CN109776441A

CN109776441A - Unformed Valsartan Sha Kuba song sodium compound

Info

Publication number: CN109776441A
Application number: CN201910165492.2A
Authority: CN
Inventors: 汪吴林; 程开生; 孙宏张; 曹杰永
Original assignee: HEFEI HEYUAN DRUG INDUSTRY Co Ltd
Current assignee: HEFEI HEYUAN DRUG INDUSTRY Co Ltd
Priority date: 2018-05-24
Filing date: 2019-03-05
Publication date: 2019-05-21
Anticipated expiration: 2039-03-05
Also published as: CN109776441B

Abstract

It applies the present invention provides a kind of unformed Valsartan Sha Kuba song sodium compound, preparation method, its composition and its in the diseases such as heart failure.Unformed Valsartan Sha Kuba song sodium compound of the invention, moisture absorption rate is suitable with crystalline state, and solubility is greatly improved.

Description

Unformed Valsartan Sha Kuba song sodium compound

Technical field

The present invention relates to organic chemistry fileds and pharmaceutical field, and in particular to unformed Valsartan Sha Kuba song compound and Preparation method, pharmaceutical composition and unformed Valsartan Sha Kuba comprising unformed Valsartan Sha Kuba song compound Bent compound is in preparation for preventing or treating the purposes in the drugs such as heart failure.

Background technique

Valsartan Sha Kuba song compound be by Valsartan (valsartan) or its salt and Sha Kuba it is bent (sacubitril, Also known as: AHU-377, Sha Ku are than bent) or the compound that is formed of its salt." compound " refer to Valsartan or its salt and Sha Kuba it is bent or Its salt combines the compound with fixed stoichiometric ratio coexisted by the effect of hydrogen bond or other non-covalent bonds, for example, Eutectic well known in the art is exactly one of specific manifestation form of the compound.The compound still further comprises the more of it The forms such as brilliant, unformed, solvate, solvate polycrystalline, hydrate, hydrate polycrystalline.

It is LCZ-696, chemical name are as follows: [4- { [(2S, 4R) -1- that Valsartan Sha Kuba song compound is most representative The amyl- 2- yl of ([1,1 '-phenylbenzene] -4- base) -5- ethyoxyl -4- methyl -5- oxo] amino } -4- ketobutyric acid-(S)-N- penta Acyl group-N- { [2 "-(1H- tetrazole -5- base) [1 ', 1 "-phenylbenzene] -4 '-yls] methyl }-valine] half pentahydrate of trisodium, Structure is as shown in following formula I

U.S. Food and Drug Administration (hereinafter referred to as FDA) ratifies LCZ-696 (trade name Entresto) tablet and uses In treatment heart failure, China national food and medicine supervision and management general bureau (CFDA) also ratifies its listing in July, 2017, is used for Adult chronic's patients with heart failure that ejection fraction reduces, to reduce the risk that its cardiovascular death and heart failure are hospitalized.

The crystalline solid state of half pentahydrate of Valsartan Sha Kuba song trisodium salt, powder are disclosed in patent CN101098689A Last X-ray diffraction feature (being radiated using Cu-K α) are as follows: 2 θ values be 4.5,5.5,5.6,9.9,12.8,15.7,17.0, 17.1,17.2,18.3,18.5,19.8,21.5,21.7,23.2,23.3,24.9,25.3,27.4,27.9,28.0,30.2, position It sets and is corresponding with characteristic diffraction peak；Disclose unformed Valsartan Sha Kuba song calcium in additional embodiment 4, but be not known preparation or Prompt preparation, the unformed solid-state for confirming Valsartan Sha Kuba song sodium.

CN106032361A discloses the deuterated hydrate of Valsartan Sha Kuba song trisodium.

