CN106496189A - Hydrochloric acid Ripasudil crystal formations - Google Patents
Hydrochloric acid Ripasudil crystal formations Download PDFInfo
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- CN106496189A CN106496189A CN201610884386.6A CN201610884386A CN106496189A CN 106496189 A CN106496189 A CN 106496189A CN 201610884386 A CN201610884386 A CN 201610884386A CN 106496189 A CN106496189 A CN 106496189A
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- sulfonyl
- bases
- methyl isophthalic
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- 0 C[C@@](CNCCC1)N1S1(=*c2cncc3cccc1c23)=O Chemical compound C[C@@](CNCCC1)N1S1(=*c2cncc3cccc1c23)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the novel crystal forms B of (S) () 1 (4 fluoro isoquinolin, 5 base) 2 methyl of sulfonyl, 1,4 homopiperazine hydrochloride of the invention, with being included in 2 θ of the angle of diffraction：6.499 ± 0.2 degree, 8.95 ± 0.2 degree, 11.153 ± 0.2 degree, 12.66 ± 0.2 degree, 15.698 ± 0.2 degree, 16.207 ± 0.2 degree, 17.306 ± 0.2 degree, 8.553 ± 0.2 degree, 21.099 ± 0.2 degree, 21.625 ± 0.2 degree, 24.062 ± 0.2 degree, 26.634 ± 0.2 degree, 29.264 ± 0.2 degree, the diffraction maximum at 35.63 ± 0.2 degree.The novel crystal forms good thermal stability of gained of the present invention, and crystal formation is not susceptible to change, with preferable sucting wet stability, the medicinal requirements of production and transport storage are disclosure satisfy that, thus the crystallization of the present invention preferably can be used, the clinical demand of extensive patients is preferably met as medicating active ingredients.
Description
Technical field
The present invention relates to medicine novel crystal forms, relate in particular to a kind of new (S)-(-) -1- (4- fluoro isoquinolin -5-
Base) sulfonyl -2- methyl isophthalic acids, the novel crystal forms of 4- homopiperazine hydrochlorides and preparation method thereof.
Background technology
Ripasudil is a kind of Rho kinase inhibitors, for treating glaucoma and ocular hypertension, its chemistry entitled (S)-
(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazines, shown in structural formula following (I).
Patent of invention WO9920620 discloses (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids,
4- homopiperazine hydrochlorides (hydrochloric acid Ripasudil) anhydrous crystal.Patent of invention CN101068806 discloses the anhydrous crystal and is in
25 DEG C, under conditions of 92% relative humidity (RH), till moisture finally increases to 40% nearby, the anhydrous crystal is relative
Humidity more than 50% under conditions of preserve, there is hygroscopic effect, the crystalline texture of anhydrous crystal changes, and volume is also sent out therewith
Changing.That is, the anhydrous crystal causes crystalline state to change because of hygroscopic effect.
In general, solid drugs molecule has multiple crystal habits such as polycrystalline, eutectic；The not isomorphous of same drug molecule
Type might have significant difference at aspects such as crystal structure, stability, productibility and bioavilabilities, so as to directly affect medicine
The curative effect and exploitability of thing.Therefore, drug crystal forms research is extremely important in drug research and development industry.Ability
Need badly and find the good hydrochloric acid Ripasudil medicines novel crystal forms of purity height, stability and develop its preparation technology in domain.
Content of the invention
It is an object of the invention to provide a kind of stable crystal form, being difficult (S)-(-) -1- (the 4- fluoro isoquinolin -5- of moisture absorption
Base) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochloride anhydrous crystals.
The purpose of the present invention can be realized by the following method：
One kind (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochloride Form B,
The x-ray diffraction pattern of the crystal form have be included in 2 θ of the angle of diffraction：6.499 ± 0.2 degree, 8.95 ± 0.2 degree, 11.153 ±
0.2 degree, 12.66 ± 0.2 degree, 15.698 ± 0.2 degree, 16.207 ± 0.2 degree, 17.306 ± 0.2 degree, 8.553 ± 0.2 degree,
21.099 ± 0.2 degree, 21.625 ± 0.2 degree, 24.062 ± 0.2 degree, 26.634 ± 0.2 degree, 29.264 ± 0.2 degree, 35.63 ±
Diffraction maximum at 0.2 degree.
