CN103570741B - Prasugrel novel crystal forms and preparation method thereof - Google Patents
Prasugrel novel crystal forms and preparation method thereof Download PDFInfo
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- CN103570741B CN103570741B CN201210260168.7A CN201210260168A CN103570741B CN 103570741 B CN103570741 B CN 103570741B CN 201210260168 A CN201210260168 A CN 201210260168A CN 103570741 B CN103570741 B CN 103570741B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention discloses the novel crystal forms of prasugrel, additionally, the invention also discloses its preparation method.The present invention solves the problems, such as that prasugrel is unfavorable for pharmacy.The beneficial effects of the invention are as follows, there is provided various prasugrel novel crystal forms, with good stability, the advantages of dissolution rate is good after patent medicine.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to the novel crystal forms of antithrombotic reagent prasugrel and its preparation side
Method.
Background technology
Prasugrel（prasugrel）Chemical entitled 2- acetoxyl groups -5-（A- cyclopropyl carbonyl -2- luorobenzyls）-4,5,
6,7- thiophanes simultaneously [3,2-c] pyridine, structural formula is as shown in formula I.Prasugrel is to be come by gift and its affiliate first makes
The oral anti-diabetic agent of the common company's joint development of medicine three,
Formula I.
Prasugrel is a kind of adenosine diphosphate（ADP）Receptor antagonist, belongs to pro-drug, in vivo effective conversion
Into its active metabolite R-138727.R-138727 reduces the dependence to cytochrome P-450 enzyme, and rapidly,
Special, the irreversible purine bases acceptor for being attached to blood platelet P2Y12, suppresses ADP regulations hematoblastic active and poly-
Collection, so as to play the activity of anti-platelet aggregation.Clinical research proves, takes that integrated risk after prasugrel is low, good effect.Cause
The good prospect of this prasugrel receives much attention.
Current prasugrel is listed in the form of hydrochloride, in the patent of the CN0185108.6 of Sankyo Co., Ltd's application
The hydrochloride and maleate of prasugrel are protected, after claiming prasugrel to be made both salt, possesses oral absorption well
Property, metabolic activity and platelet aggregation inhibitory action, toxicity are low, easy to maintain, good stability.
On April 08th, 2010, the CN201010141713.1 of Shanghai Institute of Pharmaceutical Industry's application disclosed prasugrel salt
There is poorly water-soluble in hydrochlorate and maleate.Then prasugrel hydrochloride solvate has been invented.Other inventors
By goal displacement in the invention of other salt, such as CN102342921, WO2011127300, WO2011016686,
WO2011004392, GB2469883, WO2009130289 disclose the salt such as prasugrel hydrobromide, but prasugrel into
Salt step can undoubtedly increase industry cost in industrial production.
Some inventors begin to focus on the druggability of prasugrel free alkali.It is related to prasugrel free alkali in the prior art
The patent of crystal formation be respectively CN200910170675.X, WO2009066326, WO2009062044, WO2011057592.
On August 26th, 2009, the CN200910170675.X of Huahai Pharmaceutical Co., Ltd., Zhejiang's application discloses general
The preparation method and recrystallization method of glug thunder, and its XRD spectrum is given, its fusing point is 121.3 ~ 125.2 DEG C.Its recrystallization side
Method is recrystallized with alcohols solvent.The preparation method of WO2009062044 prasugrels and its salt, including recrystallization side
Method is：Prasugrel crude product is heated to reflux with methyl alcohol, stirs 30min, and cooling, filtering rinses filter cake, drying with methyl alcohol.It is above-mentioned
Two pieces patent is similar to the method for crystallising of prasugrel, compares the XRD spectrum of its offer, finds the pula that two pieces patent is reported
Gray's crystal formation is same crystal formation.The dissolubility of the crystal formation is undesirable, and druggability is poor, is not suitable for directly as bulk drug.
Patent WO2009066326 discloses the preparation method of prasugrel and its salt, including the knot again of prasugrel
Crystal method and prasugrel XRD spectrum, its recrystallization method be by prasugrel crude product ethyl acetate be heated to 60 ~ 65 DEG C it is molten
Solution, keeps this temperature to stir 1h, adds hexamethylene to be stirred for 1h, is cooled to 0-5 DEG C of stirring 1h, filtration drying.The patent is public
The preparation method technique of the prasugrel crystal formation opened is relatively complicated, and gained crystal formation remain unchanged with above-mentioned patent WO2009062044
Crystal formation XRD spectrum is identical.