CN105037289A discloses the crystal form II of LCZ696, which is characterized in that in the XRPD map of the crystal form II, 2 θ values (°) be 5.7,9.8,10.7,11.5,12.8,13.7,14.6,15.7,16.4,17.5,18.5,18.9,19.4,20.2, 20.9, there is diffraction maximum at 21.8,23.0,

A kind of trisodium salt hydrate novel crystal forms and preparation method thereof comprising Valsartan and AHU377 of CN105873586A, it is brilliant Type I, its X-ray powder diffraction figure measured with CuK alpha ray include be located at 5.1 ° ± 0.2 °, 4.1 ° ± 0.2 ° and 19.8 ° ± 0.2 °, the angle of diffraction (2 θ) at peak (U.S.'s crystalline substance cloud).

CN106854187A1. the preparation method of a kind of AHU-377 and Valsartan trisodium salt eutectic hydrate crystal forms II, Be characterized in that, the X-ray powder diffraction figure (CuK α radiation) of the crystal form II 2theta value be 4.3 ° ± 0.2 °, 5.0 ° ± There is characteristic peak (Suzhou crystalline substance cloud) at 0.2 °, 12.8 ° ± 0.2 °

CN105461647A discloses Valsartan sand library than bent trisodium salt composite, which is characterized in that it is crystal form A, powder Last X-ray diffracting spectrum 2 θ values be 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.6 ° ± 0.2 °, 12.5 ° ± Characteristic diffraction peak is corresponding at 0.2 °, 16.9 ° ± 0.2 °, 20.0 ° ± 0.2 °.It is preferred that 2 θ values be 4.1 ° ± 0.2 °, 4.9 ° ± 0.2°、5.0°±0.2°、5.6°±0.2°、8.3°±0.2°、12.5°±0.2°、14.8°±0.2°、16.9°±0.2°、 17.6°±0.2°、18.0°±0.2°、18.7°±0.2°、19.3°±0.2°、20.0°±0.2°、25.1°±0.2°、29.1° ± 0.2 ° of position is corresponding with characteristic diffraction peak；Also disclose unformed α, powder x-ray diffraction map 2 θ values be 4.5 °, 20.5 ° and 31.6 ° nearby have peak；Unformed β is also disclosed, powder x-ray diffraction map is near 4.0 °, 20.5 ° in 2 θ values It is corresponding with peak, is 31.6 ° nearby without corresponding peak in 2 θ values；Unformed γ is also disclosed, powder x-ray diffraction map is in 2 θ Value is 4.5 °, 20.5 ° and is nearby corresponding with peak, is 31.6 ° nearby without corresponding peak in 2 θ values.It is analyzed in conjunction with attached drawing, the patent Unformed may be a kind of mixed crystal, that is, have part crystal form and unformed mixture, and the unformed of high-purity is not made.In addition Whether these unformed purity meet the requirements, and whether hygroscopicity is subjected to, and can not judge.

It is necessary to provide a kind of stable, high-purity unformed Valsartan Sha Kuba song sodium, moisture absorption rate and crystal form phase When or it is more preferable, solubility or rate of dissolution are more preferable than crystal form.

Summary of the invention

Technical problem to be solved of the invention is to provide a kind of stable, high-purity unformed Valsartan sand library Ba Qu sodium compound, moisture absorption rate and crystal form are quite or more preferable, and solubility or rate of dissolution are more preferable than crystal form.

The present invention also provides the preparation methods of unformed Valsartan Sha Kuba song sodium compound.

The present invention also provides the compositions for containing unformed Valsartan Sha Kuba song sodium compound.

The present invention also provides purposes of the unformed Valsartan Sha Kuba song sodium compound in pharmacy.

Unformed Valsartan Sha Kuba song sodium compound: radiated using Cu-K α, x-ray diffractogram of powder, 1) in 2 θ values For within the scope of 4.0-40.0 ° without obvious sharp peak or narrow peak；It 2) is that 4.2-5.0 ° of range has 0~1 broad peak or steamed bun peak in 2 θ values It is 19.5-21.5 ° that KFA, which is the corresponding 2 θ values of 10-30 ° of range 1 broad peak of formation or the peak steamed bun peak KFC, KFC arc top in 2 θ values,；3) When 2 θ values are that 4.2-5.0 ° of range has 1 broad peak or steamed bun peak, the peak intensity ratio of KFA and KFC are not more than 1.8.

