阅读说明：本技术 一种左西孟旦钠晶型b及其制备方法 (Levosimendan sodium crystal form B and preparation method thereof ) 是由 高建 王刚强 伍伟 刘力超 于 2020-07-23 设计创作，主要内容包括：本发明公开了一种左西孟旦钠晶型B、晶型B的制备方法及其稳定的药物组合物,使用Cu-Kα辐射,以2θ角度表示的X-射线粉末衍射图谱在2θ在12.2°±0.2°、14.6°±0.2°、18.3°±0.2°、27.4°±0.2°、30.0°±0.2°的位置有一处或多处特征衍射峰。本发明左西孟旦钠晶型B收率高达98％。(The invention discloses a levosimendan crystal form B, a preparation method of the crystal form B and a stable pharmaceutical composition thereof, wherein Cu-Kalpha radiation is used, and one or more characteristic diffraction peaks are arranged on an X-ray powder diffraction pattern expressed by a 2 theta angle at the positions of 12.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 18.3 degrees +/-0.2 degrees, 27.4 degrees +/-0.2 degrees and 30.0 degrees +/-0.2 degrees of 2 theta. The yield of the levosimendan crystal form B is up to 98 percent.)

1. Levosimendan sodium in crystalline form B characterized in that: an X-ray powder diffraction pattern expressed by a 2 theta angle has one or more characteristic diffraction peaks at the positions of 12.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 18.3 degrees +/-0.2 degrees, 27.4 degrees +/-0.2 degrees and 30.0 degrees +/-0.2 degrees of 2 theta by using Cu-Kalpha radiation.

2. Crystalline form B of levosimendan sodium according to claim 1 characterized in that: the HPLC purity of the crystal form is not less than 99.8%, and the single impurity content is less than 0.10%.

3. A process for the preparation of levosimendan sodium form B according to any of claims 1 or 2 comprising the steps of:

firstly, adding alkali into a salt-forming solvent to form an alkali salt-forming solvent solution;

adding levosimendan into a salt forming solvent to form a levosimendan salt forming solvent solution;

thirdly, adding the alkali salt forming solvent solution into the levosimendan salt forming solvent solution, and carrying out heat preservation reaction;

fourthly, filtering and washing

And drying to obtain the levosimendan sodium crystal form B.

4. A process for preparing levosimendan sodium form B according to claim 3, characterized in that:

the salifying solvent is an organic solvent or a mixture thereof, and preferably the organic solvent is methanol, ethanol, isopropanol or a mixture thereof; or/and

the alkali is sodium hydroxide, sodium methoxide, sodium ethoxide or a mixture thereof.

5. A process for preparing levosimendan sodium form B according to claim 3, characterized in that:

the third step is adding dropwise; or/and

in the third step, the reaction time is kept; or/and

in the fifth step, the drying is air drying or reduced pressure drying.

6. A pharmaceutical composition comprising: levosimendan sodium form B as active ingredient, and excipients; the pharmaceutical composition is preferably a dry powder.

7. The pharmaceutical composition of claim 6, wherein: the excipient is selected from cyclodextrin, cyclodextrin sodium salt, lactose, mannitol, glucose, disodium hydrogen phosphate, sodium acetate, sodium citrate, phosphoric acid, acetic acid, citric acid or their mixture; preferably, the cyclodextrin is sulfobutyl ether betacyclodextrin, and preferably, the cyclodextrin sodium salt is sulfobutyl ether betacyclodextrin sodium salt; preferably, the disodium hydrogen phosphate is anhydrous disodium hydrogen phosphate.

8. The pharmaceutical composition of claim 7, wherein: the levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 1-50, preferably 1: 10-30, most preferably 1: 12-15; the levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.1-0.45, preferably 1: 0.3-0.4, and most preferably 1: 0.35-0.39.

9. The pharmaceutical composition according to any one of claims 6 to 8, wherein:

the dry powder is used as a clinical pharmaceutical preparation; or

The dry powder is used to treat congestive heart failure or acute decompensated heart failure symptoms (ADHF); or

For administration, the dry powder is reconstituted into a liquid medicament suitable for intravenous administration; or

Reconstituting the dried powder with a solvent to form a liquid medicine, preferably the solvent is an aqueous solution; the aqueous solution is preferably water or an isotonic buffer with the pH value of 5.0-8.0; preferably, the isotonic buffer is an isotonic buffer with a pH value of 7.0-8.0.

10. A method of preparing a dry powder comprising the steps of:

step (1): weighing levosimendan sodium crystal form B and dissolving in water;

step (2): weighing an excipient, dissolving the excipient in the step (1), adding water to a constant volume to reach the total volume, and sterilizing and filtering by using a membrane;

and (3): filling each solution in the step (2) into a plurality of penicillin bottles, freezing and drying, and filling nitrogen to seal the bottles.

