CN102731400A - Novel ivabradine hydrochloride crystal form and its preparation method and use in preparation of pharmaceutical composition - Google Patents
Novel ivabradine hydrochloride crystal form and its preparation method and use in preparation of pharmaceutical composition Download PDFInfo
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- CN102731400A CN102731400A CN2011100945318A CN201110094531A CN102731400A CN 102731400 A CN102731400 A CN 102731400A CN 2011100945318 A CN2011100945318 A CN 2011100945318A CN 201110094531 A CN201110094531 A CN 201110094531A CN 102731400 A CN102731400 A CN 102731400A
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Abstract
The invention relates to a novel ivabradine hydrochloride crystal form and its preparation method and use in preparation of a pharmaceutical composition. The preparation method comprises the following steps of carrying out heating reflux stirring of a mixture of ivabradine hydrochloride and anhydrous ethanol, or a mixture of ivabradine hydrochloride, anhydrous ethanol and ethyl acetate until complete dissolution, stopping heating, carrying out natural cooling and stirring for crystallization, and after complete crystallization, carrying out pumping filtration collection of products. The novel ivabradine hydrochloride crystal form can treat or prevent various local myocardial ischemia clinical symptoms such as angina, myocardial infarction and accompanying rhythmic disorder, and also can treat or prevent symptoms related to rhythmic disorder and especially to supraventricular rhythmic disorder.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of new crystal, preparation method and purposes in pharmaceutical compositions thereof of hydrochloric acid Ivabradine.
Background technology
Hydrochloric acid Ivabradine (Ivabradine hydrochloride); [[[(8S)-3,4-dimethoxy-8-dicyclo [4.2.0] hot-1,3 for 3-for chemical name: 3-; The 5-triolefin] methyl-methylamino-] propyl group]-7; 8-dimethoxy-2,5-dihydro-1H-3-benzazepine-4-keto hydrochloride, chemical structural formula is following:
Hydrochloric acid Ivabradine is first selectivity and the specificity If channel blocker by the exploitation of French Shi Weiya company; Have simple reduction heart rate function, be used to treat symptomatic treatment with normal sinus rhythm, taboo maybe can not tolerate to the b receptor-blocking agent chronic stable angina pectoris.A plurality of countries listing in Europe at present; Have very valuable pharmacological and therapeutic action; Especially the performance of decreasing heart rate makes these compounds be used to treat or prevent the various clinical manifestations of myocardial ischaemia, like stenocardia; Myocardial infarction and the RD of following; But also be used for treatment or prevent various relate to particularly supraventricular RD of RD and heart failure, but to QTc, PR interval, the not effect of QRS interval, do not influence the parameters such as conductivity and refractory phase of atrium, atrioventricular node, Xi Shi-Purkinje system, ventricle yet.Zooperal research shows, S 16257-2 can improve kinetic myocardial ischemia and consequent cardiac muscle effectively to be pressed down time, and its interaction energy is cancelled by rapid pacing, and this explanation S 16257-2 is to improve myocardial ischemia through reducing heart rate.
The preparation and the medical use of additive salt, especially its hydrochloride of having described S 16257-2 among the EP0534859 and having formed with pharmaceutically acceptable acid; The method of synthesis of ivabradine and hydrochloride thereof; Yet EP0534859 and early stage U.S. Pat 5296428 are all used acetonitrile crystalline method; But crystal formation is not had detailed description, and the crystal of this method preparation is an imperfect crystal, poor stability, is difficult to reappear; And it is bigger to adopt acetonitrile to make solvent toxicity, suitable not medicinal.
Servier Lab had applied for new a series of patents such as CN200510051799.0, CN200610058074.6, CN200610058076.5, CN200610058077.X, CN200610058078.4, CN200610132229.6 and CN200610132230.9 in China again afterwards; The alpha-crystal form that said patent such as CN200510051779.0 obtain with N-Methyl pyrrolidone and toluene crystallization, used toluene toxicity is big, and the N-Methyl pyrrolidone boiling point is high, defective such as is difficult to remove; The crystal formation that CN200610058078.4, CN200610132229.6 and CN200610132230.9 obtain is all moisture; Raw material contains water excess can influence its stability; Need the after drying dehydration; Integrity to the gained crystal formation is unfavorable with stability, and the preparation process is loaded down with trivial details, and is not open comprehensively to fusing point, DTA and thermal weight loss and the physico-chemical property of prepared crystal formation.
CN200710044290.6 provides a kind of stable crystal formation and preparation method who relates to hydrochloric acid Ivabradine.Reproduce its preparation method through said experiment condition; Its used cooking process is difficult to the hydrochloric acid Ivabradine solid is dissolved entirely; And institute's crystal formation flowability is relatively poor, is difficult to realize the described technique effect of invention, still is that crystal formation obtains all difficult convincing from refining purity; The N-Methyl pyrrolidone of wherein using also exists boiling point high, the technical problem that is difficult to remove.