Chinese Pharmacopoeia four 0451 powder X-ray diffractometries of general rule of version in 2015 state clearly, and solid chemical material state can divide For crystalline state (or crystal) and amorphous state (or unformed shape, vitreum etc.) substance two major classes.Every kind of chemical substance, when its change It studies point when being determined with solid matter state (crystal form), it should which there is independent characteristic X-ray diffracting spectrum and data, diffraction pattern Spectrum information includes diffraction maximum quantity, diffraction maximum position (2 θ values or d value), diffraction peak intensity (relative intensity, absolute intensity), diffraction Peak geometry topological (the peak-to-peak ratio of different diffraction) etc..The powder x-ray diffraction peak of amorphous material is by tens of or even up to a hundred Sharp peak (narrow peak) composition；And the negligible amounts at the powder x-ray diffraction peak of amorphous substance and in disperse shape (for broad peak or steamed bun Peak), when measured sample chemical structure is identical, but the quantity of diffraction maximum and position, absolute strength value or diffraction peak shape geometry are opened up There are when difference, that is, show that there may be polymorphisies for the compound between flutterring.Unformed diffraction maximum be broad peak or steamed bun peak, The comparison of geometry topological diagram, such as the peak width of steamed bun peak, ratio of peak or the intensity ratio of peak height and each steamed bun peak then can be used in difference Deng.

In addition the research of four general rules of Chinese Pharmacopoeia version in 2015,9015 drug crystal form and crystal form quality control guideline carry It is bright, if judge that the crystal-form substances state of two unformed shape samples causes, it is complete that disperse diffraction maximum geometry topology should be met Unanimously.

In one embodiment of the invention, 1 its x-ray diffractogram of powder, 1) nothing within the scope of 2 θ values is 4.0-40.0 ° Obvious sharp peak or narrow peak；2) it is that 4.2-5.0 ° of range has 1 broad peak or steamed bun peak KFA in 2 θ values, is 10-30 ° of range in 2 θ values Forming the corresponding 2 θ values of 1 broad peak or the peak steamed bun peak KFC, KFC arc top is 19.5-21.5 °.

Due to unformed without obvious diffraction maximum, powder diffraction figure processing software is difficult to peak-seeking, reads or calculate the 2 of appearance θ value and peak intensity, therefore powder diffraction initial data (2 θ values and corresponding peak intensity count) can be used and carry out analytical calculation.

The 2 θ values that 2 θ value of the peak KFA is (highest peak) at maximum diffraction intensity within the scope of 4.2-5.0 ° are found (to be accurate to 0.02 °) and its peak intensity counting, and the average peak intensity for calculating 2 value ± 0.1 ° θ of highest peak counts and 2 value ± 0.2 ° θ of highest peak Average peak intensity count；It is respective value within the scope of 19.5-21.5 ° with method record 2 θ value of the peak KFC；KFA is corresponding to two peak KFC Intensity ratio (abbreviation peak intensity ratio R), formula is defined as follows:

Peak intensity ratio (R)=(counting of KFA highest peak intensity)/(counting of KFC highest peak intensity) (1)

Or

Peak intensity ratio (R_a1The average peak intensity of 2 value ± 0.1 ° θ of)=(KFA highest peak counts)/(2 θ value of KFC highest peak ± 0.1 ° of average peak intensity counts) (1a1)

Or

Peak intensity ratio (R_a2The average peak intensity of 2 value ± 0.2 ° θ of)=(KFA highest peak counts)/(2 θ value of KFC highest peak ± 0.2 ° of average peak intensity counts) (1a2)

One referred to is mentioned that, is counted and is calculated using intensity in formula, and due to being in same map, replacement uses relative intensity It calculates, result is also consistent, is also suitable and is calculated using relative intensity.

Preferably, the peak intensity ratio of KFA and KFC is not more than 1.5.

Preferably, the peak intensity ratio of KFA and KFC is not more than 1.2.

