CN109265406B - New crystal form of Sacubitril valsartan sodium and preparation method and application thereof - Google Patents

Abstract

The invention relates to a new crystal form of Sacubitril valsartan sodium, a preparation method and application thereof. The new crystal form greatly improves the hygroscopicity of the existing crystal form of the salubrozole valsartan sodium, has good fluidity of medicinal preparations, has high product purity which can reach more than 99.5 percent, can be used for preparing tablets with three specifications by adopting a direct tabletting process, has simple process, can greatly shorten the production time and reduce the cost, and is suitable for preparing various stable medicinal preparations.

Description

New crystal form of Sacubitril valsartan sodium and preparation method and application thereof

Technical Field

The patent relates to the technical field of medicines, in particular to a new crystal form of Sacubitril valsartan sodium, a preparation method and application thereof.

Technical Field

The chemical name of the sodium sacubitril valsartan (the structural formula is shown in a formula I) is octadecasodium hexa (4- { [ (1S,3R) -1- ([1,1' -biphenyl) -4-ylmethyl) -4-ethoxy-3-methyl-4-oxobutyl]Amino } -4-oxobutanoic acid) hexa (N-pentanoyl-N- { [2' - (1H-tetrazol-5-yl) biphenyl-4-yl]Methyl } -L-valine)) was developed by Nowa pharmaceutical Co., Ltd under the trade name Nooxin

Is an enkephalinase (Neprilysin) inhibitorCo-crystal drug of Sacubitril and valsartan, an angiotensin II receptor blocker (ARB), suitable for reducing the risk of cardiovascular death and hospitalization for heart failure and reducing the ejection fraction in patients with chronic heart failure. The variety obtains FDA approval to be listed in 2015 for 7 months, European Union approval to be listed in 2015 for 11 months, and China CFDA approval to be listed in 2017 months. The valsartan sodium molecule is a supermolecule eutectic formed by crystallization of 6 valsartan sodium molecules, 6 valsartan sodium molecules and 15 water molecules. The valsartan sodium of Sacubitril has the characteristics of relatively viscous property, easy moisture absorption, poor fluidity and the like, so that the compressibility is poor in the preparation process of the tablet, the components are easily layered, direct tabletting is difficult, and the industrial production of a preparation process is not facilitated.

For this reason, it has been prepared in a crystalline form to improve physicochemical properties. Chinese patent application CN200680001733.0 discloses a crystalline form of sabotartan sodium, the XRD spectrum of which comprises the following lattice plane spacings:

21.2，17.0，7.1，5.2，4.7，4.6，4.2，3.5，3.3。

chinese patent application CN201510422360.5 provides a crystalline form II of sabotara valsartan sodium.

Chinese patent application CN201580002782.5 provides crystalline form I, crystalline form II and crystalline form III of valsartan sodium from sabotara. The preparation method of the crystal form I comprises the steps of dissolving valsartan, AHU377 and sodium hydroxide in acetone to form a solution, stirring and crystallizing to obtain the crystal form I of the valsartan sodium Sacubitril. The crystal form II has peaks at 2 theta positions of 4.3, 5.0, 5.5, 5.8, 12.8, 14.6, 18.5, 18.9 and 20.1, and the preparation method of the crystal form comprises the steps of dissolving the valsartan sodium from Sacubitril in methanol to form a solution, adding toluene, stirring and crystallizing to obtain the crystal form II of the valsartan sodium from Sacubitril. The crystal form III has peaks at 2 theta positions of 4.1, 8.2, 12.4, 15.3, 16.5, 17.2, 18.4, 18.7, 19.6 and 25.0, and the preparation method of the crystal form comprises the step of heating the crystal form I to 100-140 ℃ to obtain the crystal form III of the sargasubrovalsartan sodium.

Chinese patent application CN201510902127.7 also provides crystalline form II of sabotartan sodium having peaks at 2 θ of 4.3, 5.0, 12.8. The preparation method of the crystal form comprises the steps of adding valsartan and sabotara to toluene, uniformly dispersing, adding a sodium hydroxide methanol solution, dissolving and clarifying. And then decompressing and evaporating, adding the crystal seed II for ultrasonic dispersion, adding ethyl acetate and water, stirring and crystallizing to obtain the crystal form II of the valsartan sodium sakubazamii.

