CN101570531A - Gamma-crystalline form of landiolol hydrochloride, preparation method of same and pharmaceutical composition containing same - Google Patents
Gamma-crystalline form of landiolol hydrochloride, preparation method of same and pharmaceutical composition containing same Download PDFInfo
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- CN101570531A CN101570531A CNA2009100161337A CN200910016133A CN101570531A CN 101570531 A CN101570531 A CN 101570531A CN A2009100161337 A CNA2009100161337 A CN A2009100161337A CN 200910016133 A CN200910016133 A CN 200910016133A CN 101570531 A CN101570531 A CN 101570531A
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- landiolol hydrochloride
- landiolol
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Abstract
The invention relates to a gamma-crystalline form of landiolol hydrochloride shown in a general formula (I), a preparation method of the same and a pharmaceutical composition containing the same.
Description
Technical field
The present invention relates to general formula (I) landiolol hydrochloride (landiolol hydrochloride) γ-crystalline form, its preparation method and contain its pharmaceutical composition.
Background technology
Landiolol hydrochloride is a selectivity β1Shou Ti blocker, and main antagonism is present in the β1Shou Ti of heart, increases by the heartbeat number that suppresses to be caused by catecholamine, improves the tachycardia arrhythmia.The emergency treatment of tachycardia arrhythmia (comprising atrial fibrillation, auricular flutter, sinus tachycardia) takes place in the time of can being used for the treatment of operation clinically; Under the postoperative circulation dynamic surveillance to the emergency treatment of (comprising atrial fibrillation, auricular flutter, sinus tachycardia) of tachycardia arrhythmia.
Patent JP3072475 discloses Landiolol and the preparation method and the therepic use of the additive salt that forms with pharmaceutically acceptable acid.
In view of the drug value of this compound, so the most important thing is to obtain to have this compound of splendid purity.In addition importantly can by a kind of method that is easy to change into industrially scalable synthetic it, especially allow to filter fast and the exsiccant form.Finally, this crystalline form must can be reproduced fully, is easy to preparation and enough stable so that its long storage, and the level of temperature, light or oxygen is not had specific requirement.
The synthetic method of Landiolol and hydrochloride thereof has been described among the patent specification JP3072475.Yet the purity of the Landiolol hydrochloride that this documents recrystallization method obtains is not high, and yield is not high yet.
Summary of the invention
The invention provides a kind of γ-crystalline form of stablizing, being easy to the landiolol hydrochloride of commercial scale production.
The invention provides a kind of preparation method of γ-crystalline form of landiolol hydrochloride.
More specifically, the present invention relates to the γ-crystalline form of landiolol hydrochloride, it is characterized in that following x-ray diffractogram of powder, described diffractogram uses the Japanese D/max-rC of company type anode of science to change the target x-ray instrument and measures, and represent according to position of spectral line (Bragg angle 2 θ show with kilsyth basalt), I/IO and minute surface spacing d:
| The spectrum wire size | 2 θ (degree) | I/IO | Spacing (d) |
| 1 | 3.260 | 76 | 27.0796 |
| 2 | 6.580 | 24 | 13.4219 |
| 3 | 9.900 | 100 | 8.9270 |
| 4 | 12.820 | 19 | 6.8995 |
| 5 | 15.540 | 29 | 5.6975 |
| 6 | 16.560 | 78 | 5.3488 |
| 7 | 17.020 | 32 | 5.2052 |
| 8 | 18.460 | 21 | 4.8023 |
| 9 | 19.520 | 26 | 4.5439 |
| 10 | 20.000 | 49 | 4.4359 |
| 11 | 20.640 | 71 | 4.2997 |
| 12 | 21.240 | 41 | 4.1796 |
| 13 | 21.540 | 23 | 4.1221 |
| 14 | 21.940 | 20 | 4.0478 |
| 15 | 23.140 | 68 | 3.8406 |
| 16 | 23.680 | 22 | 3.7542 |
| 17 | 24.660 | 42 | 3.6072 |
| 18 | 25.720 | 29 | 3.4609 |
| 19 | 29.560 | 20 | 3.0194 |
| 20 | 32.940 | 19 | 2.7169 |
γ-the crystalline form of landiolol hydrochloride of the present invention can adopt following method preparation, but this product never only limits to this preparation method: landiolol hydrochloride is dissolved in acetone, adds gac, and reflux 15 minutes, heat filtering is removed gac.Cooling crystallization below 10 ℃ 2 hours filters, and collects product, gets the γ-crystalline form of landiolol hydrochloride of the present invention, yield 82.2%.