Preferably, the peak intensity ratio of KFA and KFC is R or Ra1.

The qualitative method that crystal form type identifies includes absolute discrimination method (single crystal method of X-ray diffractometry (SXRD)) and opposite mirror Other method, opposite differential method further include other than powder X-ray diffractometry (PXRD) infra-red sepectrometry (IR), Raman spectroscopy (RM, Differential scanning calorimetry (DSC), thermogravimetry (TG) etc..

The unformed Valsartan Sha Kuba song sodium compound: its infrared spectroscopy is in following wave number cm^-1There is an absorption peak: 1724 ±2。

Preferably, In a particular embodiment, infrared spectroscopy is in following wave number cm^-1There is an absorption peak: 1724 ± 2, 1582 ± 2,1487 ± 2,1460 ± 2.

The unformed Valsartan Sha Kuba song sodium compound, without the crystallization water and moisture content is not more than 10%.Its water Dividing is free water, is changed according to drying condition, can also be changed with moisture absorption.In certain embodiments, moisture content exists 0.4778%~5.4782%.

The preparation method one of the compound takes Valsartan Sha Kuba song sodium composite solids or Valsartan sodium and Sha Kuba Bent sodium molar ratio is the solid of 1:1, is dissolved in good solvent, and then direct solvent evaporated, which is made or is added anti-solvent, makes it that system be precipitated ?；Good solvent is selected from methanol, ethyl alcohol, isopropanol, acetone.Valsartan Sha Kuba song sodium composite solids can be crystallization, such as Valsartan Sha Kuba song trisodium half five water object crystal form A or other crystal forms；It is also possible to unformed, such as unformed α, β, γ；Very To it is of the invention it is unformed can also；It can also be various crystal forms, unformed mixture.Crystallization or unformed indifference after being dissolved in solvent Not, Valsartan sodium is dissolved in also identical as state after the dissolution of Valsartan Sha Kuba song sodium compound after solvent with Sha Kuba song sodium.

The preparation method two of the compound takes Valsartan and Sha Kuba bent, and molar ratio 1:1 is dissolved in good solvent, slowly The solution of the alkaline sodium compound of molar equivalent is added, being made or be added anti-solvent for then direct solvent evaporated makes its precipitation system ?；Good solvent is selected from methanol, ethyl alcohol, isopropanol, acetone；Alkaline sodium compound be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium methoxide or sodium ethoxide；Anti-solvent be selected from Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ether, Isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene or their mixing Object.The molar ratio of molar equivalent and Valsartan of the alkaline sodium compound in terms of sodium is preferably 3:1.The solution of alkaline sodium compound is adopted It is prepared with water, methanol, ethyl alcohol, isopropanol, acetone or combinations thereof.

The composition of the compound contains compound and pharmaceutically acceptable carrier.

The carrier includes filler, adhesive, wetting agent, disintegrating agent, sorbefacient, the table of pharmaceutical field routine Face activating agent, glidant, lubricant etc..Filler such as starch, sucrose, lactose, microcrystalline cellulose etc.；For example low substitution hydroxyl of disintegrating agent Propyl cellulose, croscarmellose sodium, crospovidone etc.；Glidant such as silica, lubricant such as magnesium stearate, Sodium stearyl fumarate etc..

Composition can be made into conventional solid pharmaceutical preparation, such as tablet, capsule, preferred tablet.

The preparation process of tablet adopts direct pressed powder or dry granulation can be used after tabletting, preferably after dry granulation Tabletting.

The application that the compound is applicable in following disease medicament in preparation, hypertension, heart failure, left ventricular function Incomplete, hypertrophic cardiomyopathy, diabetes cardiomyopathy, supraventricular and ventricular arrhythmia, auricular fibrillation, auricular flutter are harmful Vascular remodeling, myocardial infarction, atherosclerosis, angina pectoris, renal insufficiency, diabetes, secondary aldosteronism/ Primary and condary pulmonary hypertension and/

The present invention has the advantages that

The present invention provides a kind of stable, high-purity unformed Valsartan Sha Kuba song sodium, moisture absorption rate and crystal form Quite, and solubility is greatly improved.

