CN101768117B - New crystalline form of hydrochloric acid Ivabradine and preparation method thereof - Google Patents
New crystalline form of hydrochloric acid Ivabradine and preparation method thereof Download PDFInfo
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- CN101768117B CN101768117B CN200810246548.9A CN200810246548A CN101768117B CN 101768117 B CN101768117 B CN 101768117B CN 200810246548 A CN200810246548 A CN 200810246548A CN 101768117 B CN101768117 B CN 101768117B
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- hydrochloric acid
- acid ivabradine
- crystalline form
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- ivabradine
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Abstract
The invention discloses a new crystalline form of hydrochloric acid Ivabradine and a preparation method thereof. A mixture of the hydrochloric acid Ivabradine, methanol and acetone is heated to be completely dissolved, natural stewing is carried out for complete crystallization, and products are collected through filtration so as to obtain the new crystalline form of the hydrochloric acid Ivabradine.
Description
Technical field
The present invention relates to new crystalline form of Ivabradine hydrochloride and preparation method thereof.
Background technology
S 16257-2 and the additive salt forming with pharmaceutically acceptable acid thereof, more specifically for its hydrochloride has very valuable pharmacology and treat characteristic, especially decreasing heart rate (bradycardic) characteristic, thereby these compounds be used for the treatment of or prevent the various clinical settings of myocardial ischemia as stenocardia, myocardial infarction and relevant arhythmicity, and relating to the various pathologic conditions of arhythmicity, especially supraventricular arhythmicity and heart failure.
Additive salt that S 16257-2 and pharmaceutically acceptable acid thereof forms, more particularly preparation and the therepic use of its hydrochloride have been described in European patent specification EP 0534859.
In view of the drug value of this compound, so the most important thing is to obtain this compound with splendid purity.In addition importantly can by a kind of method that is easy to change into industrially scalable synthetic it, especially allow fast filtering and dry form.Finally, this crystalline form must can be reproduced completely, is easy to configuration and enough stablizes so that it is stored for a long time, and the level of temperature, light or oxygen is not had to specific requirement.
Synthetic method for S 16257-2 and hydrochloride thereof has been described in patent specification EP 0534859.Yet this documents does not describe in detail for can playback system to obtain the condition of the S 16257-2 form that shows those features.Yet French Se Weier company recrystallization condition in the patent CN200610132230 of China's application and CN200610132229 adopt EP 0534859 has equally obtained the δ d of hydrochloric acid Ivabradine and two kinds of new crystal formations of the δ of crystal water form; French Se Weier company has applied for that in China patent CN200610058078, CN200610058077, CN200610058074, CN200610058076 and CN200510051779 have protected respectively γ, γ d, β d, β and α-five kind of the new crystal formation of hydrochloric acid Ivabradine in addition.
Summary of the invention
The object of the present invention is to provide a kind of new crystalline form and preparation method thereof of new hydrochloric acid Ivabradine, it is different from all openly new crystal habits of crystal formation, its sharp outline, can be perfect online, and with regard to filtering, with regard to dry, stability, method preparation and workability, it shows valuable feature, can be used as the purposes in the medicine of bradycardic.
New crystalline form of hydrochloric acid Ivabradine provided by the invention, its x-ray diffractogram of powder, described diffractogram is used Rigaku RigakuD/MAXRC diffractometer to measure, and according to position of spectral line (Bragg angle 2 θ, with degree, represent), the line width (" FWHM ", to spend expression) of height of spectral line (to count expression), spectral line area (to count * to spend expression), half eminence and spacing d (with
represent).
The present invention also provides the preparation method of new crystalline form of hydrochloric acid Ivabradine, use the mixture heating of crystal or unformed hydrochloric acid Ivabradine and methyl alcohol and acetone, until dissolve completely naturally standing crystallization, until crystallization is complete, and by overanxious collection product.
The present invention also provide a kind of prepare hydrochloric acid Ivabradine without the method for determining crystal formation, hydrochloric acid Ivabradine is complete with dissolve with methanol, and solvent evaporated is collected product.
