CN109988074A - A kind of preparation method being suitble to medicinal terbutaline sulphate crystal B - Google Patents
A kind of preparation method being suitble to medicinal terbutaline sulphate crystal B Download PDFInfo
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- CN109988074A CN109988074A CN201810557346.XA CN201810557346A CN109988074A CN 109988074 A CN109988074 A CN 109988074A CN 201810557346 A CN201810557346 A CN 201810557346A CN 109988074 A CN109988074 A CN 109988074A
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- crystal
- bricalin
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- terbutaline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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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
Abstract
The invention discloses a kind of preparation methods for being suitble to medicinal terbutaline sulphate crystal B, comprising the following steps: S1, armorphous B bricalin is dissolved in pure water, stirring and dissolving obtains bricalin aqueous solution；S2, armorphous B bricalin aqueous solution obtained by step S1 is added dropwise in alcohols or ketones solvent, the crystal seed of terbutaline sulphate crystal B is added in stirring and dissolving, and stirring and crystallizing obtains the bricalin crystal solution of crystal form B；S3, the bricalin crystal solution of crystal form B obtained by step S2 is filtered, is dried to obtain terbutaline sulphate crystal B；Armorphous B bricalin quality in preparation method (unit: gram): pure water quality (unit: gram): the crystal seed quality (unit: gram) of Terbutaline crystal form B: alcohols or ketones solvent volume (unit: milliliter) are 1:4~5:0.01~0.1:50~60.Operation of the present invention is simple, and repeatability is high, and raw material is environmental-friendly, it is easy to accomplish industrialized production and application.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of preparations for being suitble to medicinal terbutaline sulphate crystal B
Method.
Background technique
α-[(tertiary fourth amino) methyl] -3,5- dihydroxybenzyl alcohol sulfate (2:1), i.e. bricalin
(Terbutaline Sulfate), CAS# [23031-32-5], molecular formula are (C12H19NO3)2.H2SO4, chemical structural formula is such as
Under:
Bricalin also known as Terbutaline, terbutaline, by AstraZeneca, pharmaceutical Co. Ltd is developed,
In 1988 in foreign countries' production listing.Bricalin is a kind of 2-adrenergic agonist components, alternative excitement beta 2-receptor
To oedema caused by diastole bronchial smooth muscle, the release of inhibition endogenous cause spasm substance and endogenous mediator, branch is improved
Tunica mucosa tracheae cilliated epithelium cleans up ability, can also diastole uterine smooth muscle.Clinically it is mainly used for bronchial asthma, asthma type branch
Bronchial spasm treatment when tracheitis and chronic obstructive lung illness.
Patent US3937838 discloses the structure of compound bricalin, preparation process and its alternatively property β
The clinical application of 2- adrenoceptor agonists.Patent CN201310560213.5, patent CN201510758230.9, patent
Synthesis [J] Chinese Journal of Pharmaceuticals of CN201510758230.9, document bricalin, 1999,30 (1): 1-4, text
Offer the improvement in synthesis of terbutaline, [J] Shenzhen University journal science and engineering version, 2005,22 (2): 105-108, above-mentioned patent and
Document is each provided with the preparation method of bricalin compound.
Study (Jaeschke R, Guyall GH, Willan A, et al.The effect of increasing
Doses of betaagonists on spirometry, exercise capa city, and quality oflife in
Patients with chronic ai rflow limitation.Thorax, 1994,49:478.) show sulfuric acid Te Buta
Woods nebulizer administration is the best administration mode of beta receptor agonist, which there is lesser heart, blood vessel pair to make
With.Clinical bricalin atomization medication is suspension aerosol, and preparation process is needed to bricalin bulk pharmaceutical chemicals
It is micronized, for polymorph medicine, micronization may result in the variation of crystal form.Document Robin K.Harris, Paul
Hodgkinson, Tomas Larsson, etc. Characterization of Polymorphs and Solvates of
Terbutaline Sulfate [J] Crystal Grownth&Design, 2008, Vol 18, No.180-90, to sulfuric acid spy's cloth
His woods crystal form type and stability are studied, it was recently reported that at least there are five types of crystal forms to exist, respectively crystal form A, crystal form B, list
Hydrate, polyhydrate, acetic acid close object and meet bricalin suspension type gas research shows that wherein crystal form B is stable crystal form
The requirement of mist agent preparation.