Technical Field

The invention relates to the field of pharmaceutical chemistry, and in particular relates to a levosimendan sodium crystal form B and a preparation method thereof.

Background

Levosimendan is the first marketed variety in the new generation of cardiotonic drugs, calcium sensitizers, and is mainly used for treating various acute heart failure diseases clinically. The drug was developed by the company Freon (Orion) in Finland and first marketed in Sweden in l0 month 2000. Levosimendan is currently marketed in several dozen countries, both europe and america. There is no disclosure of the use of levosimendan and its pharmaceutically acceptable salt compounds, particularly levosimendan sodium and its thermostable crystalline forms of levosimendan sodium, in the published literature, and for the treatment of congestive heart failure or acute decompensated heart failure symptoms (ADHF).

Levosimendan is practically insoluble in water and the preparation of levosimendan-containing injections requires the use of high concentrations of ethanol or the use of large amounts of solubilizing agents, such as cyclodextrins. Because absolute ethyl alcohol is a non-aqueous solvent used for assisting dissolution of levosimendan, although an isotonic solution such as a 5% glucose injection is used after dilution in clinical application, in the dilution process, levosimendan is easily separated out due to the fact that the concentration of absolute ethyl alcohol is diluted, particulate matters in liquid medicine exceed the standard, the safety of clinical medication is affected, and meanwhile, the liquid medicine containing the ethyl alcohol is subjected to intravenous drip, and muscle and blood vessel irritation is caused, and hemolysis is seriously caused.

Although the preparation of levosimendan injection can be achieved by using solubilizing agents such as sulfobutylbetacyclodextrin, the amount of such solubilizing agents is generally very high, and the effect and amount of cyclodextrin-based products are known to be closely related to the safety of the human body, and such high dosage amounts also pose a safety risk.

Disclosure of Invention

In view of the above problems, the present invention provides levosimendan sodium having a good solubility in water, which solves the problem of insolubility of levosimendan in water, which can prevent irritation and hemolysis caused by the use of ethanol as a solvent in levosimendan injection solutions, and which can reduce the amount of a solubilizing agent such as cyclodextrin or can obtain a clinically administrable concentration of levosimendan aqueous solution without the use of a solubilizing agent.

Levosimendan sodium, chemically known as (R) - [ [4- (1,4,5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl ] hydrazono ] malononitrile sodium, of formula I:

the technical problem in the background art can be solved by adopting the levosimendan sodium of the invention. Levosimendan sodium has a solubility in water of the order of dissolution and a drug concentration after dissolution of about 1g/20 ml.

On one hand, the invention also provides a levosimendan crystal form B which has better solubility in water, completely solves the problem that levosimendan is insoluble in water, and can avoid irritation and hemolysis caused by using ethanol as a solvent in levosimendan injection.

The technical scheme is as follows: levosimendan sodium crystal form B has one or more characteristic diffraction peaks at the positions of 12.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 18.3 degrees +/-0.2 degrees, 27.4 degrees +/-0.2 degrees and 30.0 degrees +/-0.2 degrees of 2 theta in an X-ray powder diffraction pattern expressed by the angle of 2 theta by using Cu-Kalpha radiation.

Preferably, the HPLC purity of the crystal form is greater than or equal to 99.8%, and the single impurity content is less than 0.10%.

In one aspect, the present invention also provides a process for preparing levosimendan sodium in crystal form B as described above.

The technical scheme is as follows: a process for preparing levosimendan sodium in crystalline form B as described above, comprising the steps of:

firstly, adding alkali into a salt-forming solvent to form an alkali salt-forming solvent solution;

adding levosimendan into a salt forming solvent to form a levosimendan salt forming solvent solution;

thirdly, adding the alkali salt forming solvent solution into the levosimendan salt forming solvent solution, and carrying out heat preservation reaction;

fourthly, filtering and washing

And drying to obtain the levosimendan sodium crystal form B.

Preferably, the salt-forming solvent is an organic solvent or a mixture thereof, and preferably the organic solvent is methanol, ethanol, isopropanol or a mixture thereof.

Preferably, the base is sodium hydroxide, sodium methoxide, sodium ethoxide or a mixture thereof.

Preferably, the addition in the third step is dropwise addition.

Preferably, in the third step, the reaction is carried out for a heat-preserving reaction time.

Preferably, in the fifth step, the drying is air drying or reduced pressure drying.

In one aspect, the invention also provides a pharmaceutical composition.

