CN104817555A - M crystal form of solifenacin succinate and preparation method of M crystal form - Google Patents
M crystal form of solifenacin succinate and preparation method of M crystal form Download PDFInfo
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- CN104817555A CN104817555A CN201510261314.1A CN201510261314A CN104817555A CN 104817555 A CN104817555 A CN 104817555A CN 201510261314 A CN201510261314 A CN 201510261314A CN 104817555 A CN104817555 A CN 104817555A
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- succsinic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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Abstract
The invention discloses an M crystal form of (3R)-1-azabicyclo[2.2.2]octane-3-yl(1S)-1-phenyl-3, 4-dihydroisoquinoline-2(1H)-carboxylate butanedioic acid (solifenacin succinate). Cu-Kalpha radiation is adopted, and 2theta measured according to degree serving as a unit has diffraction peaks at the wavelengths as follows: 3.781+/-0.2, 7.465+/-0.2, 11.188+/-0.2, 18.680+/-0.2, 21.860+/-0.2 and 25.165+/-0.2 in an X-ray diffraction map. The invention also provides a preparation method of solifenacin succinate with the crystal form. The preparation method is characterized by comprising the following steps of dissolving crude solifenacin succinate into a solvent; dissolving by stirring at the temperature of 80 DEG C; and cooling for crystallizing, carrying out suction filtration, washing and re-crystallizing to obtain solifenacin succinate with the crystal form disclosed by the invention. The crystal form has very high stability.
Description
Technical field
This area belongs to medical art, is specifically related to a kind of succsinic acid YM-905 M crystal formation and preparation method thereof.
Background technology
The molecular formula of YM-905 is C
23h
26n
2o
2, molecular weight 362.46, chemistry (3R)-1-azabicyclo [2.2.2] octane-3-base (1S)-1-phenyl-3,4-dihydro-isoquinoline-2 (1H)-manthanoate by name.
YM-905 salt, especially succsinic acid YM-905, chemistry (3R)-1-azabicyclo [2.2.2] octane-3-base (1S)-1-phenyl-3,4-dihydro-isoquinoline-2 (1H)-manthanoate succinate by name, as a kind of muscarine M
3-receptor antagonist and be widely used in the urgent incontinence of symptomatic treatment superfunction bladder patient and/or micturition frequency increases and urgent urination of urinating.It is in 2004 first in Holland, Germany, Britain, France and Denmark's listing, and within 2005, in U.S.'s listing, within 2009, in Discussion on Chinese Listed, so far in more than 50 the countries and regions list marketing in the whole world, its structural formula is as follows:
In general, solid pharmaceutical molecule has multiple crystal habit.The different crystal forms of same drug molecule may there were significant differences in crystalline structure, stability, producibility and bioavailability etc., thus directly affect curative effect and the exploitability of medicine, therefore, drug crystal forms research is extremely important in drug research and development industry.About the research of succsinic acid YM-905 crystal formation, there are reports, as: US Patent No. 20080114028 is pointed out: publication IPCOM000147748D discloses a kind of crystal formation of succsinic acid YM-905, it is characterized in that, powder x-ray diffraction figure is in 2 θ=3.9 °, and 11.2 °, there is characteristic peak at 14.3 ° and 18.8 ° ± 0.2 ° place, with PXRD in 2 θ=7.6 °, 19.3 °, 21.1 °, there is characteristic peak at 23.2 ° and 25.2 ° ± 0.2 ° place.In addition, US20080114028 discloses the another kind of crystal formation of succsinic acid YM-905, it is characterized in that, powder x-ray diffraction figure is in 2 θ=4.3 °, 11.7 °, 14.7 °, 16.2 °, 18.3 °, 19.9 °, 22.3 °, there is characteristic peak at 23.7 ° and 25.6 ° ± 0.2 ° place, and this patent also describes the synthetic route of succsinic acid YM-905.Patent of invention CN201110199259 discloses a kind of crystal formation of succsinic acid YM-905, it is characterized in that, powder x-ray diffraction figure is in 2 θ=3.5 °, 7.1 °, 10.8 °, 18.3 °, 21.5 °, 22.1 °, there is characteristic peak at 24.9 ° and 35.5 ° ± 0.2 ° place.