Summary of the invention
Consider the pharmacy value of this compound; It is extremely important to obtain highly purified this compound stability crystal formation; The present invention provides the crystal formation that a kind of hydrochloric acid Ivabradine purity is high, stability is strong; Can realize industrialization production very easily through a kind of industrially scalable and preparation method who practices thrift cost of being easy to; The technical problem that the present invention will solve is that the method through the inexpensive solvent recrystallization of low toxicity obtains that purity is splendid, crystal formation fully, enough stablize, Ivabradine crystal that granularity is moderate, and have enough stability, be beneficial to prolonged storage and temperature, illumination and oxygen are not had special requirement.
The applicant stablizes crystal formation through a large amount of experimental study discovery hydrochloric acid Ivabradines and can obtain with the form of confirming fully, and it shows valuable stability and workability characteristic.
The present invention provides a kind of new crystal of hydrochloric acid Ivabradine, relate to new crystal have following characteristic, its X ray diffracting spectrum representes to have the following characteristics peak with 2 θ: 14.5 ± 0.2,17.1 ± 0.2,18.1 ± 0.2,21.4 ± 0.2 characteristic peak; Further has 14.5 ± 0.2,17.1 ± 0.2,18.1 ± 0.2,21.4 ± 0.2,23.9 ± 0.2,26.3 ± 0.2 characteristic peak; Further has 8.5 ± 0.2,11.6 ± 0.2,14.5 ± 0.2,15.1 ± 0.2,17.1 ± 0.2,18.1 ± 0.2,21.4 ± 0.2,23.9 ± 0.2,26.3 ± 0.2,27.0 ± 0.2 characteristic peak.
Instrument: Japanese motor of science (Rigaku) D/max-γ B powder x-ray diffraction
Condition: use Cu K alpha-ray, divergency is 1 °, and nephelometric turbidity unit is 1 °, voltage 40kV, and electric current 100mA, sweep velocity 4 degree/minute, 0.02 ° at interval.
With position of spectral line (Bragg angle 2 θ; Show with kilsyth basalt), the line width (" FWHM " shows with kilsyth basalt) and the spacing (representing with
) of height of spectral line (with counting expression), spectral line area (showing with counting * kilsyth basalt), half eminence represent like following table:
The new crystal of the hydrochloric acid Ivabradine that the present invention relates to, its differential thermal collection of illustrative plates are presented at 160～210 ℃ and are single absorption peak.
Its fusing point of the new crystal of the hydrochloric acid Ivabradine that the present invention relates to is 195～198 ℃, is decomposing more than 210 ℃;
Its thermal weight loss collection of illustrative plates demonstration of the new crystal of the hydrochloric acid Ivabradine that the present invention relates to does not contain crystal water or solvent.
The new crystal of the hydrochloric acid Ivabradine that the present invention relates to is highly stable to humiture and illumination, helps the storage of bulk drug and preparation.
The present invention also provides the preparation method 1 of the new crystal of hydrochloric acid Ivabradine; Mixture heating up with hydrochloric acid Ivabradine and absolute ethyl alcohol; Until dissolving fully; After cooling and stirring crystallization to 20～30 ℃, stirring and crystallizing 2～3h under 0～5 ℃ of ice-water bath, and collect through suction filtration and to obtain product.The solvent absolute ethyl alcohol is 1～10: 1 with the volume mass ratio of hydrochloric acid Ivabradine, preferred 1～5: 1.
The present invention also provides the preparation method 2 of the new crystal of hydrochloric acid Ivabradine; Mixture heating up with hydrochloric acid Ivabradine and absolute ethyl alcohol and ETHYLE ACETATE; Until dissolving fully; After cooling and stirring crystallization to 20～30 ℃, stirring and crystallizing 2～3h under 0～5 ℃ of ice-water bath, and collect through suction filtration and to obtain product.Absolute ethyl alcohol is 1: 0～20 with ETHYLE ACETATE mixed volume ratio, preferred 1: 0.25～4.Absolute ethyl alcohol and ETHYLE ACETATE mixed solvent are 1～10: 1 with the volume mass ratio of hydrochloric acid Ivabradine, preferred 1～5: 1.
In crystallization method of the present invention, can use the hydrochloric acid Ivabradine that obtains by any method, the hydrochloric acid Ivabradine that for example obtains by the preparation method described in the patent specification EP0534859.