Further,
One kind (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochloride Form B,
The x-ray diffraction pattern of the crystal form have be included in 2 θ of the angle of diffraction：5.319 ± 0.2 degree, 6.499 ± 0.2 degree, 8.95 ±
0.2 degree, 11.153 ± 0.2 degree, 12.66 ± 0.2 degree, 13.698 ± 0.2 degree, 14.592 ± 0.2 degree, 15.698 ± 0.2 degree,
16.207 ± 0.2 degree, 17.306 ± 0.2 degree, 8.553 ± 0.2 degree, 21.099 ± 0.2 degree, 21.625 ± 0.2 degree, 23.003 ±
0.2 degree, 24.062 ± 0.2 degree, 26.253 ± 0.2 degree, 26.634 ± 0.2 degree, 29.264 ± 0.2 degree, 29.813 ± 0.2 degree,
30.285 ± 0.2 degree, 30.661 ± 0.2 degree, 31.258 ± 0.2 degree, 35.63 ± 0.2 degree, the diffraction at 36.271 ± 0.2 degree
Peak.
In a kind of scheme, one kind (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, the high piperazines of 4-
Piperazine hydrochloride Form B has the peak form characteristics shown in Figure of description 1, the angle of diffraction (2 θ), interplanar distance (d) and relative intensity
(%) such as following table：
Table 1
| Peak sequence number | 2θ,° | D values | Intensity | Relative intensity |
| 1 | 5.319 | 16.602 | 549.7 | 12.1 |
| 2 | 6.499 | 13.589 | 1250.8 | 27.4 |
| 3 | 8.950 | 9.873 | 1091.2 | 23.9 |
| 4 | 11.153 | 7.927 | 2337.8 | 51.3 |
| 5 | 12.660 | 6.986 | 1059.6 | 23.2 |
| 6 | 13.698 | 6.459 | 470.3 | 10.3 |
| 7 | 14.592 | 6.066 | 423.2 | 9.3 |
| 8 | 15.698 | 5.640 | 1100.6 | 24.1 |
| 9 | 16.207 | 5.465 | 4559.5 | 100.0 |
| 10 | 17.306 | 5.120 | 1338.5 | 29.4 |
| 11 | 18.553 | 4.779 | 1616.2 | 35.5 |
| 12 | 21.099 | 4.207 | 1298.9 | 28.5 |
| 13 | 21.625 | 4.106 | 3872.6 | 84.9 |
| 14 | 23.003 | 3.863 | 701.8 | 15.4 |
| 15 | 24.062 | 3.696 | 3369.9 | 73.9 |
| 16 | 26.253 | 3.392 | 559.5 | 12.3 |
| 17 | 26.634 | 3.344 | 3852.8 | 84.5 |
| 18 | 29.264 | 3.049 | 1076.9 | 23.6 |
| 19 | 29.813 | 2.994 | 682.6 | 15.0 |
| 20 | 30.285 | 2.949 | 435.3 | 9.6 |
| 21 | 30.661 | 2.913 | 612.6 | 13.4 |
| 22 | 31.258 | 2.859 | 747.0 | 16.4 |
| 23 | 35.630 | 2.518 | 1638.9 | 36.0 |
| 24 | 36.271 | 2.475 | 437.2 | 9.6 |
(S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, the DSC of 4- homopiperazine hydrochloride Form B
In thermal analysis curue, at 248.34 DEG C start to melt, 255.76 DEG C nearby have a sharp endothermic peak, and fusing point is 248 DEG C of left sides
The right side, described 10 DEG C/min of DSC heating rates, error are 3 DEG C.
Present invention also offers one kind (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, the high piperazines of 4-
The preparation method of piperazine hydrochloride Form B, comprises the steps of：
1) by (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazines hydrochloride salt in
In water；
2) by step 1) gained mixture cooling freeze；
3) freeze-drying obtains pressed powder.
The crystal formation B of gained of the present invention is in 25 DEG C, under conditions of 92% relative humidity (RH), moisture finally increases
To near 3%, the anhydrous crystal is preserved under conditions of relative humidity is more than 50%, without notable hygroscopic effect, the present invention
B crystal form do not occur under high humidity environment crystalline state change.
This product is preserved at 40 DEG C, 60 DEG C and 80 DEG C two weeks good heat endurance, with preferably storage and processing
Stability.
For the crystal formation of the same race of same compound, its X-ray diffractogram has similitude on the whole, characterizes peak position
, typically within ± 2%, not over ± 2%, relative intensity error may be larger for most of error, but changes for d values error
Gesture is consistent.In addition, in the identification of mixture, as the factors such as content decline can cause part diffracted ray disappearance, now, need not
The whole bands of a spectrum that observes in high-purity sample are relied on, or even bands of a spectrum are likely to the crystallization for giving be distinctive.Determine
During 2 θ of the angle of diffraction of the powder x-ray diffraction collection of illustrative plates in the specification and claims of the present invention, the value of gained is interpreted as
In the range of ± 1.0 degree of the value, preferably in the range of ± 0.2 degree of the value, the powder x-ray diffraction figure is
The collection of illustrative plates obtained with CuK alpha rays.Fusing point in DSC thermal analysis curues, the value of gained are interpreted as what ± 3.0 DEG C in the value were spent
In the range of, preferably in the range of ± 1 DEG C of the value.