Patent WO2011057592 discloses the preparation method of prasugrel and its salt, and wherein recrystallization method is：Will be general
Glug thunder crude product acetone solution, adds activated carbon, and filtering, filter cake acetone rinsing, filtrate is cooled to -15 ~ -10 DEG C, adds
Water, stirs 2h, filtering.Regrettably, the crystal formation that patent is related to is also consistent with the crystal formation disclosed in WO2009062044.
For the polymorphic of medicine, the polymorphic of medicine directly affects the physicochemical property of medicine（Such as fusing point, dissolving
Degree, dissolution rate and stability etc.）And clinical efficacy（Absorbability and efficacy）.Different polymorphics can directly affect bulk drug
With the treatment or production of preparation, and stability, solubility and the bioavilability of preparation can be influenceed.Come for prasugrel
Say, the crystal formation that presently, there are is unable to reach medicinal requirements well, therefore its listing raw material is only prasugrel hydrochloride.In original
Should try one's best the selection shorter process route of route in the industrial production for expecting medicine, prasugrel salt-forming steps undoubtedly increased it is industrial into
This.Therefore the novel crystal forms of new prasugrel are researched and developed, to improve its dissolution rate, improves bioavilability to improve medicinal substances
Amount, it is ensured that clinical drug effect endeavours issue to be resolved as current those skilled in the art.
The content of the invention
In order to solve the technical problem of existing prasugrel free alkali discomfort synthetic drug, inventor is through substantial amounts of
Research, there is provided three kinds of good stabilities, solubility is high, dissolution rate prasugrel novel crystal forms high and preparation method thereof.
It is an object of the invention to provide new prasugrel crystal formation thing.
Specifically, the invention provides a kind of new prasugrel M crystal formations, radiated using Cu-Ka, its X-ray diffraction
Figure, has diffraction maximum to spend 2 θ for representing at 8.6 ± 0.2 and 20.1 ± 0.2.
Further, new prasugrel M crystal formations provided by the present invention, are radiated, its X-ray diffraction using Cu-Ka
Figure, also has diffraction maximum to spend 2 θ for representing at 16.4 ± 0.2,17.3 ± 0.2,30.9 ± 0.2.
Further, new prasugrel M crystal formations provided by the present invention, are radiated, its X-ray diffraction using Cu-Ka
Figure, with spend 2 θ for representing also 13.2 ± 0.2,13.6 ± 0.2,19.0 ± 0.2,19.3 ± 0.2,19.5 ± 0.2,20.0 ±
0.2nd, there is diffraction maximum at 21.7 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,24.4 ± 0.2.
Present invention also offers a kind of new prasugrel N crystal form, radiated using Cu-Ka, its x-ray diffraction pattern, to spend
2 θ for representing have highest peak at 19.5 ± 0.2.
Further, new prasugrel N crystal form provided by the present invention, is radiated, its X-ray diffraction using Cu-Ka
Figure, has strong diffraction to spend 2 θ for representing at 7.9 ± 0.2,11.4 ± 0.2,14.6 ± 0.2,15.6 ± 0.2,31.5 ± 0.2
Peak, the relative intensity of the strong diffraction maximum is more than 80%.
Further, new prasugrel N crystal form provided by the present invention, is radiated, its X-ray diffraction using Cu-Ka
Figure, with spend 2 θ for representing 7.9 ± 0.2,11.4 ± 0.2,14.6 ± 0.2,14.9 ± 0.2,15.6 ± 0.2,19.0 ± 0.2,
The relative intensity for having strong diffraction maximum, the strong diffraction maximum at 21.6 ± 0.2,31.5 ± 0.2 is more than 70%.
Present invention also offers a kind of new prasugrel P crystal formations, radiated using Cu-Ka, its x-ray diffraction pattern, to spend
2 θ for representing have highest peak at 18.9 ± 0.2.
Further, new prasugrel P crystal formations provided by the present invention, are radiated, its X-ray diffraction using Cu-Ka
Figure, to spend 2 θ for representing 13.5 ± 0.2,14.8 ± 0.2,19.4 ± 0.2,21.5 ± 0.2,23.5 ± 0.2,24.4 ± 0.2
The relative intensity that there is strong diffraction maximum, the strong diffraction maximum at place is more than 60%.
It is a further object of the present invention to provide the preparation method of new prasugrel crystal formation.
Specifically, the invention provides the preparation method of the prasugrel M crystal formations：
（1）Prasugrel crude product is added in organic solvent；
（2）Heating for dissolving；
（3）Room temperature is slowly dropped under stirring, there is white solid to separate out；
（4）Growing the grain 0.5 ~ 4 hour；
（5）Filtering, obtains white crystal, is vacuum dried；
Wherein, described organic solvent is the one kind in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran and DMF
Or it is various.
