CN109988158A - X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application - Google Patents
X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application Download PDFInfo
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- CN109988158A CN109988158A CN201810004736.4A CN201810004736A CN109988158A CN 109988158 A CN109988158 A CN 109988158A CN 201810004736 A CN201810004736 A CN 201810004736A CN 109988158 A CN109988158 A CN 109988158A
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- crystal form
- doxazosin mesylate
- doxazosin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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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Abstract
The present invention provides X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application, the angle of diffraction 2 θ angle of the X crystal form on X-ray diffraction within the scope of 5.195 ° -5.200 °, 15.938 ° -15.944 °, 20.550 ° -20.570 °, 25.375 ° -25.385 ° shows diffraction maximum, and X crystal form is the new crystal form of one kind of doxazosin mesylate.The doxazosin mesylate preparation method of the X containing crystal form is simple in the present invention, and condition is easier to control in the industrial production, can be widely applied to preparation treatment hypertension and benign prostatic hyperplasis drug.It is the doxazosin mesylate containing form D that the doxazosin mesylate of the crystal form containing X, which is passed through thermal conversion, provides a kind of new approach for doxazosin mesylate of the preparation containing form D.
Description
Technical field
The present invention relates to a kind of new doxazosin mesylate crystal forms, more particularly to a kind of X crystal form, contain X crystal form
Doxazosin mesylate and its preparation method and application.
Background technique
Solid drugs are there are diversified forms, such as amorphous, glassy state, crystal form, solvate and hydrate, wherein crystal form
Drug is the most common form.Same drug usually has different crystalline structures, and the polymorphism of drug directly affects medicine
The physicochemical property (such as fusing point, solubility, dissolution rate and stability) and clinical efficacy of product.It was found that different crystal forms finds physics and chemistry
The medicinal crystal-form of good properties is also the important content of new drug development.
Doxazosin is quinazoline derivative, can selectively, competitively 1 adrenergic of α after block nerves section
Receptor reduces peripheral vascular resistance loose matrix, envelope and bladder neck smooth muscle simultaneously.It is first disclosed as US 4,188,390
In, it can mostly China be listed in 1988 with sustained-release preparation by Pfizer, be used to treat hyperplasia of prostate and various types
The treatment of hypertension.The Doxazosin of clinical use is the current Doxazosin methylsulphur reported in the literature with mesylate salt form
There are many hydrochlorate crystal forms.Firstly, Xu Liying etc. (Chinese journal of Medicinal Chemistry, 1995,5:266-270) reports three kinds of crystal forms,
It is tri- kinds of crystal forms of A, B, C respectively；Thereafter, M.Greman etc. (Farmacevtski vestnik, 1997,48:292-293) is reported again
The 5 kinds of crystal forms in road: A, five kinds of crystal forms of B, C, D, E.Young-Taek Sohn etc. (Arch Pharm Res, 2005,28 (6):
730-735) summarize to the crystal form of doxazosin mesylate reported in the literature, share crystal form in 9 be respectively as follows: A, B, C,
D, E, F, G, H, I crystal.
Inventor herein has found a kind of new crystal form by carrying out research to doxazosin mesylate crystal form for a long time, will
The novel crystal forms are named as crystal form X.The preparation method of the new crystal form X is simple, and condition is easier to control in the industrial production.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of X crystal form, contain X crystal form
Doxazosin mesylate and its preparation method and application, the doxazosin mesylate preparation method containing X crystal form is simple,
Condition is easier to control in the industrial production.
To achieve the above object, the present invention provides: in a first aspect, a kind of doxazosin mesylate X crystal form, described sandy
Azoles piperazine mesylate X crystal form on X-ray diffraction 5.195 ° -5.200 °, 15.938 ° -15.944 °, 20.550 ° -
2 angle θ of the angle of diffraction within the scope of 20.570 °, 25.375 ° -25.385 ° shows diffraction maximum.
Second aspect, the present invention provide the doxazosin mesylate containing X crystal form as described above of crystal form,
The doxazosin mesylate has following X-ray diffraction model:
Preferably, the DSC data peak value of the doxazosin mesylate containing X crystal form of the crystal form are as follows: 265 DEG C
~266 DEG C, starting point are as follows: 263 DEG C~264 DEG C.
It is highly preferred that the DSC data peak value of the doxazosin mesylate containing X crystal form of the crystal form are as follows:
265.46 DEG C, starting point are as follows: 263.96 DEG C.
The third aspect, the present invention provide a kind of Doxazosin containing X crystal form for preparing crystal form as described above
The method of mesylate, which comprises the following steps:
1) Doxazosin, methanol solution is added to reactor, then methanesulfonic acid is slowly added dropwise at 16-21 DEG C in stirring；
2) reacted after methanesulfonic acid is added dropwise to complete, reaction temperature be no more than 25 DEG C, insulation reaction 1.5-2.5 hours,
Obtain white emulsion；
3) the white emulsion is filtered, obtains filter cake, the filter cake is multiple using methanol solution rinse, it sets
It is dried in vacuum environment, prepares doxazosin mesylate.