Chinese patent application CN201510618916.8 provides crystalline form I, crystalline form II and crystalline form a of valsartan sodium from sabotara. The crystal form A has peaks at 2 theta of 4.1, 4.9, 5.0, 5.6, 8.3, 12.5, 14.8, 16.9, 17.6, 18.0, 18.7, 19.3, 20.0, 25.1 and 29.1, and the preparation method of the crystal form A comprises the steps of dissolving valsartan and sabotara in ethanol, adding an aqueous solution of sodium hydroxide, adding isopropyl acetate, stirring and crystallizing to obtain the crystal form A of the valsartan sodium sabotara.

Chinese patent application CN201580030123.2 provides a new crystal form of sabotara valsartan sodium having peaks at 2 θ of 4.1, 4.9, 5.2, 9.6, 12.5, 16.9, 18.1, 19.4, 27.1. The preparation method of the crystal form comprises the steps of dissolving valsartan and sabotara in a proper organic solvent, adding an alkaline compound, and enabling the solution to reach supersaturation and crystallization to obtain the valsartan sodium crystal form of sabotara.

WO2016151525 discloses crystalline form I of valsartan sodium from sabotara having peaks at 2 Θ of 4.24, 5.05, 9.96, 12.68, 14.88. The preparation method of the crystal form comprises the steps of dissolving valsartan and sabotara in acetone, adding a sodium hydroxide aqueous solution, carrying out reduced pressure concentration, adding isopropyl acetate, carrying out reduced pressure concentration, adding methyl tert-butyl ether, stirring and crystallizing to obtain the crystal form I of the valsartan sodium of the sabotara.

WO2017009784 discloses crystalline forms II, III and IV of valsartan sodium from sabotara, wherein form II has peaks at 2 θ of 4.1, 4.9, 9.8, 12.5, 14.7. The preparation method of the crystal form II comprises the steps of dissolving valsartan and sabotara in acetone, adding a sodium hydroxide aqueous solution, carrying out reduced pressure concentration, adding isopropyl acetate, carrying out reflux stirring, cooling, stirring and crystallizing to obtain the crystal form II of the valsartan sodium of sabotara. Form III has peaks at 4.1, 5.0, 9.7, 12.4, 14.8, 16.8, 22.6 at 2 θ. The preparation method of the crystal form III comprises the steps of dissolving valsartan and sabotara in acetone, adding a sodium hydroxide aqueous solution, carrying out reduced pressure concentration, adding methyl tert-butyl ether, carrying out reflux stirring, cooling, stirring and crystallizing to obtain the crystal form III of the valsartan sodium of sabotara. Form IV has peaks at 3.0, 6.0, 7.0, 11.7, 12.5, 16.2, 18.1, 19.6 at 2 θ. The preparation method of the crystal form IV comprises the steps of stirring and crystallizing valsartan sodium and sabotartan sodium in cyclohexane to obtain the crystal form IV of the sabotartan sodium.

Disclosure of Invention

The invention aims to overcome the defects of the physicochemical properties of the existing sabotara valsartan sodium crystal, and a new crystal form of the sabotara valsartan sodium is obtained unexpectedly in the research process of the crystal form of the sabotara valsartan sodium. The crystal form greatly improves the hygroscopicity of the existing crystal form of the salubrozole valsartan sodium, has good fluidity of medicinal preparations, has high product purity which can reach more than 99.5 percent, can be used for preparing tablets with three specifications by adopting a direct tabletting process, has simple process, can greatly shorten the production time, reduces the cost, and is suitable for preparing various stable medicinal preparations.

The above object of the present invention is achieved by the following technical means.

In one aspect, the present invention provides a new crystalline form of valsartan sodium shakubara (referred to as form Y) using Cu-ka radiation having characteristic peaks at 4.1 ± 0.2 °, 4.9 ± 0.2 °, 5.0 ± 0.2 °, 12.4 ± 0.2 ° in a powder X-ray diffraction pattern expressed in 2 θ angles (°), wherein the peak at 4.1 ± 0.2 ° is the most intense peak, the relative intensities of the diffraction peaks at 4.9 ± 0.2 ° and 5.0 ± 0.2 ° are 70-90%, and the relative intensity of the diffraction peaks at 12.4 ± 0.2 ° is 20-30%.