Present invention also offers the preparation method of the prasugrel N crystal form：
（1）Prasugrel crude product is added in the mixed solution of organic solvent A and petroleum ether；
（2）Heating for dissolving；
（3）Standing is slowly dropped to room temperature, has white solid to separate out；
（4）Growing the grain 0.5 ~ 3 hour；
（5）Filtering, obtains white crystal, is vacuum dried；
Wherein, described organic solvent A is selected from butanone, acetone, ethyl acetate, butyl acetate, Ethyl formate, methyl tert-butyl
One kind in ketone.
Further, the organic solvent A described in the preparation method of prasugrel N crystal form is with the volume ratio of petroleum ether
1:0.5~3。
Present invention also offers a kind of preparation method of new prasugrel P crystal formations：
（1）Prasugrel crude product is added in organic solvent, is dissolved；
（2）Solution is poured into purified water；
（3）Stand, there is white solid to separate out；
（4）Growing the grain 0.5 ~ 1.5 hour；
（5）Filtering, obtains white crystal, is vacuum dried；
Wherein, described organic solvent is selected from acetonitrile, ethanol, methyl alcohol, isopropanol, tetrahydrofuran, N, N- dimethyl formyls
One or more in amine and dimethyl sulfoxide (DMSO).
The new pula Cray crystal formation that the present invention is provided overcomes problems of the prior art, embodies following beneficial
Technique effect：
1st, new prasugrel crystal formation provided by the present invention improves the stability of medicine compared with original crystal formation；
2nd, the preparation process is simple of the prasugrel crystal formation that the present invention is provided, compared with the prasugrel hydrochloride of listing,
Salt-forming steps are reduced, industrial cost is reduced, production line is shortened；
3rd, the present invention is using provided prasugrel the novel crystal forms tablet for preparing and the prasugrel hydrochloride tablet for listing
It is suitable compared to dissolution rate.
Brief description of the drawings
Accompanying drawing 1 is the XRD spectrum of the prasugrel M crystal formations prepared using embodiment 1.
Accompanying drawing 2 is the XRD spectrum of the prasugrel N crystal form prepared using embodiment 3.
Accompanying drawing 3 is the XRD spectrum of the prasugrel P crystal formations prepared using embodiment 5.
The prasugrel tablets stripping curve of accompanying drawing 4.
Specific embodiment
Following examples are illustrated to of the invention, and the scope of the present invention should not be construed as limiting.
The preparation of the prasugrel M crystal formations of embodiment 1
By prasugrel crude product, 2 grams are added in 6ml Isosorbide-5-Nitraes-dioxane, are heated to 30 degree of dissolvings, delay under stirring condition
Slowly room temperature is cooled to, there is white solid to separate out, continue to stir 2 hours, filtering obtains white crystal, and vacuum drying obtains product
1.71 grams, yield 85.5%.
The preparation of the prasugrel M crystal formations of embodiment 2
By prasugrel crude product, 2 grams are added in 6ml tetrahydrofurans, are heated to 30 degree of dissolvings, are slowly dropped under stirring condition
Warm to room temperature, there is white solid to separate out, continue to stir 0.5 hour, filtering obtains white crystal, and vacuum drying obtains product 1.58
Gram, yield 79.0%.
The preparation of the prasugrel N crystal form of embodiment 3
By prasugrel crude product, 2 grams are added to 10ml butanone：Petroleum ether=1:In 2 mixed solvent, be heated to 80 degree it is molten
Solution, stands slow cooling to room temperature, has white solid to separate out, and growing the grain 2 hours, filtering obtains white crystal, and vacuum drying is obtained
1.66 grams of product, yield 83.1%.
The preparation of the prasugrel N crystal form of embodiment 4
By prasugrel crude product, 2 grams are added to 10ml ethyl acetate：Petroleum ether=1:In 0.5 mixed solvent, it is heated to
80 degree of dissolvings, stand slow cooling to room temperature, have white solid to separate out, growing the grain 2 hours, and filtering obtains white crystal, and vacuum is dried
It is dry, obtain 1.57 grams of product, yield 78.5%.
The preparation of the prasugrel P crystal formations of embodiment 5
By prasugrel crude product, 2 grams are added in 20ml DMFs, stirring, at room temperature dissolving clarification, will
Solution is poured into 100ml purified waters, has white solid to separate out, growing the grain 1 hour, filtering, obtains white crystal, and vacuum drying is obtained
1.64 grams of product, yield 82.0%.