The crystal formation of the present inventor to succsinic acid YM-905 is studied, and provides that a kind of preparation technology is simple, the succsinic acid YM-905 M crystal formation of excellent in stability.
Summary of the invention
The object of this invention is to provide a kind of succsinic acid YM-905 M crystal formation and preparation method thereof, the advantages such as preparation technology is simple, excellent in stability that it has.
The succsinic acid YM-905 M crystal formation prepared in the present invention adopts D/Max-2500 type Powder X-ray Diffractometer, use Cu-K α radiation, at 40KV, the powder x-ray diffraction figure recorded under 40mA condition determination, 2 θ represented with degree are 3.781 ± 0.2, 7.465 ± 0.2, 11.188 ± 0.2, 18.680 ± 0.2, there is diffraction peak at 21.860 ± 0.2 and 25.165 ± 0.2 places, further, 2 θ represented with degree are 3.781 ± 0.2, 7.465 ± 0.2, 11.188 ± 0.2, 13.570 ± 0.2, 14.204 ± 0.2, 18.213 ± 0.2, 18.680 ± 0.2, 19.307 ± 0.2, 21.011 ± 0.2, 21.860 ± 0.2, 22.413 ± 0.2, 23.077 ± 0.2, there is diffraction peak at 25.165 ± 0.2 and 28.648 ± 0.2 places, as shown in Figure 1, its powder x-ray diffraction digital proof is another new crystal being different from above-mentioned openly crystal formation.
In the DSC thermogram of succsinic acid YM-905 M crystal formation, have the absorption peak that sharp-pointed, fusing point is 146.5 DEG C, described DSC temperature rise rate 10 DEG C/min.
For achieving the above object, present invention also offers the preparation method of the bulk drug crude product for the preparation of succsinic acid YM-905 M crystal formation, chemical reaction is expressed as follows, but is not limited only to this method:
Dissolved by YM-905 crude product Virahol, add succinic acid, heated and stirred, reaction terminates rear cooling, except desolventizing, adds acetone crystallization, suction filtration, washing, dry succsinic acid YM-905 crude product.
Present invention also offers the preparation method of succsinic acid YM-905 M crystal formation, chemical reaction is expressed as follows, but is not limited only to following method:
Succsinic acid YM-905 crude product is dissolved in solvent, and at 80 DEG C, heated and stirred is clearly molten, cooling crystallization, suction filtration, washing, recrystallization, obtains the succsinic acid YM-905 of this crystal formation.Described solvent is selected from: acetone, Virahol, ethyl acetate.
Succsinic acid YM-905 involved in the present invention and former grind product content and related substance testing conditions be: with 0.02molL
-1kH
2pO
4(pH=3.0) and acetonitrile be respectively mobile phase A and Mobile phase B, adopt gradient elution, determined wavelength is 210nm, and sample size is 10 μ L, and flow velocity is 1mLmin
-1, eluent gradient elution program is as shown in table 1 below:
Table 1 eluent gradient elution program
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 5 | 80 | 20 |
| 60 | 30 | 70 |
| 70 | 30 | 70 |
Stability test:
Prepare its crystal formation thing with reference to former method of grinding in patent US8765785B2, utilize aforesaid method to test succsinic acid YM-905 M crystal formation and former stability of grinding product.
1, illumination experiment
Succsinic acid YM-905 M crystal formation is evenly split in uncovered culture dish, Hou Du≤5mm, adjustable range, makes intensity of illumination be 4500 ± 500 lx, respectively at sampling in the 5th and the 10th day, and contrast with the result of 0 day.Use the same method and carry out exposure experiments to light to the former product that grind, comparing result is in table 2.
Table 2 exposure experiments to light (4500 ± 500lx)
Note: range of temperature is 23 DEG C ~ 26 DEG C; Relative humidity variations scope is 55% ~ 64%.