In this patent, both the diffraction peak position and the intensity of the crystalline form are important. In fact, luyang is indicated in the book "drugs in crystal form" (renwei press, 2009.10): the X-ray diffraction peak position and the X-ray diffraction peak intensity of the crystal form powder are the same in importance, the number of diffraction peaks, the diffraction peak position and the relative intensity among all diffraction peaks are important parameters for reflecting the fingerprint characteristics in the crystal form substance, all the parameters represent different meanings in the crystal form drug substance, and the change of any parameter represents the change in the crystal form substance.

Further, crystalline form Y of sarcurbara valsartan sodium of the present invention, using Cu-ka radiation, has diffraction peaks in the powder X-ray diffraction pattern expressed in 2 θ angles (°) also at the following positions: 9.8 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.9 +/-0.2 degrees and 17.8 +/-0.2 degrees, and the relative intensity of diffraction peaks is 5-15 percent.

Further, crystalline form Y of sarkubara valsartan sodium of the present invention has a powder X-ray diffraction pattern expressed in 2 θ degrees (°) using Cu-ka radiation as shown in fig. 1.

In another aspect, the invention also relates to a preparation method of the crystalline form Y of valsartan sodium of Sacubitril, which comprises the following steps:

dissolving the solid of the valsartan sodium sabotara in an alcohol and water solvent system at room temperature, concentrating under reduced pressure to dryness, heating and stirring in a solvent system of ketone and ether, and cooling and crystallizing to obtain the crystal form Y of the valsartan sodium sabotara.

Preferably, in the preparation method, the heating and stirring temperature is 20-60 ℃, and preferably 30-50 ℃.

Preferably, in the preparation method, the temperature for cooling and crystallizing is-10 to 30 ℃, and preferably 0 to 20 ℃.

Preferably, in the preparation method, the mass ratio of the alcohol to the water to the sodium valsartan is 1-50: 0.1-2: 1, and preferably 2-20: 0.2-1: 1.

Preferably, in the preparation method, the mass ratio of the ketone to the ether to the sodium valsartan is 1-50: 1-100: 1, and preferably 2-20: 5-50: 1.

Preferably, in the above preparation method, the alcohol is selected from one or more of methanol, ethanol, isopropanol and butanol, and is preferably methanol or ethanol.

Preferably, in the above preparation method, the ketone is selected from one or more of acetone, butanone and methyl isobutyl ketone, and is preferably acetone or butanone.

Preferably, in the above preparation method, the ether is selected from one or more of methyl tert-butyl ether, isopropyl ether and propyl ether, preferably methyl tert-butyl ether or isopropyl ether.

In the above preparation method, solid of valsartan sodium sabotartate can be prepared according to the methods reported in documents such as CN200680001733.0, CN201510073609.6 and CN201510998089.X, the contents of which are incorporated herein by reference.

In yet another aspect, the present invention also provides a pharmaceutical composition comprising the aforementioned crystalline form Y.

In a further aspect, the present invention also provides the use of the aforementioned crystalline form Y for the preparation of a medicament for the prevention and/or treatment of chronic heart failure.

Compared with the prior art, in the process of researching the crystal form of the salvastrum valsartan sodium, the prepared salvastrum valsartan sodium is a new crystal form, the crystal form greatly improves the hygroscopicity of the existing crystal form of the salvastrum valsartan sodium, has good medical preparation fluidity, has high product purity which can reach more than 99.5 percent, can be prepared into tablets with three specifications by adopting a direct tabletting process, has a simple process, can greatly shorten the production time and reduce the cost, and is suitable for preparing various stable pharmaceutical preparations.

Drawings

Fig. 1 is a powder X-ray diffraction diagram of crystalline form Y of sabatriptan sodium obtained in the present invention, wherein the ordinate axis represents diffraction intensities (counts) in counts and the abscissa axis represents diffraction angles (2 θ).