The preparation of the prasugrel P crystal formations of embodiment 6
By prasugrel crude product, 2 grams are added in 20ml ethanol, stirring, and dissolving clarification, solution is poured at room temperature
In 100ml purified waters, there is white solid to separate out, growing the grain 0.5 hour, filtering obtains white crystal, and vacuum drying obtains product
1.52 grams, yield 76.0%.
Comparative example 1
According to the preparation method of embodiment in CN200910170675.X 8, under nitrogen protection, with isopropanol to 2g pulas lattice
Thunder is recrystallized, 12 hours of room temperature reaction, and crystallization separates out solid, obtains off-white powder 0.63g, and yield is 31.5%.
Comparative example 2
According to the preparation method of prasugrel in WO2009066326,2g prasugrel crude products are heated to ethyl acetate
60-65 DEG C of dissolving, keeps this temperature to stir 1h, adds hexamethylene to be stirred for 1h, is cooled to 0-5 DEG C of stirring 1h, filtration drying.
Obtain light yellow crystal.
Comparative example 3
Patent WO2011057592 discloses the preparation method of prasugrel and its salt, and wherein recrystallization method is：Will be general
Glug thunder crude product acetone solution, adds activated carbon, and filtering, filter cake acetone rinsing, filtrate is cooled to -15 ~ -10 DEG C, adds
Water, stirs 2h, filtering.
The stability test of embodiment 7
1st, exposure experiments to light
Prasugrel M, N, P crystal formation, the prasugrel crystal formation of comparative example 1-3, original are ground into unit prasugrel hydrochloride
Crystal formation raw material is uniformly shared into open culture dish, thickness≤5mm, adjustable range, makes intensity of illumination for 4500 ± 500Lx, in
Sampling detection in 10 days, and result with 0 day compareed.The results are shown in Table 1,
The exposure experiments to light of table 1（4500±500Lx）
Note：23 ~ 26 DEG C of temperature change；Relative humidity variations 56 ~ 63%.
2nd, hot test
By prasugrel M, N, P crystal formation, the prasugrel crystal formation of comparative example 1-3, prasugrel hydrochloride crystal formation raw material
It is respectively placed in sealing clean vial, is placed in 60 DEG C of thermostatic drying chambers, in sampling detection in 10 days, and the result with 0 day
Compareed.The results are shown in Table 2,
The hot test of table 2（60℃）
Note：Relative humidity variations 54%-62%.
3rd, wet test high
By prasugrel M, N, P crystal formation, the prasugrel crystal formation of comparative example 1-3, prasugrel hydrochloride crystal formation raw material
Uniformly share into open culture dish, thickness≤5mm is placed in room temperature（25 DEG C or so）, the constant temperature perseverance of relative humidity 92.5 ± 5%
In wet incubator, compareed in sampling detection in 10 days, and result with 0 day.The results are shown in Table 3,
The wet test high of table 3（92.5±5%）
Note：23-26 DEG C of temperature change.
4th, accelerated test
By prasugrel M, N, P crystal formation, the prasugrel crystal formation of comparative example 1-3, prasugrel hydrochloride crystal formation raw material
Packed with polyethylene film plastic bag sealing, be placed in 40 ± 2 DEG C, during relative humidity is for 75 ± 5% constant temperature and humidity incubator, put
Put six months, respectively at 1, the sampling detection of 2,3 the end of month, and result with 0 month compareed.The results are shown in Table 4,
The accelerated test of table 4（40 DEG C, relative humidity 75%）
Test result indicate that, in stability test, the testing result of prasugrel M, N, P crystal formation that the present invention is provided,
It is superior to the crystal formation of prasugrel in the prior art and commercially available prasugrel hydrochloride.The prasugrel crystal formation tool that the present invention is provided
Standby preferable stability.
Embodiment 8
The preparation method of prasugrel tablets
Prescription（Specification 5mg, 100）
Prasugrel is pre-mixed with lauryl sodium sulfate, then again with mannitol, microcrystalline cellulose, hydroxypropyl first
Base cellulose, Ac-Di-Sol, magnesium stearate are well mixed, and dry method is made particle.Crosslinking is added to particle China and foreign countries
Sodium carboxymethylcellulose, magnesium stearate are pressed into the tablet of 125-250mg weights after mixing.Then obtained tablet is carried out into film
It is coated.
The prasugrel crystal formation of prasugrel M, N, P crystal formation, comparative example 1-3 is prepared into piece agent 100 as stated above.