Detailed description of the invention

Unformed powder x-ray diffraction figure is made in Fig. 1 embodiment 1.

Unformed powder x-ray diffraction figure is made in 2 method 3 of Fig. 2 embodiment.

Crystal form A powder x-ray diffraction figure is made in Fig. 3 comparative example 1.

Crystal form A is made through 90 DEG C of dry 48h sample powder x-ray diffraction pattern in comparative example 1 in Fig. 4 embodiment 4

Crystal form A infrared spectrogram is made in Fig. 5 comparative example 1.

Unformed infrared spectrogram is made in Fig. 6 embodiment 1.

Unformed heat analysis (TGA/DSC) figure is made in Fig. 7 embodiment 1.

Crystal form A heat analysis (TGA/DSC) figure is made in Fig. 8 comparative example 1.

Specific embodiment

The present invention will be further described with reference to the accompanying drawings and detailed description, and following embodiment is intended to illustrate hair Bright rather than limitation of the invention further.

Unless otherwise specified, each parameter measures as follows in embodiment.

1. water content detection

Instrument: DL31 moisture teller (Mei Tele-support benefit, instrument number: HYS08017)

Test method: taking sample about 0.2g, using methanol as solvent, surveys by " Chinese Pharmacopoeia " 2015 editions four 0,832 first methods Fixed (Er Feixiushi method).

2. infrared spectroscopy

Instrument: FTIR-8400S Fourier Transform Infrared Spectrometer (Japanese Shimadzu Corporation, instrument number: HYS08020)

Test method: KBr pressed disc method.It takes potassium bromide to cross 200 meshes, sets in 120 DEG C of baking ovens, dry 4h.Take potassium bromide: to Sample about (100:1), is fully ground, tabletting.

3. powder x-ray diffraction

Instrument: DX-27mini X- diffractometer (the great member in Dandong, instrument number: HYS16016)

Test method: slit width: 1 ° 1 ° of 0.30mm；Wavelength=1.5406 angstrom (Cu/ κ α 1)；Stepping measurement；Stride 0.02°；4 ° of start angle；40 ° of termination point；1.0 seconds/step of scanning speed；Tube voltage 35KV；Tube current 15mA.

4. heat analysis (TGA/DSC)

Instrument: DTG-60A (Shimadzu, HYS16018)

Test method: atmosphere: air atmosphere；Temperature program: initial temperature is room temperature, is warming up to 10 DEG C of rates per minute 300℃。

Comparative example 1

The preparation of half pentahydrate of Valsartan Sha Kuba song trisodium

It is made, is described as follows according to CN101098689A:

It takes Sha Kuba song free acid 4.2g and Valsartan 4.1g to be dissolved in 400ml acetone, the NaOH of 1.11g is separately taken to be dissolved in 70ml In water.Two kinds of solution are merged, stirs 1 hour at room temperature, obtains clear solution.The solution is obtained into glass in 35 DEG C of evaporations Glass shape solid.Then, vitreous solid residue is placed in 400ml acetone, obtained mixture is stirred and is ultrasonically treated Until precipitating is formed.Filtering precipitate and by the solid crystalline solid of air drying 2 days until obtaining stable quantity at room temperature. Powder x-ray diffraction figure is as shown in Fig. 3, and infrared spectroscopy is as shown in Fig. 5, following wave number cm^-1There is absorption peak 2958.60, 1712.67,1639.38,15898.88,1488.94,1460.01,1402.15, with 3 infrared light of CN101098689A embodiment Spectrum is consistent, shows to have obtained half pentahydrate crystalline state of Valsartan Sha Kuba song trisodium, is defined as crystal form A.