The technical scheme is as follows: a pharmaceutical composition comprising: levosimendan sodium form B as active ingredient, and excipients; the pharmaceutical composition is preferably a dry powder.

Preferably, the excipient is selected from cyclodextrin, cyclodextrin sodium salt, lactose, mannitol, glucose, disodium hydrogen phosphate, sodium acetate, sodium citrate, phosphoric acid, acetic acid, citric acid or a mixture thereof; .

Preferably, the cyclodextrin is sulfobutyl ether betacyclodextrin.

Preferably, the cyclodextrin sodium salt is sulfobutyl ether betacyclodextrin sodium salt. .

Preferably, the disodium hydrogen phosphate is anhydrous disodium hydrogen phosphate.

Preferably, the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 1-50.

Preferably, the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 10-30.

Preferably, the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 12 to 15.

Preferably, the ratio of levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.1-0.45.

Preferably, the ratio of levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.3-0.4.

Preferably, the ratio of levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.35-0.39.

Preferably, the dry powder is used as a clinical pharmaceutical preparation.

Preferably, the dry powder is used to treat congestive heart failure or acute decompensated heart failure symptoms (ADHF).

Preferably, for administration, the dry powder is reconstituted into a liquid medicament suitable for intravenous administration.

Preferably, the dry powder is reconstituted with a solvent to form a liquid medicine, preferably the solvent is an aqueous solution; the aqueous solution is preferably water or an isotonic buffer with the pH value of 5.0-8.0; preferably, the isotonic buffer is an isotonic buffer with a pH value of 7.0-8.0.

In one aspect, the invention also provides a method of preparing a dry powder.

The technical scheme is as follows: a method of preparing a dry powder comprising the steps of:

step (1): weighing levosimendan sodium crystal form B and dissolving in water;

step (2): weighing an excipient, dissolving the excipient in the step (1), adding water to a constant volume to reach the total volume, and sterilizing and filtering by using a membrane;

and (3): filling each solution in the step (2) into a plurality of penicillin bottles, freeze-drying, filling nitrogen, and sealing.

The principle and the beneficial effects of the invention are as follows:

levosimendan is insoluble in water and soluble in ethanol. The absolute ethyl alcohol is a non-aqueous solvent used for assisting dissolution of levosimendan, although an isotonic solution such as 5% glucose injection is used after dilution in clinical application, in the dilution process, levosimendan is easily separated out due to the fact that the concentration of the absolute ethyl alcohol is diluted, particulate matters in liquid medicine exceed the standard, the safety of clinical medication is affected, and meanwhile, the liquid medicine containing the ethyl alcohol is subjected to intravenous drip, so that muscle and blood vessel irritation is caused, and hemolysis is seriously caused. The crystalline levosimendan sodium crystal form B prepared by the invention has obvious advantages in the aspect of water solubility, solves the problem of water solubility, can avoid the use of ethanol in preparation production, and avoids the irritation and hemolysis caused by using ethanol as a solvent in levosimendan injection.

Compared with the levosimendan crystal form A, the preparation method comprises the steps of firstly adding a base into a salt forming solvent to form a base salt forming solvent solution, adding levosimendan into the salt forming solvent to form a levosimendan salt forming solvent solution, then adding the base salt forming solvent solution into the levosimendan salt forming solvent solution, carrying out heat preservation reaction, wherein the yield is up to 98%, the redissolving time of freeze-dried powder prepared from the levosimendan crystal form B is only 90 seconds, the particle size of the solution is 32 particles with the particle size of 10μm, the particle size of 25μm is 0, and the OR-1420 is only 0.151%.

Drawings

Figure 1 is an X-ray powder diffraction pattern of levosimendan sodium crystalline form B;

figure 2 is an HPLC purity profile of levosimendan sodium crystalline form B;

figure 3 is an X-ray powder diffraction pattern of levosimendan sodium form a;

figure 4 is an HPLC purity profile of levosimendan sodium form a.

Detailed Description

The invention will be further explained with reference to the drawings.

The examples provided herein are merely to further illustrate the invention and should not be construed as limiting the invention in any way.

It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified, in the following.

The invention relates to an X-ray powder diffraction detection instrument, which comprises the following parts: DX-2700B X-ray powder diffractometer

The test method comprises the following steps: the sample is filled in the blind hole sample plate, and the sample is lightly pressed by a glass slide, so that the surface of the sample in the window hole is completely on the same plane with the surface of the sample plate. And inserting the prepared sample plate on a sample table of a diffractometer goniometer for scanning. A copper X-ray source of 40KV and 40mA is used, the scanning angle is 3-53 degrees (2 theta), and the scanning speed is 0.05 degrees/second.