Among the γ-crystalline form preparation method of the invention described above landiolol hydrochloride, in the cooling crystallization step, can in cooling fluid, add landiolol hydrochloride, carry out kind of a crystalline substance.
A kind of pharmaceutical composition comprises γ-crystalline form and the described auxiliary material of one or more pharmacy as the landiolol hydrochloride of the present invention of activeconstituents.
γ-the crystalline form of landiolol hydrochloride of the present invention can be used for preparing treatment tachycardia arrhythmia medicine.
The invention still further relates to pharmaceutical composition, comprise γ-crystalline form and one or more suitable inert non-toxic vehicle as the landiolol hydrochloride of activeconstituents.In pharmaceutical composition of the present invention, what more specifically can mention is to be suitable for those tablets of oral, parenteral (intravenously or subcutaneous) or nasal administration or sugar-coat agent, Sublingual tablet, lozenge, suppository, creme, ointment, skin gel, injectable formulation, drinkable suspension.
Useful dosage can change according to the character of disease and severity, route of administration and patient's age and body weight.This dosage changed between 25mg～300mg/ days, in single or divided doses.
For proving technique effect of the present invention, carry out following test, prepare the γ-crystalline form of landiolol hydrochloride of the present invention by embodiment 1 method, measure this product related substance.
Chromatographic condition and system suitability test are weighting agent with octadecylsilane chemically bonded silica; With 0.05mol/L sodium dihydrogen phosphate-methyl alcohol (60: 40) is moving phase, and the detection wavelength is 220nm, and flow velocity is 1.0ml/min.Number of theoretical plate calculates by the landiolol hydrochloride peak and is not less than 2000.
It is an amount of that the determination of related substances method is got this product, add moving phase make contain 1mg among every 1ml solution as need testing solution, precision is measured 1ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, in contrast solution.According to the chromatographic condition under the assay item, get contrast solution 10 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 10%～20% of a full range, precision is measured need testing solution and each 10 μ l of contrast solution again, inject liquid chromatograph respectively, the record color atlas calculates the related substance size to 3 times of principal constituent peak retention time according to external standard method in Chinese Pharmacopoeia appendix (2005 editions) regulation.According to Chinese Pharmacopoeia appendix (2005 editions) regulation, measure product fusing point of the present invention, the result is as follows:
| Project | Fusing point | Retention time (minute) | Related substance (%) |
| The result | 124.3～125.7 | 11.169 | 0.24 |
Specific embodiment
In order to understand the present invention better, the specific embodiment of the invention is explained, but the present invention never only limits to embodiment.
Embodiment 1
Get the landiolol hydrochloride crude product 36g of JP3072475 method preparation, add 360ml acetone, the 3.6g gac.Reflux 15 minutes.Heat filtering is removed gac.Crystallization below 10 ℃ 2 hours.Suction filtration, solid 80ml washing with acetone.40 ℃ of drying under reduced pressure got the γ-crystalline form thing 29.6g of landiolol hydrochloride in 6 hours, and fusing point is 124.3 ℃～125.7 ℃, yield 82.2%.