Comparative example 2

The unformed preparation of Valsartan Sha Kuba song trisodium

B1 according to CN105461647A specification implements 2, and to prepare Valsartan sand library α more unformed than bent trisodium salt, is described as follows: At room temperature, Valsartan 2.00g (4.60mmol), Sha Kuba song 1.88g (4.60mmol) and dehydrated alcohol (10ml) are mixed, Obtain clear solution.Into said mixture, the aqueous solution 1ml of sodium methoxide 0.75g (13.8mmol) is added dropwise.Heat above-mentioned system Isopropyl acetate 50ml, Cheng Junyi liquid, without Precipitation are added dropwise in 30~50 DEG C, about 5 minutes.Stirring cooling, still without White solid is precipitated；Ultrasound is still precipitated without solid.Unformed α can not be prepared

B2 according to CN105461647A specification implements 5, and to prepare Valsartan sand library β more unformed than bent trisodium salt, is described as follows: Valsartan 2.00g (4.60mmol), Sha Kuba song 1.88g (4.60mmol) and dehydrated alcohol 10ml are mixed, obtained clear Clear solution；Into said mixture, the aqueous solution 1ml of sodium hydroxide 0.55g (13.8mmol) is added dropwise；Above-mentioned system is heated to 40 Isopropyl acetate 50ml is added dropwise in~50 DEG C, about 5 minutes；At uniform liquid, without Precipitation.Stirring cooling, still without white Solid is precipitated；Ultrasound is still precipitated without solid.Unformed β can not be prepared.

B3 implements 8 according to CN105461647A specification and prepares the Valsartan Sha Kuba unformed γ of song trisodium salt, is described as follows: Valsartan 2.00g (4.60mmol), Sha Kuba song 1.88g (4.60mmol) and dehydrated alcohol 10ml are mixed, obtained clear Clear solution；Into said mixture, the ethanol solution 10ml of sodium hydroxide 0.55g (13.8mmol) is added dropwise；It is clarified Solution when decompression concentrated solution volume is to about 5ml at 30~40 DEG C, is still clarified sticky, normal heptane 15ml, solution point is added Layer, upper layer is normal heptane, and about 5ml is concentrated under reduced pressure at 30~40 DEG C, and wall is precipitated minute quantity solid and adheres to；Then it repeats to add It normal heptane 15ml and is concentrated into, no obvious granular solids are precipitated, colourless or white viscous substance adhesive organ operation for 10 times of about 5ml Wall.Show that unformed γ can not be made.Increase post-processing, take out, be dried under reduced pressure at 40~45 DEG C, obtain white solid, quickly inhales Tide, it is difficult to prepare sample measurement powder x-ray diffraction figure.

Above method B1-B3 is summarized as Valsartan and Sha Kuba song is dissolved in good solvent dehydrated alcohol, and sodium hydroxide alkali is added Valsartan Sha Kuba song sodium salt is made in the solution of ethyl alcohol, so in the aqueous solution or ethanol solution of sodium methoxide or sodium hydroxide Anti-solvent isopropyl acetate or normal heptane is added afterwards solid is precipitated.As a result three methods can not be precipitated.The possible reason is Dissolubility is too high in ethanol for Valsartan Sha Kuba song sodium, close to easily dissolved state, anti-solvent isopropyl acetate or card heptane It is not enough to for drug being precipitated, can not obtain unformed.

B4 implements 8 with reference to CN105461647A specification and prepares the Valsartan Sha Kuba unformed γ of song trisodium salt, and description is such as Under: half pentahydrate crystal form A of Valsartan Sha Kuba song trisodium prepared by preparation example 1 adds dehydrated alcohol 20ml；It obtains clarifying molten Liquid when decompression concentrated solution volume is to about 5ml at 30~40 DEG C, is still clarified sticky, is added normal heptane 15ml, solution layering, Upper layer is normal heptane, and about 5ml is concentrated under reduced pressure at 30~40 DEG C, and wall is precipitated minute quantity solid and adheres to；Then it repeats to add just It heptane 15ml and is concentrated into, no obvious granular solids are precipitated, and white viscous substance adheres to wall operation for 10 times of about 5ml.Not Obtain solid amorphous.

B4 is identical as B3 subsequent step, is only omitted the process for preparing compound, and directlys adopt crystal form A preparation, Solid amorphous can not be made.

