art were readily available.
Embodiment 1
In tri-mouthfuls of vials of a 250mL, add melilotal (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester
(13.7g, 0.096mol), adds 18.2g methanol solution of sodium methylate (mass concentration is 25%) and 20mL isopropanol, heats up
To 50 DEG C, after insulation 4h, keep in as reactant liquor a.
Take tri-mouthfuls of vials of another one 500mL, add 50mL isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride (17.4g,
0.078mol) with trifluoroacetic acid (0.42g, 0.0037mol), when being warming up to 55 DEG C, add reactant liquor a, after reaction 1h, add
After entering 50mL water, be warming up to 65 DEG C complete molten, per hour cooling 10 DEG C, be down to 15 DEG C, sucking filtration, 45 DEG C of drying under reduced pressure are filled in
Carrying out former times cloth A crystal formation 24.06g, yield is 85%, and HPLC detection purity is 99.7%.
The XRD figure of celecoxib crystal formation A is at Degree(2 θ) 5.42,10.80,13.10,14.92,16.18,19.73,
21.60, there is characteristic absorption peak on 22.28,27.06,29.68.
Embodiment 2
In tri-mouthfuls of vials of a 250mL, add melilotal (10g, 0.075mol) and trifluoro-acetate
(13.4g, 0.105mol), adds 20g methanol solution of sodium methylate (mass concentration is 28%) and 40mL isopropanol, is warming up to
45 DEG C, after insulation 2h, keep in as reactant liquor a.
Take tri-mouthfuls of vials of another one 500mL, add 100mL isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride (13.4g,
0.06mol) with trifluoroacetic acid (0.6g, 0.005mol), when being warming up to 45 DEG C, add reactant liquor a, after reaction 0.5h, add
After 80mL water, be warming up to 60 DEG C complete molten, cooling 20 DEG C, is down to 25 DEG C per hour, sucking filtration, and 60 DEG C of drying under reduced pressure obtain plug to be come
Former times cloth A crystal formation 22.64g, yield is 80%, and HPLC detection purity is 99.5%.
Embodiment 3
In tri-mouthfuls of vials of a 250mL, add melilotal (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester
(10.7g, 0.075mol), adds 30g alcohol sodium alcohol solution (mass concentration is 30%) and 50mL isopropanol, is warming up to
65 DEG C, after insulation 10h, keep in as reactant liquor a.
Take tri-mouthfuls of vials of another one 500mL, add 50mL isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride (20g,
0.09mol) with trifluoroacetic acid (0.6g, 0.005mol), when being warming up to 55 DEG C, add reactant liquor a, after reaction 1h, add
After 100mL water, be warming up to 80 DEG C complete molten, per hour cooling 20 DEG C, be down to 15 DEG C, sucking filtration, 65 DEG C of drying under reduced pressure are filled in
Carrying out former times cloth A crystal formation 24.1g, yield is 85%, and HPLC detection purity is 99.8%.
Embodiment 4
In tri-mouthfuls of vials of a 250mL, add melilotal (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester
(13.85g, 0.0975mol), adds 40g methanol solution of sodium methylate (mass concentration is 35%) and 60mL isopropanol, heats up
To 50 DEG C, after insulation 2h, keep in as reactant liquor a.
Take tri-mouthfuls of vials of another one 500mL, add 50mL isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride (19.3g,
0.086mol) with trifluoroacetic acid (0.42g, 0.0037mol), when being warming up to 55 DEG C, add reactant liquor a, after reaction 1h, add
After entering 120mL water, be warming up to 70 DEG C complete molten, per hour cooling 6 DEG C, be down to 20 DEG C, sucking filtration, 45 DEG C of drying under reduced pressure are filled in
Carrying out former times cloth A crystal formation 23.49g, yield is 83%, and HPLC detection purity is 99.5%.
Comparative example 5
In tri-mouthfuls of vials of a 250mL, add melilotal (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester (13.85g,
0.0975mol), add 40g methanol solution of sodium methylate (mass concentration is 35%) and 60mL isopropanol, be warming up to 50 DEG C,
After insulation 2h, keep in as reactant liquor a.