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

In the following examples, the detection conditions for the powder X-ray diffraction pattern drawings are as follows:

the instrument comprises the following steps: german BRUKER D2 PHASER powder X-ray diffractometer

Conditions are as follows: cu radiation, a Ni monochromator, a tube pressure of 30kV, a tube flow of 10mA, a 2 theta scanning range of 3-41 degrees, a scanning speed of 2.4 degrees/minute and a step size of 0.02 degrees.

Example 1Preparation method of Sacubitril valsartan sodium (refer to CN200680001733.0 example 2)

In a 500mL flask, 9.45g of Sacubitril (22.96mmol), 10.0g of valsartan (22.96mmol) and 300mL of acetone are added, stirred to dissolve, an aqueous sodium hydroxide solution (2.76g, 68.90mmol, dissolved in 8mL of water) is dropped at room temperature, and stirred for 2h at 20-25 ℃. Concentrating under reduced pressure at 15-30 ℃ to 150 mL. Adding 150mL of isopropyl acetate, and concentrating at 15-30 ℃ under reduced pressure to reach a volume of 150 mL. Adding 150mL of isopropyl acetate, and concentrating at 15-30 ℃ under reduced pressure to reach a volume of 150 mL. Stirring for 1h at 20-25 ℃. And (3) carrying out suction filtration, washing with isopropyl acetate, and carrying out vacuum drying on the solid at the temperature of 30-35 ℃ to obtain 19.51g of sarubatra valsartan sodium.

Example 2Preparation method of Sacubitril valsartan sodium crystal form Y

In a 100mL three-necked flask, 1g of valsartan sodium sabotara (1.04mmol, prepared in example 1), 1mL of water and 10mL of ethanol were added, stirred at room temperature for 1 hour and concentrated to dryness under reduced pressure. 8mL of acetone and 30mL of methyl t-butyl ether were added, and the mixture was stirred at 50 ℃ for 2 hours. Cooling to 10 deg.C, and stirring for 1 h. And (3) carrying out suction filtration, washing with methyl tert-butyl ether, and drying in vacuum to obtain 0.908g of off-white solid, wherein the yield is 90.8%, the HPLC purity is 99.8%, all single impurities are less than 0.1%, and the solid is a crystalline solid by XRD (X-ray diffraction) (shown in figure 1).

The X-ray diffraction data are shown in the following table:

serial number	2 theta angle (°)	d value	Relative strength
				1	4.083	21.62231	100.0％
2	4.925	17.92727	77.1％
				3	5.005	17.64164	73.3％
4	9.828	8.99209	5.1％
				5	12.426	7.11745	21.2％
6	14.834	5.96703	10.6％
				7	16.883	5.24733	8.0％
8	17.796	4.98018	7.1％
				9	19.719	4.49859	3.3％
10	22.847	3.88929	3.7％

Example 3: preparation of existing Crystal forms (CN201580002782.5 Crystal forms II and I, CN201510618916.8 Crystal Form A, WO2016151525Form I)

Preparation of CN201580002782.5 crystal form ii: in a 250mL reaction flask, 667mg of valsartan sodium is dissolved with 10mL of methanol and 100mL of toluene, filtered, sealed with a sealing film with a pinhole, and left to evaporate at room temperature. And (5) carrying out suction filtration to obtain the crystal form II of the valsartan sodium of the Sacubitril.

Preparation of CN201580002782.5 form i: suspending 205mg of the crystalline form II of the valsartan sodium from the solution in 1mL of cumene, stirring the mixture for 2 days at 50 ℃, and separating the mixture to obtain the crystalline form I of the valsartan sodium from the sabotara.

Preparation of CN201510618916.8 form a: at room temperature, 2.0g (4.6mmol) of valsartan and 1.88g (4.6mmol) of sabotara were dissolved in absolute ethanol (10 mL). 1mL of an aqueous solution of 0.55g (13.8mmol) of sodium hydroxide was added thereto, the temperature was raised to 40 ℃ and 100mL of isopropyl acetate was added thereto within 10 minutes, and a white solid precipitated from the solution. And (3) cooling, separating out solids, performing suction filtration, washing the solids with acetone, and drying at 30-40 ℃ to obtain the crystalline form A of the valsartan sodium of the Sacubitril.