Three kinds of unformed powder x-ray diffraction maps show that no absolute intensity is surveyed with reference to the accompanying drawings in CN105461647A Estimation is measured, wherein 4 ordinate of Figure of description (scale is 0,400,1600,3600,6400 from small to large) non-equal difference coordinate Non-logarithmic coordinate is divided equally again using the sum of two coordinate values and is estimated.

2 θ (°) absolute intensity of peak counts	α type	β type	γ type
				4~5	3750	4700	3600+ (3600+6400)/5=5600
20.5	1500	1800	1600+ (1600+3600)/4=2900
				Peak intensity ratio	2.50	2.61	1.93

It can be seen that three kinds of unformed peak intensity ratios are between 1.93~2.61.

Embodiment 1

The half pentahydrate crystal form A 2.0g of Valsartan Sha Kuba song trisodium that method 1 takes comparative example 1 to be prepared, adds anhydrous Ethyl alcohol 10ml, is stirred at room temperature dissolved clarification, and decompression boils off solvent, obtains white blister solid, 60 DEG C forced air drying 4 hours, obtain unformed. Solid after drying is ground or is crushed and to be obtained white powder.

Its powder x-ray diffraction figure is as shown in Fig. 1, and 1) the nothing obvious sharp peak or narrow within the scope of 2 θ values is 4.0-40.0 ° Peak；2) be that 4.2-5.0 ° of range has 1 broad peak or steamed bun peak KFA in 2 θ values, 2 θ values be 10-30 ° of range formed 1 broad peak or The corresponding 2 θ values in the peak steamed bun peak KFC, KFC arc top are 19.5-21.5 °.

Or

Calculated result such as following table, no more than 1.8.Wherein R and R_a1Relatively, R_a2It is smaller, it is because of average range It is too wide, lead to data distortion.It is therefore preferable that peak intensity ratio is R and R_a1。

1 peak intensity ratio of table

Comparing three kinds of unformed peak intensity ratios in CN105461647A is 1.93~2.61, therefore is different from disclosing without fixed Type, topological diagram intuitively compare it has also been found that distinguishing obvious.

The infrared spectroscopy of unformed sample is made in following wave number cm in this law^-1There is an absorption peak: 2960.53,1724.24, 1581.52,1487.01,1460.01, in wave number cm^-1It is at 1711,1631,1597 without peak., it is different from comparative example 1, most obviously Distinguishing characteristics wave number cm-1 is 1724.Reaffirm it is not half pentahydrate of Valsartan Sha Kuba song trisodium crystallized.With

Embodiment 2

Method 2a: taking LCZ696 crystal form A 1.0g made from comparative example 1, and lower addition ethyl acetate 10ml is stirred at room temperature can not Dissolved clarification continues to add ethyl acetate 390ml, still can not dissolved clarification.Show that the LCZ696 of crystalline state is insoluble in ethyl acetate.

Method 2: embodiment 1 is made unformed, and lower addition ethyl acetate is stirred at room temperature to dissolved clarification, and n-hexane is added dropwise in room temperature, It is precipitated to no solid and stops being added dropwise, 30min is stirred at room temperature, filtered under nitrogen obtains white solid, and to be unformed, powder spreads out It penetrates figure and method 3 is consistent.

Method 3a: taking LCZ696 crystal form A 1.0g made from comparative example 1, and lower addition methylene chloride 10ml is stirred at room temperature can not Dissolved clarification continues the 390ml that adds methylene chloride, still can not dissolved clarification.Show that the LCZ696 of crystalline state is insoluble in methylene chloride.