Preferably, in step 1), the volume ratio of the weight of the Doxazosin and the methanol solution is g:mL=
(25-35): (290-340).
Preferably, in step 1), the weight ratio of the methanesulfonic acid and the Doxazosin is (7-7.5): (25-35).
Preferably, in step 1), the water content of the methanol solution is 0.03%~0.5%.
It is highly preferred that the water content of the methanol solution is 0.05%~0.2% in step 1).
Preferably, in step 1), the addition while Doxazosin and the methanol solution are added into reactor
Doxazosin mesylate containing form D, the weight of the doxazosin mesylate containing form D and the Doxazosin
Amount is than being (2-4): (25-35).The Doxazosin first containing form D is added as crystal seed in the doxazosin mesylate of form D
Sulfonate is more advantageous to the generation of induction X crystal form.
Preferably, in step 3), the temperature of the vacuum environment is 50~70 DEG C.
It is highly preferred that the temperature of the vacuum environment is 55~65 DEG C in step 3).
Preferably, in step 3), the water content of the methanol solution is 0.03%~0.5%.
It is highly preferred that the water content of the methanol solution is 0.05%~0.2% in step 3).
Fourth aspect, the present invention provide a kind of preparation method of doxazosin mesylate containing form D, including following
The doxazosin mesylate containing X crystal form of crystal form as described above is placed in a vacuum drying oven progress by step
It is dried under reduced pressure until constant weight, prepares the doxazosin mesylate containing form D.
Preferably, the temperature of the vacuum oven is 100~200 DEG C.
It is highly preferred that the temperature of the vacuum oven is 100~120 DEG C.
5th aspect, the present invention provide a kind of Doxazosin methylsulphur containing X crystal form of crystal form as described above
Hydrochlorate is in the purposes for being used to prepare treatment hypertension and benign prostatic hyperplasis drug.
As described above, a kind of X crystal form of the invention, doxazosin mesylate containing X crystal form and preparation method thereof and
Purposes has the advantages that
By for a long time to doxazosin mesylate crystal form the study found that the water content difference in recrystallization solvent to more
The generation of husky azoles piperazine Mesylate Form has significant impact, can effectively control difference by the control to solvent water content
The generation of crystal form.A kind of new crystal form is found by carrying out research to doxazosin mesylate crystal form for a long time, and the present invention should
Novel crystal forms are named as X crystal form.The preparation method for containing the doxazosin mesylate of X crystal form is simple, in the industrial production item
Part is easier to control.Doxazosin mesylate simultaneously containing X crystal form can also be to contain the more of form D by thermal conversion
Husky azoles piperazine mesylate provides a kind of new approach for doxazosin mesylate of the preparation containing form D.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction spectrogram of the doxazosin mesylate containing X crystal form in the present invention.
Fig. 2 is the thermal gravimetric analysis curve and differential scanning calorimetry of the doxazosin mesylate containing X crystal form in the present invention
Method (DSC) trajectory line.
Specific embodiment
Embodiments of the present invention are illustrated by particular specific embodiment below, those skilled in the art can be by this explanation
Content disclosed by book is understood other advantages and efficacy of the present invention easily.
Embodiment 1
30.0g Doxazosin is sequentially added in 500mL three-necked flask, 300mL water content is 0.1% methanol solution, machine
Tool stirring, is slowly added dropwise 7.2g methanesulfonic acid at 18 DEG C.After methanesulfonic acid is added dropwise to complete, reaction temperature is no more than 25 DEG C, and heat preservation is anti-
It answers 2 hours, obtains white emulsion.It filters after reaction, obtains filter cake, use 50mL water content for 0.1% methanol filter cake
Solution rinse twice, is placed under 60 DEG C of vacuum drying, can be prepared into 28.8g and contain X crystal form doxazosin mesylate.
Fig. 1 is shown as the X-ray powder diffraction spectrogram of the doxazosin mesylate containing X crystal form.Fig. 2 is shown as
The thermal gravimetric analysis curve and DSC trajectory line of doxazosin mesylate containing X crystal form.In Fig. 2, line 1 is to contain X crystal form
Doxazosin mesylate DTG curve, line 2 be the doxazosin mesylate containing X crystal form DSC trajectory line, line 3 be containing
The TG curve of the doxazosin mesylate of X crystal form.
Embodiment 2
30.0g Doxazosin is sequentially added in 500mL three-necked flask, the Doxazosin methanesulfonic acid that 3.0g contains form D
7.2g methanesulfonic acid is slowly added dropwise at 20 DEG C in the methanol solution that salt and 330mL water content are 0.1%, mechanical stirring.Methanesulfonic acid drop
After the completion of adding, reaction temperature is no more than 25 DEG C, insulation reaction 2 hours, obtains white emulsion.It filters, is filtered after reaction
Cake, by filter cake use 50mL water content for 0.1% methanol solution rinse twice, be placed in 60 DEG C vacuum drying under can be prepared into
31.2g contains the doxazosin mesylate of X crystal form.