X-ray powder diffraction figure:
Under following test conditions, measure X-ray powder diffraction spectrum:
The instrument model: the Japanese D/max-rC of company type anode of science changes the target x-ray instrument
Condition: 40kV, 50mA, beam wavelength CuKa
DS=SS=1 °, RS=0.3mm, 0～40.0 ° of sweep limit, 5.0 °/min of scanning speed.
By the important spectral line of putting in order in the following table, provided the X-ray powder diffraction collection of illustrative plates of landiolol hydrochloride γ-crystalline form:
| The spectrum wire size | 2 θ (degree) | I/IO | Spacing (d) |
| 1 | 3.260 | 76 | 27.0796 |
| 2 | 6.580 | 24 | 13.4219 |
| 3 | 9.900 | 100 | 8.9270 |
| 4 | 12.820 | 19 | 6.8995 |
| 5 | 15.540 | 29 | 5.6975 |
| 6 | 16.560 | 78 | 5.3488 |
| 7 | 17.020 | 32 | 5.2052 |
| 8 | 18.460 | 21 | 4.8023 |
| 9 | 19.520 | 26 | 4.5439 |
| 10 | 20.000 | 49 | 4.4359 |
| 11 | 20.640 | 71 | 4.2997 |
| 12 | 21.240 | 41 | 4.1796 |
| 13 | 21.540 | 23 | 4.1221 |
| 14 | 21.940 | 20 | 4.0478 |
| 15 | 23.140 | 68 | 3.8406 |
| 16 | 23.680 | 22 | 3.7542 |
| 17 | 24.660 | 42 | 3.6072 |
| 18 | 25.720 | 29 | 3.4609 |
| 19 | 29.560 | 20 | 3.0194 |
| 20 | 32.940 | 19 | 2.7169 |
Embodiment 2
Prepare 1000 every freeze-dried prescription that contains the 50mg landiolol hydrochloride:
The γ of landiolol hydrochloride-crystalline form thing 50g
N.F,USP MANNITOL 50g
Sodium hydroxide is an amount of
Water for injection adds to 2000ml
According to the common process preparation, promptly.
Claims (5)
1. γ-the crystalline form of the landiolol hydrochloride of general formula (I):
It is characterized in that following x-ray diffractogram of powder, described diffractogram uses the Japanese D/max-rC of company type anode of science to change the target x-ray instrument and measures, and represents according to position of spectral line (Bragg angle 2 θ show with kilsyth basalt), I/IO and spacing d:
2. according to the method for the γ-crystalline form of the landiolol hydrochloride of claim 1, it is characterized in that landiolol hydrochloride is dissolved in acetone, gac reflux 15 minutes.Heat filtering is removed gac.Cooling crystallization below 10 ℃ 2 hours, and by filtering the collection product.
3. according to the method for claim 2, it is characterized in that in the cooling crystallization step, the solution kind crystalline substance of landiolol hydrochloride.
4. pharmaceutical composition is characterized in that comprising γ-crystalline form and the described auxiliary material of one or more pharmacy according to the landiolol hydrochloride of claim 1 as activeconstituents.
γ-the crystalline form of landiolol hydrochloride according to claim 4 in preparation treatment tachycardia arrhythmia medicine in application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100161337A CN101570531A (en) | 2009-06-05 | 2009-06-05 | Gamma-crystalline form of landiolol hydrochloride, preparation method of same and pharmaceutical composition containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100161337A CN101570531A (en) | 2009-06-05 | 2009-06-05 | Gamma-crystalline form of landiolol hydrochloride, preparation method of same and pharmaceutical composition containing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101570531A true CN101570531A (en) | 2009-11-04 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100161337A Pending CN101570531A (en) | 2009-06-05 | 2009-06-05 | Gamma-crystalline form of landiolol hydrochloride, preparation method of same and pharmaceutical composition containing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101570531A (en) |
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2009
- 2009-06-05 CN CNA2009100161337A patent/CN101570531A/en active Pending
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Application publication date: 20091104 |