The present invention also provides a kind of pharmaceutical composition, that described pharmaceutical composition comprises is suitable as the new crystalline form of hydrochloric acid Ivabradine of the present invention of activeconstituents and one or more, inertia and nontoxic vehicle, can be oral for being suitable for, the tablet of parenteral (intravenously or subcutaneous) or nasal administration or drageeing, tablet, capsule, lozenge, suppository, frost, ointment, skin gel, injectable formulation, citable suspension for hypogloeeis.
Accompanying drawing explanation
The accompanying drawing that the application comprises is a component part of specification sheets, and accompanying drawing and specification sheets and claims one are used from flesh and blood of the present invention, for understanding better the present invention.
Fig. 1: the X-ray powder diffraction spectrum of Ivabradine hydrochloride crystal formation W.
Embodiment
The analytical instrument that the following example adopts, X-ray Japan Ricoh RigakuD/MAXRC type powder crystal diffractometer
The hydrochloric acid Ivabradine of embodiment 1:W-crystallized form
Ivabradine hydrochloride 1.0g is joined in 30mL acetone and 2mL methyl alcohol and refluxes and dissolve, the standing crystallization of filtrate.Then filter, consider a small amount of washing with acetone of cake.Consider cake in 85 ℃ of vacuum-dryings to constant weight.Obtain crystal formation W sample 0.85g.Fusing point 196.5-197.7 ℃.
X-ray diffractogram of powder is shown in figure (1).
Embodiment 2: pharmaceutical composition
For the preparation of 1000 tablets of tablets, every tablet of tablet that tablet contains 5mg S 16257-2 alkali wherein, adopt the compound 5.39g of following prescription embodiment 1, lactose 60.0g, Microcrystalline Cellulose 20.0g, magnesium stearate 1.0g, starch 13.61g, and prepare by conventional tablet preparation technology.
Claims (1)
1. a method of preparing hydrochloric acid Ivabradine crystal formation, it is characterized in that the mixture heating of hydrochloric acid Ivabradine and methyl alcohol and acetone, until dissolve completely, naturally standing crystallization, until crystallization is complete, and by overanxious collection product, described S 16257-2 crystal formation has substantially X-ray powder diffraction figure as shown in Figure 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810246548.9A CN101768117B (en) | 2008-12-29 | 2008-12-29 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810246548.9A CN101768117B (en) | 2008-12-29 | 2008-12-29 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101768117A CN101768117A (en) | 2010-07-07 |
| CN101768117B true CN101768117B (en) | 2014-05-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810246548.9A Expired - Fee Related CN101768117B (en) | 2008-12-29 | 2008-12-29 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012025940A1 (en) * | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Polymorphic form of ivabradine hydrochloride and process for preparation thereof |
| CN102731400A (en) * | 2011-04-11 | 2012-10-17 | 山东新时代药业有限公司 | Novel ivabradine hydrochloride crystal form and its preparation method and use in preparation of pharmaceutical composition |
| EP2589594A1 (en) * | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
| CN103012269B (en) * | 2013-01-05 | 2014-08-13 | 江苏宇田生物医药科技有限公司 | Novel ivabradine hydrochloride crystal form C and preparation method thereof |
| CN107056706B (en) * | 2015-12-21 | 2020-05-05 | 江苏恒瑞医药股份有限公司 | Method for preparing ivabradine hydrochloride α crystal form |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN1683341A (en) * | 2004-04-13 | 2005-10-19 | 瑟维尔实验室 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN1948293A (en) * | 2005-10-11 | 2007-04-18 | 瑟维尔实验室 | Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it |
| CN101284813A (en) * | 2007-04-12 | 2008-10-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
-
2008
- 2008-12-29 CN CN200810246548.9A patent/CN101768117B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN1683341A (en) * | 2004-04-13 | 2005-10-19 | 瑟维尔实验室 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN1948293A (en) * | 2005-10-11 | 2007-04-18 | 瑟维尔实验室 | Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it |
| CN101284813A (en) * | 2007-04-12 | 2008-10-15 | 上海优拓医药科技有限公司 | Preparation method of ivabradine |
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| CN101768117A (en) | 2010-07-07 |
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