The invention still further relates to pharmaceutical composition, said pharmaceutical composition comprise as the S 16257-2 crystal formation of the present invention of activeconstituents and one or more suitable, inertia and nontoxic vehicle.In pharmaceutical composition of the present invention, possibly to should be mentioned that more especially that those are suitable for pharmaceutical dosage forms such as tablet oral or other form of medication, capsule, suppository, injection and suspension.Doses available can be according to the character and the severity of disease, and drug delivery route and patient's age and body weight are and different, and dosage changed between every day 1 to 500mg, can the single or multiple administration.
The present invention is the pharmaceutical composition of activeconstituents with this compound; Can be used for treating or preventing the various clinical manifestations of myocardial ischaemia; Like stenocardia, myocardial infarction and the RD followed, but also be used for treatment or prevent various relate to particularly supraventricular RD of RD and heart failure.
Description of drawings
Fig. 1: hydrochloric acid Ivabradine infrared absorption spectrum
Fig. 2: a kind of x-ray diffractogram of powder spectrum of new crystal of hydrochloric acid Ivabradine
Fig. 3: a kind of differential scanning calorimetric collection of illustrative plates of new crystal of hydrochloric acid Ivabradine
Fig. 4: a kind of thermal weight loss collection of illustrative plates of new crystal of hydrochloric acid Ivabradine
Embodiment
Further describe technique effect of the present invention with embodiment at present; Be interpreted as that embodiment of the present invention only is used for the purpose of illustration; Do not limit protection domain of the present invention, those skilled in the art are also contained within the present invention conspicuous change of the present invention and modification.
Embodiment 1:
Hydrochloric acid Ivabradine 100g is stirred to whole dissolvings with absolute ethyl alcohol 200ml reflux, stops heating, the cooling and stirring crystallization naturally cools to after 21 ℃, and stirring and crystallizing is 2 hours under 1 ℃ of ice-water bath.Suction filtration after crystallization finishes, with a small amount of absolute ethyl alcohol drip washing filter cake, filter cake places 65 ℃ of vacuum drying ovens to be dried to constant weight, gets a kind of hydrochloric acid Ivabradine of new crystal, and purity is greater than 99.90%.
Embodiment 2:
Hydrochloric acid Ivabradine 100g is stirred to whole dissolvings with absolute ethyl alcohol 400ml reflux, stops heating, the cooling and stirring crystallization naturally cools to after 26 ℃, and stirring and crystallizing is 3 hours under 0 ℃ of ice-water bath.Suction filtration after crystallization finishes, with a small amount of absolute ethyl alcohol drip washing filter cake, filter cake places 70 ℃ of vacuum drying ovens to be dried to constant weight, gets a kind of hydrochloric acid Ivabradine of new crystal, and purity is greater than 99.89%.
Embodiment 3:
Hydrochloric acid Ivabradine 100g is stirred to whole dissolvings with ETHYLE ACETATE and absolute ethyl alcohol (3: 1) 800ml reflux, stops heating, the cooling and stirring crystallization naturally cools to after 25 ℃, stirring and crystallizing 2h under 1 ℃ of ice-water bath.Suction filtration after crystallization finishes, with amount of ethyl acetate drip washing filter cake, filter cake places 71 ℃ of vacuum drying ovens to be dried to constant weight, gets a kind of new crystal hydrochloric acid Ivabradine, and purity is greater than 99.8%.
Embodiment 4:
Hydrochloric acid Ivabradine 100g is stirred to whole dissolvings with ETHYLE ACETATE and absolute ethyl alcohol (1: 1) 400ml reflux, stops heating, the cooling and stirring crystallization naturally cools to after 23 ℃, stirring and crystallizing 3h under 1 ℃ of ice-water bath.Suction filtration after crystallization finishes, with amount of ethyl acetate drip washing filter cake, filter cake places 70 ℃ of vacuum drying ovens to be dried to constant weight, gets a kind of new crystal hydrochloric acid Ivabradine, and purity is greater than 99.76%.
Embodiment 5:
Hydrochloric acid Ivabradine 100g is stirred to whole dissolvings with ETHYLE ACETATE and absolute ethyl alcohol (1: 2) 300ml reflux, stops heating, the cooling and stirring crystallization naturally cools to after 23 ℃, stirring and crystallizing 3h under 1 ℃ of ice-water bath.Suction filtration after crystallization finishes, with amount of ethyl acetate drip washing filter cake, filter cake places 70 ℃ of vacuum drying ovens to be dried to constant weight, gets a kind of new crystal hydrochloric acid Ivabradine, and purity is greater than 99.85%.