2, high temperature test
Succsinic acid YM-905 M crystal formation raw material is positioned in the vial of sealing clean, is placed in 60 DEG C of thermostatic drying chambers, respectively at sampling in the 5th and the 10th day, and contrast with the result of 0 day.Use the same method and carry out high temperature test to the former product that grind, comparing result is in table 3.
Table 3 high temperature test (60 DEG C)
Note: relative humidity variations scope is 53% ~ 64%.
3, high wet test
Succsinic acid YM-905 M crystal formation raw material opening is put in constant humidity encloses container, 25 DEG C respectively at relative humidity 90% ± 5% condition under place 10 days, in sampling in the 5th and the 10th day, and to contrast with the result of 0 day.Use the same method and carry out high wet test to the former product that grind, comparing result is in table 4.
The high wet test of table 4 (relative humidity 90% ± 5%)
4, accelerated test
Succsinic acid YM-905 M crystal formation raw material polyethylene film plastic bag sealing is packed, be placed in 40 DEG C ± 2 DEG C, relative humidity be 75% ± 5% fixed temperature and humidity incubator, place 6 months, detect respectively at 1st month, 2 months, 3 months, 6 samplings at the end of month, and contrast with the result of 0 day.Use the same method and carry out accelerated test to the former product that grind, comparing result is in table 5.
Table 5 accelerated test (40 DEG C ± 2 DEG C, relative humidity 75% ± 5%)
5, test of long duration
Succsinic acid YM-905 M crystal formation raw material polyethylene film plastic bag sealing is packed, place 12 months under the condition of temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10%, sampling in every 3 months once, detect respectively at sampling in 0 month, 3 months, 6 months, 9 months, 12 months, and contrast with the result of 0 day.Use the same method and carry out test of long duration to the former product that grind, comparing result is in table 6.
Table 6 test of long duration (25 DEG C ± 2 DEG C, relative humidity 60% ± 10%)
6, M stability of crystal form test
Through high temperature (60 DEG C), high humidity (90% ± 5%), illumination (4500 ± 500lx), accelerated test (temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%) and test of long duration (temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10%) and grinding, carry out powder x-ray diffraction test to M crystal formation after compressing tablet, result is as shown in following table 7-1 and 7-2:
The test of table 7-1 stability of crystal form
The test of table 7-2 stability of crystal form
Test-results shows: the succsinic acid YM-905 M crystal formation that the present invention obtains, illumination, high temperature, high wet test and accelerate 6 months, long-term 12 the middle of the month its outward appearance, related substance and content has no significant change, and its stable in physicochemical property is described.The succsinic acid YM-905 with crystal formation of the present invention is in high temperature, high humidity, illumination, accelerated test 6 months, keep sample 12 months and grind, after compressing tablet for a long time, fusing point is substantially constant, test through powder x-ray diffraction, main 2 θ angles and peak intensity do not have noticeable change, illustrate that this product stability of crystal form in storage process and production process is excellent.
Above-mentioned test shows that the crystal habit of the succsinic acid YM-905 M crystal formation that the present invention obtains is relatively stable, is applicable to make medicine and preparation thereof.
Accompanying drawing explanation
Figure 1 shows that the powder x-ray diffraction figure of succsinic acid YM-905 M crystal formation of the present invention.The longitudinal axis represents peak intensity, and transverse axis represents diffraction angle (2 θ).
Figure 2 shows that the DSC thermogram of succsinic acid YM-905 M crystal formation of the present invention.The longitudinal axis represents mW/mg, and transverse axis represents temperature (DEG C).
Embodiment
Following examples are for further describing the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
The synthesis of embodiment 1 succsinic acid YM-905 crude product
YM-905 crude product 200mL Virahol is dissolved, adds 7.2g succinic acid, 80 DEG C of heated and stirred 1h.Reaction terminates the cooling of rear room temperature, and concentrated removal solvent, add 200mL acetone hold over night crystallization, suction filtration, drain after filter cake 50mL washing with acetone, drying obtains 23.4g succsinic acid YM-905 crude product.