Term " multi-crystalline compounds " refers to the different crystal forms of identical compound and including but not limited to comprising identical chemical combination
The hydrate of thing is (for example：There is the combination water in crystalline texture) and solvate is (for example：Than water other combine molten
Agent) other solid state molecular forms.Same drug molecule forms the phenomenon of multiple crystal formations and is referred to as polymorph in pharmaceuticals, medicine polycrystalline
Type is the phenomenon of generally existing in solid drugs.
Term " powder x-ray diffraction collection of illustrative plates " (abbreviation XRD) refers to the diffraction pattern or the ginseng from which that experimental observation arrives
Number.Powder x-ray diffraction collection of illustrative plates is characterized by peak position and peak intensity.
In XRD spectrum, " intensity, CPS " is " intensity integration counts per second "
Write a Chinese character in simplified form, represent diffraction peak intensity, the powder x-ray diffraction figure is the collection of illustrative plates obtained with CuK alpha rays.
Description of the drawings
Fig. 1 show the present invention (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazines
The powder x-ray diffraction figure of hydrochloride B crystal form.The longitudinal axis represents that peak intensity, transverse axis represent the angle of diffraction (2 θ).
Fig. 2 show the present invention (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazines
The DSC thermal analysis curues of hydrochloride B crystal form.The longitudinal axis represents that mW/mg, transverse axis represent temperature DEG C.
The invention provides the present invention (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, the high piperazines of 4-
Novel crystal forms B of piperazine hydrochloride and preparation method thereof.The novel crystal forms of gained of the present invention have good stability, and crystal formation is not susceptible to become
Change, with preferable sucting wet stability, disclosure satisfy that the medicinal requirements of production and transport storage, thus the crystallization of the present invention can be compared with
Use as medicating active ingredients well, preferably meet the clinical demand of extensive patients.
Specific embodiment
Following examples further describe the present invention, but, these embodiments are only for the explanation present invention, rather than right
The restriction of the scope of the invention.
1 (S)-(-) -1- of embodiment (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochlorides are thick
The preparation of product
1.60g intermediates are dissolved in ethyl acetate in 100mL single port bottles, the ethyl acetate solution of 4N hydrochloric acid is added
16mL, stirs 8h.Crystallization, suction filtration, filter cake 15mL ethyl acetate beating washing.35 DEG C of dried in vacuum overnight of filter cake obtain hydrochloride
White solid 1.29g.Yield 86%.HPLC purity 99.5%.
2 (S)-(-) -1- of embodiment (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazines hydrochloride are brilliant
The preparation of type B
By 1.00g (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochlorides are thick
Product mix molten with water 5mL, and freeze-drying obtains (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4-
Homopiperazine hydrochloride.Through K.F determinations of moisture, scope belongs to nothing within 1.10% to the crystal provided in the embodiment of the present invention
Water crystallization.
3 stability study of embodiment
The crystal formation B pressed powders that embodiment 2 is prepared sample every part of 0.200g and are positioned in closed glass jar, respectively
Preserve under different temperatures in thermostatic drying chamber, thermally-stabilised data are as follows：
Table 2
As a result show that this product is preserved at 40 DEG C, 60 DEG C and 80 DEG C two weeks and has good heat endurance.
4 crystal formation B stability studies of embodiment
The B crystal form and reference patent of invention of in measuring cup, add 300mg to obtain in example 2 respectively the present invention
Anhydrous crystal prepared by CN101068806 methods, is kept for 25 DEG C to be placed under opening status, the bar of 92% relative humidity (RH)
In container under part.Then, through when weigh measuring bottle, draw weight increase, and to place two weeks after sample carry out XRD tests,
Detector crystal formation situation of change.
Elapse over time, the moisture of the anhydrous crystal prepared with reference to CN101068806 methods becomes 0～42%
Change, have been surprisingly found that the moisture content change of crystal formation B of the present invention 0～3%, it is shown that preferable sucting wet stability, in addition XRD
Show the application B crystal form place under conditions of high humidity after XRD spectrum main 2 θ angles and diffraction peak intensity do not occur significantly
There is no significant change in change, crystal formation species and fusing point, crystalline state does not change, and be not susceptible to turn crystalline substance, it is shown that good
Good stability of crystal form.
Additionally, contrast experiment shows bar of the anhydrous crystal of CN101068806 methods preparation in relative humidity more than 50%
Preserve under part, hygroscopic effect occurs, the crystalline texture of anhydrous crystal changes, and volume is also changed therewith.That is, this is anhydrous
Crystallization causes crystalline state to change because of hygroscopic effect.