Tablet appearance and content are investigated, 5 are the results are shown in Table,
The product of table 5 Nature comparison in blocks
Conclusion：From the above results, the present invention obtained by prasugrel crystal formation M, N, P after medicine is prepared into, outward
It is qualified to see, and uniformity of dosage units meets the requirements, hence it is evident that better than the tablet prepared by the crystal formation of comparative example 1 ~ 3.
Embodiment 9
Tablet obtained by embodiment 1, embodiment 3, embodiment 5, comparative example 1 ~ 3 and commercially available prasugrel hydrochloride are carried out
Dissolution experiments, the results are shown in Table 6,
The dissolution rate testing result of table 6
Conclusion：Tablet prepared by M, N, P crystal formation of prasugrel provided by the present invention, and prepared by existing crystal formation
Tablet is compared, and has preferable dissolution rate.It is suitable with commercially available prasugrel hydrochloride tablet result of extraction.
Claims (7)
1. a kind of prasugrel M crystal formations, are radiated using Cu-Ka, its x-ray diffraction pattern, with spend 2 θ for representing 8.6 ± 0.2,
13.2±0.2、13.6±0.2、16.4±0.2、17.3±0.2、19.0±0.2、19.3±0.2、19.5±0.2、20.0±
0.2nd, there is diffraction maximum at 20.1 ± 0.2,21.7 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,24.4 ± 0.2,30.9 ± 0.2.
2. a kind of prasugrel N crystal form, is radiated using Cu-Ka, its x-ray diffraction pattern, with spend 2 θ for representing 7.9 ± 0.2,
11.4±0.2、14.6±0.2、14.9±0.2、15.6±0.2、19.0±0.2、19.5±0.2、21.6±0.2、31.5±
The relative intensity for having strong diffraction maximum, the strong diffraction maximum at 0.2 is more than 70%.
3. a kind of prasugrel P crystal formations, are radiated using Cu-Ka, its x-ray diffraction pattern, with spend 2 θ for representing 13.5 ± 0.2,
There is strong diffraction maximum at 14.8 ± 0.2,18.9 ± 0.2,19.4 ± 0.2,21.5 ± 0.2,23.5 ± 0.2,24.4 ± 0.2, it is described
The relative intensity of strong diffraction maximum is more than 60%.
4. the preparation method of prasugrel M crystal formations as claimed in claim 1：
(1) prasugrel crude product is added in organic solvent；
(2) heating for dissolving；
(3) room temperature is slowly dropped under stirring, there is white solid to separate out；
(4) growing the grain 0.5~4 hour；
(5) filter, obtain white crystal, be vacuum dried；
Wherein, described organic solvent is the one kind or many in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran and DMF
Kind.
5. the preparation method of prasugrel N crystal form as claimed in claim 2：
(1) prasugrel crude product is added in the mixed solution of organic solvent A and petroleum ether；
(2) heating for dissolving；
(3) stand and be slowly dropped to room temperature, there is white solid to separate out；
(4) growing the grain 0.5~3 hour；
(5) filter, obtain white crystal, be vacuum dried；
Wherein, described organic solvent A is in butanone, acetone, ethyl acetate, butyl acetate, Ethyl formate, methylisobutylketone
It is a kind of.
6. the preparation method of prasugrel N crystal form as claimed in claim 5, it is characterized in that, described organic solvent A and oil
The volume ratio of ether is 1:0.5~3.
7. the preparation method of prasugrel P crystal formations as claimed in claim 3：
(1) prasugrel crude product is added in organic solvent, is dissolved；
(2) solution is poured into purified water；
(3) stand, there is white solid to separate out；
(4) growing the grain 0.5~1.5 hour；
(5) filter, obtain white crystal, be vacuum dried；
Wherein, described organic solvent be selected from acetonitrile, ethanol, methyl alcohol, isopropanol, tetrahydrofuran, DMF and
One or more in dimethyl sulfoxide (DMSO).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| CN101993447A (en) * | 2009-08-26 | 2011-03-30 | 浙江华海药业股份有限公司 | Method for synthesizing Prasugrel artificially |
| CN102612519A (en) * | 2009-11-16 | 2012-07-25 | 赞蒂瓦有限合伙公司 | Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100261908A1 (en) * | 2007-11-09 | 2010-10-14 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of prasugrel , and its salts and polymorphs |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
-
2012
- 2012-07-26 CN CN201210260168.7A patent/CN103570741B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| CN101993447A (en) * | 2009-08-26 | 2011-03-30 | 浙江华海药业股份有限公司 | Method for synthesizing Prasugrel artificially |
| CN102612519A (en) * | 2009-11-16 | 2012-07-25 | 赞蒂瓦有限合伙公司 | Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof |
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