Patent US3937838 discloses the structure of compound bricalin, preparation process and its alternatively property β
The clinical application of 2- adrenoceptor agonists.Patent CN201310560213.5, patent CN201510758230.9, patent
Synthesis [J] Chinese Journal of Pharmaceuticals of CN201510758230.9, document bricalin, 1999,30 (1): 1-4, text
The improvement in synthesis of terbutaline is offered, 2005,22 (2): [J] Shenzhen University journal science and engineering version is prepared disclosed in 105-108 etc.
Method, obtained product crystal form are mostly the crystal forms such as a water of bricalin, polyhydrate, are not stable crystal form B, cannot
Meet medicinal standard.
Patent CN101475497A discloses a kind of method for preparing terbutaline sulphate crystal B using mixed solvent, should
The system that method uses water saturation esters solvent A or water saturation esters solvent A to mix with one or more organic solvent solvent B,
By the bricalin product of armorphous B, it is converted into the bricalin product of crystal form B；Mixed solution used in it
Complicated for operation, mixed proportion is difficult to control, and obtained bricalin product may be a variety of crystal form mixtures, and use
Solvent type has the risk for causing dissolvent residual to be unsatisfactory for medicinal standard, by vaporing away organic solvent or 50 DEG C of nitrogen under normal pressure
The operation for being dried to obtain terbutaline sulphate crystal B is flowed down, industrialized production and application are not easy to.
Summary of the invention
The purpose of the present invention is to defects present in existing terbutaline sulphate crystal B preparation method, provide one
Kind is suitble to the preparation method of medicinal terbutaline sulphate crystal B, easy to operate, and repeatability is high, and raw material is environmental-friendly, is easy to
Realize industrialized production and application.
To achieve the goals above, the present invention adopts the following technical scheme: a kind of be suitble to medicinal bricalin brilliant
The preparation method of type B, the terbutaline sulphate crystal B use the X-ray powder diffraction method of Co-K α, are in 2 θ of the angle of diffraction
At 9.9 ± 0.2 °, 12.9 ± 0.2 °, 21.5 ± 0.2 °, 22.7 ± 0.2 °, 25.0 ± 0.2 °, 27.6 ± 0.2 °, 28.9 ± 0.2 °
There is peak, it can be with positioned at about 8.5 ± 0.2 °, 11.3 ± 0.2 °, 14.9 ± 0.2 °, 15.8 ± 0.2 °, 20.0 ± 0.2 °, 23.6
± 0.2 ° of powder xrd pattern case further characterization, as shown in Figure 1, or carrying out table no more than 0.5% with KF moisture measurement result
Sign, preparation method includes the following steps:
S1, armorphous B bricalin is dissolved in pure water, the stirring and dissolving at 0~60 DEG C obtains armorphous B sulphur
Sour Terbutaline aqueous solution；
S2, armorphous B bricalin aqueous solution obtained by step S1 is added dropwise in alcohols or ketones solvent, is stirred molten
Solution, is added the crystal seed of terbutaline sulphate crystal B, stirring and crystallizing 10 minutes~100 hours, obtain crystal form B's at 0~30 DEG C
Bricalin crystal solution；
S3, by the bricalin crystal solution filtering of crystal form B obtained by step S2, be dried to obtain and meet pharmaceutical formulation standard
Terbutaline sulphate crystal B product.
Wherein, the optimum temperature of solubilization temperature in the step S1 is 20~30 DEG C；Best crystallization temperature in the step S2
It is 10~15 DEG C, the best crystallization time is 36 hours~48 hours.
Further, armorphous B bricalin quality in the preparation method (unit: gram): pure water quality is (single
Position: gram): the crystal seed quality of Terbutaline crystal form B (unit: gram): alcohols or ketones solvent volume (unit: milliliter) be 1:4~
5:0.01~0.1:50~60.
Further, in the S2 alcohols solvent be ethyl alcohol, isopropanol, normal propyl alcohol, the tert-butyl alcohol or other have it is certain water-soluble
One of property alcohols solvent.
Further, in the S2 ketones solvent be acetone, butanone, methylisobutylketone or other have certain water-soluble ketone
One of solvent.
Wherein, the alcohols/ketones solvent is environmentally friendly solvent, is after reaction danger to product, environment
Evil.
Compared with prior art, the present invention realize the utility model has the advantages that the present invention is suitble to medicinal terbutaline sulphate crystal B
Preparation method in, reaction condition is mild, and preparation process and purification step are simple and direct safely, and product yield is high, and repeatability is high, easily
In realization industrialized production and application.
Detailed description of the invention
The XRD diffraction pattern of Fig. 1 terbutaline sulphate crystal B.