Take tri-mouthfuls of vials of another one 500mL, add 50mL isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride (19.3g,
0.086mol) with trifluoroacetic acid (0.42g, 0.0037mol), when being warming up to 55 DEG C, add reactant liquor a, after reaction 1h, add
After entering 120mL water, be warming up to 70 DEG C complete molten, per hour cooling 1 DEG C, be down to 20 DEG C, sucking filtration, 45 DEG C of drying under reduced pressure are filled in
Carrying out former times cloth III crystal formation 21.22g, yield is 75%, and HPLC detection purity is 99.8%.
The XRD figure of crystalline form III of celecoxib is at Degree(2 θ) 5.56,11.22,13.24,15.06,1631,18.16,
18.63、18.93、19.86、20.72、21.71、22.61、23.67、24.80、25.22、25.60、27.19、27.92、28.47、
29.72, there is characteristic absorption peak on 30.21.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is exemplary,
Being not considered as limiting the invention, those of ordinary skill in the art is in the case of without departing from the principle of the present invention and objective
Above-described embodiment can be changed within the scope of the invention, revise, replace and modification.
Claims (8)
1. the method preparing celecoxib crystal formation A, it is characterised in that use following steps,
(1) Claisen condensation reaction: add aqueous slkali and isopropanol in melilotal and alkyl trifluoroacetate, be warming up to
45～65 DEG C, react 2～10h, keep in as reactant liquor a；
(2) in another reactor, isopropanol, 4-hydrazinobenzene-1-sulfonamide hydrochloride and trifluoroacetic acid are warming up to 45～55 DEG C, add
Reactant liquor a, continues reaction 0.5～2h；
(3) add water, be heated to 60～80 DEG C complete molten, make in reactant liquor without solid；
(4) controlling rate of temperature fall, make system fast cooling, crystallize, wherein, fast cooling speed is cooling 5～20 DEG C per hour,
Finally it is cooled to 15～25 DEG C；
(5) sucking filtration, general's crystallization drying under reduced pressure 4～10h, obtain Novel celecoxib crystal form A；
Described celecoxib crystal formation A uses Cu-Ka radiation, has X-ray powder diffraction pattern as shown in Figure 1, with 2 θ
The X-ray powder diffraction spectrum that angle represents 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,
27.06 and 29.68 have peak, and DSC endothermic transition is at 161.3-163.1 DEG C.
2. preparation method as claimed in claim 1, it is characterised in that feeding intake mole of melilotal and alkyl trifluoroacetate
It is 1:0.8～1:1.2 than the mol ratio for 1:1.0～1:1.4,4-hydrazinobenzene-1-sulfonamide hydrochloride and melilotal, trifluoroacetic acid
It is 1:0.02～1:0.07 with the mol ratio of melilotal.
3. preparation method as claimed in claim 1, it is characterised in that the alkali in aqueous slkali described in step (1) is selected from methanol
At least one in sodium, Sodium ethylate, normal propyl alcohol sodium, sodium isopropylate, prepare the solvent selected from methanol required for this solution, ethanol,
Normal propyl alcohol, isopropanol.
4. preparation method as claimed in claim 1, it is characterised in that described aqueous slkali is Feldalat NM/methanol solution.
5. preparation method as claimed in claim 3, it is characterised in that the mass concentration of described aqueous slkali is 25～35%.
6. preparation method as claimed in claim 3, it is characterised in that the mass concentration of described aqueous slkali is 28～30%.
7. preparation method as claimed in claim 1, it is characterised in that in step (1) isopropanol amount is melilotal 2～
6 volumes, in step (2), isopropanol is recrystallisation solvent, in an amount of from 5～12 times of volumes of melilotal.
8. preparation method as claimed in claim 1, it is characterised in that described fast cooling, its cooling rate be lower the temperature per hour 6～
10℃。
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Families Citing this family (2)
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| CN103923011A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Synthetic method of celecoxib |
| CN105130901A (en) * | 2015-08-06 | 2015-12-09 | 苏州二叶制药有限公司 | Celecoxib preparation method |
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