Preparation of WO2016151525Form I: at 25 ℃, 0.74g (1.7mmol) of valsartan, 0.7g (1.7mmol) of sabotara and 21mL of acetone are added into a 100mL reaction bottle and stirred to dissolve. The temperature was reduced to 20 ℃ and 0.7mL of an aqueous solution of 0.2g (5mmol) of sodium hydroxide was added, and the mixture was stirred for 2 hours while the temperature was raised to 25 ℃. At 25 deg.C, concentrate to dryness under reduced pressure. To this was added 13.5mL of isopropyl acetate, and the mixture was concentrated to dryness at 25 ℃ under reduced pressure. To this was added 13.5mL of isopropyl acetate, and the mixture was concentrated to dryness at 25 ℃ under reduced pressure. To this was added 13.5mL of methyl t-butyl ether and stirred at 25 ℃ for 1 h. And (4) carrying out suction filtration, washing with methyl tert-butyl ether, and drying at 25 ℃ to obtain the sodium valsartan Form I of the Sacubitril.

Example 4: determination of physical properties of Sacubitril valsartan sodium crystal form Y powder

An intelligent powder characteristic tester is adopted to measure the powder properties of the crystal form Y (prepared from example 2) of the valsartan sodium from Sacubitril, and the experimental instrument and method are as follows:

intelligent powder characteristic tester (model: BT-1001, manufacturer: Baite instruments Co., Ltd., Dandong City)

Angle of repose: in a static equilibrium state, the acute angle between the powder accumulation inclined plane and the bottom horizontal plane is called the angle of repose. The powder is formed by naturally dropping powder on a specific platform in a specific mode. The size of the angle of repose directly reflects the flowability of the powder, and the smaller the angle of repose, the better the flowability of the powder. Selecting an angle of repose test interface, and setting parameters: and (3) testing times: 2, a calculation method: boundary fitting method, feed rate: 4, feeding time: and (5) measuring the addition for 200 s.

Bulk density: the density of the powder after being naturally filled in a specific container.

Selecting a non-metal powder apparent density test interface, reading the quality of an empty cup, and setting parameters: the number of times of measurement: 2, feed rate: and 4, feeding for 200s, scraping the cup mouth by using a scraper, and reading the quality of the cup and the powder.

Tap density: after a certain weight (or volume) of powder is filled in a specific container, the container is vibrated with a certain strength, thereby breaking the gaps among the powder particles and keeping the particles in a compact state.

Selecting a tap density test interface, measuring by a click solid mass method, weighing 20g of powder, and setting parameters: the number of times of measurement: 2, tap number: the measurement can be carried out 2000 times.

Particle size distribution: selecting a sieving particle size measurement interface, selecting a sieve with a size of 45 μm, 75 μm, 150 μm, 250 μm, 355 μm, 425 μm and 1000 μm, weighing an empty sieve, adding 20g of sample, sieving, and weighing each sieve and powder.

The experimental results are as follows:

note: carr index ═ (tap density-bulk density)/tap density%

Hausner ratio tap density/bulk density

The powder properties of the raw materials show that: the raw materials have uniform particle size distribution, the angle of repose of the raw materials is less than 40 degrees, the Carl index is between 21 and 25 percent, and the Hausner ratio is between 1.21 and 1.34, which shows that the raw materials have good fluidity and compressibility and can meet the requirement of a direct powder tabletting process.

The same method is adopted to determine the powder properties of the crystal form product in the prior art in the example 3, and the results are as follows:

as can be seen, the crystal form in the prior art has larger particles with the size of 425 and 1000 mu m due to moisture absorption and agglomeration. And the repose angle of the raw materials is more than 40 degrees, the Carl index is between 26 and 37 percent, and the Hausner ratio is between 1.35 and 1.59, which indicates that the fluidity of the existing crystal form is poorer than that of the crystal form of the patent.