Embodiment 3
The doxazosin mesylate containing X crystal form for taking 20g embodiment 1 to prepare is placed in a vacuum drying oven, in 105 DEG C
Under be dried under reduced pressure until constant weight, prepare the doxazosin mesylate containing form D, the sandy azoles containing X crystal form
Piperazine mesylate is completely converted into the doxazosin mesylate containing form D.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (10)
1. a kind of doxazosin mesylate X crystal form, which is characterized in that the doxazosin mesylate X crystal form spreads out in X-ray
Penetrate spreading out within the scope of 5.195 ° -5.200 °, 15.938 ° -15.944 °, 20.550 ° -20.570 °, 25.375 ° -25.385 °
2 angle θ of firing angle shows diffraction maximum.
2. the doxazosin mesylate containing X crystal form as described in claim 1 of crystal form, which is characterized in that described
Doxazosin mesylate has following X-ray diffraction model:
3. the doxazosin mesylate containing X crystal form of crystal form according to claim 2, which is characterized in that institute
State the DSC data peak value of the doxazosin mesylate containing X crystal form of crystal form are as follows: 265 DEG C~266 DEG C, starting point are as follows:
263 DEG C~264 DEG C.
4. a kind of prepare such as the doxazosin mesylate containing X crystal form of the crystal form as described in claim 2 to 3 is any
Method, which comprises the following steps:
1) Doxazosin, methanol solution is added to reactor, then methanesulfonic acid is slowly added dropwise at 16-21 DEG C in stirring；
2) it is reacted after methanesulfonic acid is added dropwise to complete, reaction temperature is no more than 25 DEG C, insulation reaction 1.5-2.5 hours, obtains
White emulsion；
3) the white emulsion is filtered, obtains filter cake, the filter cake is multiple using methanol solution rinse, it is placed in true
It is dried in Altitude, prepares doxazosin mesylate.
5. the preparation method of the doxazosin mesylate containing X crystal form of crystal form as claimed in claim 4, feature
It is, in step 1), the volume ratio of the weight of the Doxazosin and the methanol solution is g:mL=(25-35): (290-
340)；
And/or in step 1), the weight ratio of the methanesulfonic acid and the Doxazosin is (7-7.5): (25-35)；
And/or in step 1), it is added while the Doxazosin and the methanol solution are added into reactor and contains D
The doxazosin mesylate of crystal form, the weight ratio of the doxazosin mesylate containing form D and the Doxazosin
For (2-4): (25-35).
6. the preparation method of the doxazosin mesylate containing X crystal form of crystal form as claimed in claim 4, feature
It is, in step 1), the water content of the methanol solution is 0.03%~0.5%.
7. the preparation method of the doxazosin mesylate containing X crystal form of crystal form as claimed in claim 4, feature
It is, in step 3), the temperature of the vacuum environment is 50~70 DEG C；
And/or in step 3), the water content of the methanol solution is 0.03%~0.5%.
8. a kind of preparation method of the doxazosin mesylate containing form D, which is characterized in that include the following steps, it will be as
The doxazosin mesylate containing X crystal form of any crystal form of claim 2 to 3 be placed in a vacuum drying oven into
Row is dried under reduced pressure until constant weight, prepares the doxazosin mesylate containing form D.
9. the preparation method of the doxazosin mesylate according to claim 8 containing form D, which is characterized in that institute
The temperature for stating vacuum oven is 100~200 DEG C.
10. a kind of doxazosin mesylate containing X crystal form of the crystal form as described in claim 2 to 3 is any with
In preparation treatment hypertension and the purposes of benign prostatic hyperplasis drug.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810004736.4A CN109988158A (en) | 2018-01-03 | 2018-01-03 | X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810004736.4A CN109988158A (en) | 2018-01-03 | 2018-01-03 | X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303130A (en) * | 2018-12-11 | 2020-06-19 | 合肥立方制药股份有限公司 | Doxazosin mesylate crystal form, and preparation method and application thereof |
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| EP0849264A1 (en) * | 1996-12-20 | 1998-06-24 | HEUMANN PHARMA GmbH | Novel polymorphic form of doxazosin mesylate (form I) |
| EP0849265A1 (en) * | 1996-12-20 | 1998-06-24 | HEUMANN PHARMA GmbH | Novel polymorphic form of doxazosin mesylate (form II) |
| JPH10175974A (en) * | 1996-12-13 | 1998-06-30 | Alfa Chem It Srl | Powdery crystal of doxazosin mesylate and its production |
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| WO2009081087A1 (en) * | 2007-12-24 | 2009-07-02 | Cipla Limited | Crystalline polymorph of doxazosin mesylate (form iv) and process for preparation thereof |
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2018
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| CN1352643A (en) * | 1999-03-18 | 2002-06-05 | Basf公司 | Novel method for producing doxazosin mesylate in a crystalline modification designated as form A |
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| WO2009081087A1 (en) * | 2007-12-24 | 2009-07-02 | Cipla Limited | Crystalline polymorph of doxazosin mesylate (form iv) and process for preparation thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303130A (en) * | 2018-12-11 | 2020-06-19 | 合肥立方制药股份有限公司 | Doxazosin mesylate crystal form, and preparation method and application thereof |
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