Fig. 2 is the XRD diffraction pattern of 1 gained terbutaline sulphate crystal B of embodiment.
Fig. 3 is the XRD diffraction pattern of 2 gained terbutaline sulphate crystal B of embodiment.
Fig. 4 is the XRD diffraction pattern of 3 gained terbutaline sulphate crystal B of embodiment.
Fig. 5 is the XRD diffraction pattern of 4 gained terbutaline sulphate crystal B of embodiment.
Specific embodiment
In order to illustrate more clearly of technical solution of the present invention, it is further described below in conjunction with each embodiment.
Embodiment 1
S1, the armorphous B bricalin of 5g is dissolved in 20mL pure water, the stirring and dissolving at 20 DEG C, obtains sulfuric acid spy
Bu Talin aqueous solution；
S2, bricalin aqueous solution obtained by step S1 is added dropwise in 300mL dehydrated alcohol, stirring and dissolving is added
The crystal seed of terbutaline sulphate crystal B, stirring and crystallizing 48 hours at 10 DEG C obtain white suspension, i.e. the sulfuric acid of crystal form B is special
Bu Talin crystal solution；
S3, white suspension obtained by step S2 is filtered, filter cake is washed with dehydrated alcohol, and it is white to obtain 2.8g for constant pressure and dry
Color solid-like terbutaline sulphate crystal B, moisture is less than 0.5%.
Embodiment 2
S1, the armorphous B bricalin of 5g is dissolved in 25mL pure water, the stirring and dissolving at 30 DEG C, obtains sulfuric acid spy
Bu Talin aqueous solution；
S2, bricalin aqueous solution obtained by step S1 is added dropwise in 200mL acetone, sulfuric acid is added in stirring and dissolving
The crystal seed of Terbutaline crystal form B, stirring and crystallizing 36 hours at 15 DEG C obtain white suspension, i.e. the sulfuric acid Te Buta of crystal form B
Woods crystal solution；
S3, white suspension obtained by step S2 is filtered, filter cake acetone washing, it is solid to obtain 3.5g white for constant pressure and dry
Body shape terbutaline sulphate crystal B, moisture is less than 0.5%.
Embodiment 3
S1, the armorphous B bricalin of 5g is dissolved in 25mL pure water, the stirring and dissolving at 30 DEG C, obtains sulfuric acid spy
Bu Talin aqueous solution；
S2, bricalin aqueous solution obtained by step S1 is added dropwise in 200mL butanone, sulfuric acid is added in stirring and dissolving
The crystal seed of Terbutaline crystal form B, stirring and crystallizing 38 hours at 15 DEG C obtain white suspension, i.e. the sulfuric acid Te Buta of crystal form B
Woods crystal solution；
S3, white suspension obtained by step S2 is filtered, filter cake is washed with butanone, constant pressure and dry, and it is solid to obtain 3.1g white
Body shape terbutaline sulphate crystal B, moisture is less than 0.5%.
Embodiment 4
S1, the armorphous B bricalin of 762g is dissolved in 5.5L pure water, the stirring and dissolving at 30 DEG C obtains sulfuric acid
Terbutaline aqueous solution；
S2, bricalin aqueous solution obtained by step S1 is added dropwise in 34L acetone, it is special that sulfuric acid is added in stirring and dissolving
The crystal seed of Bu Talin crystal form B, stirring and crystallizing 48 hours at 10 DEG C obtain white suspension, the i.e. bricalin of crystal form B
Crystal solution；
S3, white suspension obtained by step S2 is filtered, filter cake acetone washing, it is solid to obtain 650g white for constant pressure and dry
Body shape terbutaline sulphate crystal B, moisture is less than 0.5%.
The above specific embodiments are only exemplary, is to preferably make skilled artisans appreciate that originally
Patent, be not to be construed as include to this patent range limitation；As long as appointing made by the spirit according to disclosed in this patent
How with change or modification, the range that this patent includes is each fallen within.