Example 5: hygroscopicity of the crystalline form of the invention compared with that of the crystalline form of the prior art

The hygroscopicity of the crystal form Y of the present invention (the crystal form prepared in example 2) and the existing crystal form (the crystal form prepared in example 3) was determined by using a constant temperature drier (a saturated solution of ammonium chloride or ammonium sulfate was placed at the lower part) at a temperature of 25 ℃ plus or minus 1 ℃ and a relative humidity of 80% + orminus 2%.

Note: weight gain (%) - (m3-m2)/(m2-m 1). times.100%

Moisture absorption sufficient to form a liquid pharmacopoeia stipulated as deliquescence. The moisture-attracting weight gain of not less than 15% is defined as extremely moisture-attracting. The moisture-induced property is defined as the moisture-induced property within the range of 2-15%.

The results show that: although the crystal form has hygroscopicity, the crystal form is obviously improved compared with the existing crystal form.

Example 6: preparation process of Sacubitril and valsartan sodium tablets

Prescription composition (1000 tablets)

The process is described as follows: adding microcrystalline cellulose, colloidal silicon dioxide and Sacubitril valsartan sodium into a multi-directional mixer at 10rpm, mixing for 10min, adding anhydrous calcium hydrogen phosphate and crospovidone at 10rpm, continuing for 10min, adding magnesium stearate at 10pm, and mixing for 5 min. Tabletting the mixed materials and coating with a film.

As a result: the tabletting process is smooth, the tablet surface is smooth and clean, the weight difference of the tablets of the three specifications is less than +/-2%, and the tablet surface is smooth and complete after coating. The prescription has simple process and low cost, and is more suitable for mass production.

Example 7: preparation process of existing crystal form

Referring to the formulation composition and preparation method of example 6, the raw materials were replaced with the raw materials prepared by the prior art in example 3 to prepare a tablet of sarcurbaltrexartan sodium, with the following results:

the pharmacopoeia stipulates that the difference of tablet weights is required to be as follows: the weight difference limit of the tablet with the tablet weight less than 0.30g is +/-7.5 percent, and the weight difference limit of the tablet with the tablet weight more than or equal to 0.30g is +/-5.0 percent.

It can be seen that the existing crystal form has poor fluidity and larger hygroscopicity, is easy to cause sticking or has large difference of tablet weight, and cannot meet the requirement of direct tabletting process.

Claims (12)

1. A crystalline form of valsartan sodium shakubatu characterized in that it has a powder X-ray diffraction pattern, expressed in degrees 2 Θ (°), using Cu-ka radiation, as shown in figure 1.

2. A method of preparing the crystalline form of claim 1, comprising:

dissolving the solid of the valsartan sodium of the Sacubitril in an alcohol and water solvent system at room temperature, concentrating under reduced pressure to dryness, heating and stirring in a solvent system of ketone and ether, and cooling for crystallization to obtain the valsartan sodium solid;

wherein the temperature for cooling and crystallizing is 0-20 ℃;

the ketone is selected from one or more of acetone, butanone and methyl isobutyl ketone;

the ether is selected from one or more of methyl tert-butyl ether, isopropyl ether and propyl ether;

the mass ratio of the ketone to the ether to the sodium valsartan is 2-20: 5-50: 1.

3. The method according to claim 2, wherein the temperature of the heating and stirring is 20 to 60 ℃.

4. The method according to claim 2, wherein the temperature of the heating and stirring is 30 to 50 ℃.

5. The preparation method according to claim 2, wherein the mass ratio of the alcohol to the water to the sodium valsartan is 1-50: 0.1-2: 1.

6. The preparation method according to claim 2, wherein the mass ratio of the alcohol to the water to the sodium valsartan is 2-20: 0.2-1: 1.

7. The production method according to any one of claims 2 to 6, wherein the alcohol is selected from one or more of methanol, ethanol, isopropanol, and butanol.

8. The production method according to any one of claims 2 to 6, wherein the alcohol is methanol or ethanol.

9. The production method according to any one of claims 2 to 6, characterized in that the ketone is acetone or butanone.

10. The production method according to any one of claims 2 to 6, wherein the ether is methyl tert-butyl ether or isopropyl ether.

11. A pharmaceutical composition comprising the crystalline form of claim 1.

12. Use of the crystalline form of claim 1 for the preparation of a medicament for the prevention and/or treatment of chronic heart failure.

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