The preparation of embodiment 2 succsinic acid YM-905 M crystal formation
The succsinic acid YM-905 crude product 1g obtained in embodiment 1 is dissolved in 5mL Virahol, and at 80 DEG C, heated and stirred is clearly molten, 30 DEG C of more than cooling crystallization 12h, suction filtration, filter cake 5mL washed with isopropyl alcohol, recrystallization, obtains 0.58g succsinic acid YM-905 M crystal formation.
The preparation of embodiment 3 succsinic acid YM-905 M crystal formation
The succsinic acid YM-905 crude product 1g obtained in embodiment 1 is dissolved in 50mL Virahol, and at 80 DEG C, heated and stirred is clearly molten, 30 DEG C of more than cooling crystallization 12h, suction filtration, filter cake 50mL washed with isopropyl alcohol, recrystallization, obtains 0.79g succsinic acid YM-905 M crystal formation.
Claims (5)
1. a succsinic acid YM-905 M crystal formation, it is characterized in that: use Cu-K α radiation, its x-ray diffraction pattern, has diffraction peak to spend 2 θ represented at 3.781 ± 0.2,7.465 ± 0.2,11.188 ± 0.2,18.680 ± 0.2,21.860 ± 0.2 and 25.165 ± 0.2 places.
2. succsinic acid YM-905 M crystal formation according to claim 1, it is characterized in that: use Cu-K α radiation, its x-ray diffraction pattern, has diffraction peak to spend 2 θ represented at 3.781 ± 0.2,7.465 ± 0.2,11.188 ± 0.2,13.570 ± 0.2,14.204 ± 0.2,18.213 ± 0.2,18.680 ± 0.2,19.307 ± 0.2,21.011 ± 0.2,21.860 ± 0.2,22.413 ± 0.2,23.077 ± 0.2,25.165 ± 0.2 and 28.648 ± 0.2 places.
3. succsinic acid YM-905 M crystal formation according to claim 2, its x-ray diffraction pattern as shown in Figure 1.
4. the preparation method of the succsinic acid YM-905 M crystal formation in claim 1 or 2 described in arbitrary claim, it is characterized in that: succsinic acid YM-905 crude product is dissolved in solvent, at 80 DEG C, heated and stirred is clearly molten, cooling crystallization, suction filtration, washing, recrystallization, obtain succsinic acid YM-905 M crystal formation, described solvent selected from acetone, Virahol, ethyl acetate.
5. the preparation method of succsinic acid YM-905 M crystal formation according to claim 4, is characterized in that: the consumption of described solvent is 5 ~ 50 times (mL/g) of succsinic acid YM-905 crude product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407808A (en) * | 2018-04-27 | 2019-11-05 | 江苏神龙药业股份有限公司 | (1S) -1- phenyl -3,4- dihydro -1H- isoquinolin -2- carbonylic imidazole novel crystal forms and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080114028A1 (en) * | 2006-07-24 | 2008-05-15 | Tamas Koltai | Process for preparing polymorphic forms of solifenacin succinate |
-
2015
- 2015-05-21 CN CN201510261314.1A patent/CN104817555A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080114028A1 (en) * | 2006-07-24 | 2008-05-15 | Tamas Koltai | Process for preparing polymorphic forms of solifenacin succinate |
Non-Patent Citations (1)
| Title |
|---|
| -: "Crystal forms of the active ingredient in Vesikur 10mg film tablets and Emeslex 15mg tablets", 《IP.COM ELECTRONIC PUBLICATION》, 19 July 2006 (2006-07-19), pages 000137408 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407808A (en) * | 2018-04-27 | 2019-11-05 | 江苏神龙药业股份有限公司 | (1S) -1- phenyl -3,4- dihydro -1H- isoquinolin -2- carbonylic imidazole novel crystal forms and preparation method thereof |
| CN110407808B (en) * | 2018-04-27 | 2022-04-15 | 燃点(南京)生物医药科技有限公司 | Novel crystal form of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole and preparation method thereof |
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