Claims (3)
1. one kind (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochloride Form B, are somebody's turn to do
The x-ray diffraction pattern of crystal form have be included in 2 θ of the angle of diffraction：6.499 ± 0.2 degree, 8.95 ± 0.2 degree, 11.153 ± 0.2
Degree, 12.66 ± 0.2 degree, 15.698 ± 0.2 degree, 16.207 ± 0.2 degree, 17.306 ± 0.2 degree, 8.553 ± 0.2 degree, 21.099
± 0.2 degree, 21.625 ± 0.2 degree, 24.062 ± 0.2 degree, 26.634 ± 0.2 degree, 29.264 ± 0.2 degree, 35.63 ± 0.2 degree
The diffraction maximum at place, the powder x-ray diffraction figure are the collection of illustrative plates obtained with CuK alpha rays.
2. (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids described in claim 1,4- homopiperazine salt
Hydrochlorate crystal formation B, it is characterised in that the x-ray diffraction pattern of the crystal form have be included in 2 θ of the angle of diffraction：5.319 ± 0.2 degree,
6.499 ± 0.2 degree, 8.95 ± 0.2 degree, 11.153 ± 0.2 degree, 12.66 ± 0.2 degree, 13.698 ± 0.2 degree, 14.592 ± 0.2
Degree, 15.698 ± 0.2 degree, 16.207 ± 0.2 degree, 17.306 ± 0.2 degree, 8.553 ± 0.2 degree, 21.099 ± 0.2 degree,
21.625 ± 0.2 degree, 23.003 ± 0.2 degree, 24.062 ± 0.2 degree, 26.253 ± 0.2 degree, 26.634 ± 0.2 degree, 29.264
± 0.2 degree, 29.813 ± 0.2 degree, 30.285 ± 0.2 degree, 30.661 ± 0.2 degree, 31.258 ± 0.2 degree, 35.63 ± 0.2 degree,
Diffraction maximum at 36.271 ± 0.2 degree, the powder x-ray diffraction figure are the collection of illustrative plates obtained with CuK alpha rays.
3. one kind (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochloride Form B's
Preparation method, it is characterised in that comprise the steps of：
1) by (S)-(-) -1- (4- fluoro isoquinolin -5- bases) sulfonyl -2- methyl isophthalic acids, 4- homopiperazine hydrochloride salts are in water
In；
2) by step 1) gained mixture cooling freeze；
3) freeze-drying obtains pressed powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610884386.6A CN106496189A (en) | 2016-10-10 | 2016-10-10 | Hydrochloric acid Ripasudil crystal formations |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610884386.6A CN106496189A (en) | 2016-10-10 | 2016-10-10 | Hydrochloric acid Ripasudil crystal formations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106496189A true CN106496189A (en) | 2017-03-15 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610884386.6A Withdrawn CN106496189A (en) | 2016-10-10 | 2016-10-10 | Hydrochloric acid Ripasudil crystal formations |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113262226A (en) * | 2021-04-19 | 2021-08-17 | 浙江大学 | Application of lisuridil in preparation of medicament for treating bacterial infection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020620A1 (en) * | 1997-10-22 | 1999-04-29 | Nippon Shinyaku Co Ltd | Isoquinoline derivative and drug |
| CN101068806A (en) * | 2004-11-29 | 2007-11-07 | 兴和株式会社 | (s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate |
| JP2013100247A (en) * | 2011-11-09 | 2013-05-23 | Kowa Co | Isoquinoline derivative hydrochloride anhydrate crystal |
-
2016
- 2016-10-10 CN CN201610884386.6A patent/CN106496189A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020620A1 (en) * | 1997-10-22 | 1999-04-29 | Nippon Shinyaku Co Ltd | Isoquinoline derivative and drug |
| CN101068806A (en) * | 2004-11-29 | 2007-11-07 | 兴和株式会社 | (s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate |
| JP2013100247A (en) * | 2011-11-09 | 2013-05-23 | Kowa Co | Isoquinoline derivative hydrochloride anhydrate crystal |
Non-Patent Citations (2)
| Title |
|---|
| SHIGERU OHBA ET AL.: "Three derivatives of 4-fluoro-5-sulfonylisoquinoline", 《CRYSTAL STRUCTURE COMMUNICATIONS》 * |
| 姚静等: "《药物冻干制剂技术的设计及应用》", 30 June 2007, 中国医药科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113262226A (en) * | 2021-04-19 | 2021-08-17 | 浙江大学 | Application of lisuridil in preparation of medicament for treating bacterial infection |
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