Claims (4)
1. a kind of preparation method for being suitble to medicinal terbutaline sulphate crystal B, which is characterized in that the bricalin is brilliant
Type B use Co-K α X-ray powder diffraction method, 2 θ of the angle of diffraction be 9.9 ± 0.2 °, 12.9 ± 0.2 °, 21.5 ± 0.2 °,
Have peak at 22.7 ± 0.2 °, 25.0 ± 0.2 °, 27.6 ± 0.2 °, 28.9 ± 0.2 °, can with positioned at about 8.5 ± 0.2 °,
11.3 ± 0.2 °, 14.9 ± 0.2 °, 15.8 ± 0.2 °, 20.0 ± 0.2 °, 23.6 ± 0.2 ° of the further table of powder xrd pattern case
Sign, as shown in Figure 1, or characterized with KF moisture measurement result no more than 0.5%, preparation method includes the following steps:
S1, armorphous B bricalin is dissolved in pure water, the stirring and dissolving at 0~60 DEG C obtains bricalin water
Solution；
S2, bricalin aqueous solution obtained by step S1 is added dropwise in alcohols or ketones solvent, sulfuric acid is added in stirring and dissolving
The crystal seed of Terbutaline crystal form B, stirring and crystallizing 10 minutes~100 hours at 0~30 DEG C, obtains the sulfuric acid Te Buta of crystal form B
Woods crystal solution；
S3, by the bricalin crystal solution filtering of crystal form B obtained by step S2, be dried to obtain and be suitble to medicinal sulfuric acid Te Buta
Woods crystal form B.
2. being suitble to the preparation method of medicinal terbutaline sulphate crystal B as described in claim 1, which is characterized in that described
Armorphous B bricalin quality in preparation method (unit: gram): pure water quality (unit: gram): Terbutaline crystal form B's
Crystal seed quality (unit: gram): alcohols or ketones solvent volume (unit: milliliter) are 1:4~5:0.01~0.1:50~60.
3. being suitble to the preparation method of medicinal terbutaline sulphate crystal B as described in claim 1, which is characterized in that described
In S2 alcohols solvent be ethyl alcohol, isopropanol, normal propyl alcohol, the tert-butyl alcohol or other have one of certain water soluble alcohols solvent.
4. being suitble to the preparation method of medicinal terbutaline sulphate crystal B as described in claim 1, which is characterized in that described
In S2 ketones solvent be acetone, butanone, methylisobutylketone or other have one of certain water-soluble ketones solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112250586A (en) * | 2020-10-21 | 2021-01-22 | 福安药业集团宁波天衡制药有限公司 | Preparation method of terbutaline sulfate and B crystal form thereof |
| CN115210210A (en) * | 2020-03-02 | 2022-10-18 | 谭文 | Crystalline form of (R) -terbutaline hydrochloride |
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|---|---|---|---|---|
| CN1819818A (en) * | 2003-07-07 | 2006-08-16 | 阿斯利康(瑞典)有限公司 | Process for the preparation of micron-size crystalline particles using a solvent, a non-solvent and ultrasonic energy |
| CN101391965A (en) * | 2008-11-02 | 2009-03-25 | 李勤耕 | Method for preparing terbutaline sulphate crystal B fulfilling medicinal requirements |
| CN107513023A (en) * | 2017-08-30 | 2017-12-26 | 石家庄智时医药科技有限公司 | A kind of preparation method of bricalin |
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2018
- 2018-06-01 CN CN201810557346.XA patent/CN109988074A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1819818A (en) * | 2003-07-07 | 2006-08-16 | 阿斯利康(瑞典)有限公司 | Process for the preparation of micron-size crystalline particles using a solvent, a non-solvent and ultrasonic energy |
| CN101391965A (en) * | 2008-11-02 | 2009-03-25 | 李勤耕 | Method for preparing terbutaline sulphate crystal B fulfilling medicinal requirements |
| CN101475497A (en) * | 2008-11-02 | 2009-07-08 | 李勤耕 | Method for preparing terbutaline sulphate crystal form B meeting medicinal requirements |
| CN107513023A (en) * | 2017-08-30 | 2017-12-26 | 石家庄智时医药科技有限公司 | A kind of preparation method of bricalin |
Non-Patent Citations (4)
| Title |
|---|
| MAHBOOB REHMAN等: "Optimisation of powders for pulmonary delivery using supercritical fluid technology", 《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| NULL: "《化工辞典》", 31 August 1969, 燃料化学工业出版社 * |
| ROBIN K. HARRIS 等: "Characterization of Polymorphs and Solvates of Terbutaline Sulfate", 《CRYSTAL GROWTH & DESIGN》 * |
| 国家药典委员会: "《中华人民共和国药典 2部》", 31 January 2010, 中国医药科技出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115210210A (en) * | 2020-03-02 | 2022-10-18 | 谭文 | Crystalline form of (R) -terbutaline hydrochloride |
| CN112250586A (en) * | 2020-10-21 | 2021-01-22 | 福安药业集团宁波天衡制药有限公司 | Preparation method of terbutaline sulfate and B crystal form thereof |
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Application publication date: 20190709 |