Embodiment 6: pharmaceutical composition
It is following to prepare 1000 every tablet formulation that contains 5mg S 16257-2 alkali:
Claims (9)
1. the crystal formation of a hydrochloric acid Ivabradine, its spy is that the powder x-ray diffraction parameter is following:
With position of spectral line (Bragg angle 2 θ; Show with kilsyth basalt), the line width (" FWHM " shows with kilsyth basalt) and the spacing (representing with
) of height of spectral line (with counting expression), spectral line area (showing with counting * kilsyth basalt), half eminence represent like following table:
2. the crystal formation of a kind of hydrochloric acid Ivabradine according to claim 1 is characterized in that its X ray diffracting spectrum representes to have the following characteristics peak with 2 θ: 14.5 ± 0.2,17.1 ± 0.2,18.1 ± 0.2,21.4 ± 0.2; Further has 14.5 ± 0.2,17.1 ± 0.2,18.1 ± 0.2,21.4 ± 0.2,23.9 ± 0.2,26.3 ± 0.2 characteristic peak; Further has 8.5 ± 0.2,11.6 ± 0.2,14.5 ± 0.2,15.1 ± 0.2,17.1 ± 0.2,18.1 ± 0.2,21.4 ± 0.2,23.9 ± 0.2,26.3 ± 0.2,27.0 ± 0.2 characteristic peak.
3. the crystal formation of a kind of hydrochloric acid Ivabradine according to claim 1 is characterized in that its differential thermal collection of illustrative plates is presented at 160～210 ℃ and is single absorption peak.
4. the crystal formation of a kind of hydrochloric acid Ivabradine according to claim 1 is characterized in that its differential thermal collection of illustrative plates shows that fusing point is 195～198 ℃, is decomposing more than 210 ℃.
5. the preparation method of the crystal formation of the described hydrochloric acid Ivabradine of claim 1 comprises following steps:
Mixture heating up with hydrochloric acid Ivabradine and absolute ethyl alcohol; Until dissolving fully; After cooling and stirring crystallization to 20～30 ℃; Stirring and crystallizing 2～3h under 0～5 ℃ of ice-water bath, and collect through suction filtration and to obtain product, wherein the solvent absolute ethyl alcohol is 1～5: 1 with the volume mass ratio of hydrochloric acid Ivabradine.
6. the preparation method of the crystal formation of the described hydrochloric acid Ivabradine of claim 1 comprises following steps:
Mixture heating up with hydrochloric acid Ivabradine and absolute ethyl alcohol and ETHYLE ACETATE; Until dissolving fully; After cooling and stirring crystallization to 20～30 ℃, stirring and crystallizing 2～3h under 0～5 ℃ of ice-water bath, and collect through suction filtration and to obtain product; Wherein the mixed solvent of ethanol and ETHYLE ACETATE is 1～5: 1 with the volume mass ratio of hydrochloric acid Ivabradine, and absolute ethyl alcohol is 1: 0.25～4 with ETHYLE ACETATE mixed volume ratio.
7. the pharmaceutical composition of treatment or prevention myocardial ischaemia is characterized in that containing the crystal formation of the described hydrochloric acid Ivabradine of claim 1.
8. like the said pharmaceutical composition of claim 7, it is characterized in that it is tablet, capsule, suppository, injection or suspension.
9. the crystal formation of the described hydrochloric acid Ivabradine of claim 1 is used for treating or preventing the purposes of myocardial ischaemia medicine in preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100945318A CN102731400A (en) | 2011-04-11 | 2011-04-11 | Novel ivabradine hydrochloride crystal form and its preparation method and use in preparation of pharmaceutical composition |
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| CN2011100945318A CN102731400A (en) | 2011-04-11 | 2011-04-11 | Novel ivabradine hydrochloride crystal form and its preparation method and use in preparation of pharmaceutical composition |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012269A (en) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | Novel ivabradine hydrochloride crystal form C and preparation method thereof |
| CN107056706A (en) * | 2015-12-21 | 2017-08-18 | 江苏恒瑞医药股份有限公司 | A kind of method for preparing hydrochloric acid Ivabradine alpha-crystal form |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2008146308A2 (en) * | 2007-05-30 | 2008-12-04 | Ind-Swift Laboratories Limited | Process for the preparation of ivabradine hydrochloride and polymorph thereof |
| CN101768117A (en) * | 2008-12-29 | 2010-07-07 | 北京德众万全药物技术开发有限公司 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
-
2011
- 2011-04-11 CN CN2011100945318A patent/CN102731400A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2008146308A2 (en) * | 2007-05-30 | 2008-12-04 | Ind-Swift Laboratories Limited | Process for the preparation of ivabradine hydrochloride and polymorph thereof |
| CN101768117A (en) * | 2008-12-29 | 2010-07-07 | 北京德众万全药物技术开发有限公司 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012269A (en) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | Novel ivabradine hydrochloride crystal form C and preparation method thereof |
| 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 |
| CN107056706A (en) * | 2015-12-21 | 2017-08-18 | 江苏恒瑞医药股份有限公司 | A kind of method for preparing hydrochloric acid Ivabradine alpha-crystal form |
| 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 |
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Application publication date: 20121017 |