Method 3: since the LCZ696 of crystalline state is insoluble in methylene chloride, and 1 dehydrated alcohol steam seasoning of embodiment is consolidated Body operating difficulties in mass production, solubilizer, which is precipitated, after proposed adoption unformed shape is made.Take LCZ696 crystal form made from comparative example 1 A 2.0g adds dehydrated alcohol 5ml, is stirred at room temperature dissolved clarification, and decompression boils off solvent, and methylene chloride 20ml is added under heating stirring to molten Clearly, show to dissolve in the methylene chloride of 10 times of volumes after unformed shape is made, i.e., it is unformed more preferable than crystallization dissolution；Continue N-hexane is added dropwise in room temperature, stops being added dropwise until being precipitated without solid, 30min is stirred at room temperature, filter, obtain white powdery solids, is nothing Sizing.Its its powder x-ray diffraction figure such as attached drawing 2, KFA peak intensity ratio corresponding with two peak KFC, as a result such as following table, no more than 1.2。

2 embodiment of table, 2 method 3 obtains unformed peak intensity ratio

Method 4: taking LCZ696 crystal form A made from comparative example 1, lower addition acetone is stirred at room temperature to dissolved clarification, room temperature is added dropwise just Hexane stops being added dropwise, 30min is stirred at room temperature until being precipitated without solid, and filtered under nitrogen obtains white powdery solids, is nothing Sizing.

Method 5: taking LCZ696 crystal form A made from comparative example 1, lower addition isopropanol is stirred at room temperature to dissolved clarification, room temperature is added dropwise N-hexane stops being added dropwise, 30min is stirred at room temperature, filtered under nitrogen obtains white powdery solids, is until being precipitated without solid It is unformed.

1 sample physics and chemistry Comparative result table of table

Remarks: a moisture is that in 60 DEG C of air dry ovens after dry 4h, Karl_Fischer method measures solid after filtering

Method 6: taking LCZ696 crystal form A made from comparative example 1, lower addition acetone is stirred at room temperature to dissolved clarification, decompression boils off molten Agent obtains white blister solid, dry, obtain it is unformed, it is consistent with embodiment 1.

Method 7: taking LCZ696 crystal form A sample made from comparative example 1, and 10 times of volume ratio ethyl acetate are added, and 60 DEG C are stirred 2 times of volume ratio dehydrated alcohols of lower addition are mixed to dissolved clarification, ice-water bath is down to room temperature, and a large amount of n-hexanes are added and (are greater than 50 times of volumes Than), lower precipitation white solid is stirred, 30min is stood overnight at grease, and white solid is precipitated, and filtering obtains white powder Solid is crystal form A.It is related crystallization may to be generated with overnight water suction.

Method 8: ethyl acetate is added into saturated solution in unformed sample prepared by Example 1, and room temperature opening stands analysis Crystalline substance overnight, is precipitated white solid, filters under gas shield, obtain white powdery solids, is crystal form A.The difference of this law and method 2 It is that sample concentration, precipitation mode difference is precipitated, which is saturated solution, open standing process one side ethyl acetate volatilization sample The higher supersaturation of product concentration, while the moisture in air is absorbed, so that sample is formed the crystalline state containing the crystallization water.

Method 9: acetone is added into saturated solution in the unformed sample for taking method 1 to prepare, and room temperature opening stands crystallization and stays overnight, It is filtered under gas shield, obtains white powdery solids, be crystal form A.The difference of this law and method 6 is also in that solvent volatilization plus suction Water effect generates crystalline state.

Test Summary:

The LCZ696 of crystalline state is insoluble in the lesser methylene chloride of polarity, ethyl acetate etc., it is difficult to be used to prepare nothing Sizing；And the larger solvent methanol of polarity, ethyl alcohol, isopropanol, acetone have preferable solubility property to crystalline state LCZ696, can be used for making It is standby unformed.It can be used for amplifying production using the precipitation of anti-solvent method is unformed.

Embodiment 3

Valsartan 2.00g (4.60mmol), Sha Kuba song 1.88g (4.60mmol) are mixed with acetone 40ml and are mixed conjunction by C1 Stirring, obtains clear solution；Into said mixture, the aqueous solution 1ml of sodium hydroxide 0.55g (13.8mmol) is added dropwise；Decompression It is evaporated to obtain white solid, and 60 DEG C of dryings 4 hours to obtain the final product.Obtain it is unformed, it is consistent with embodiment 1.

Valsartan 2.00g (4.60mmol), Sha Kuba song 1.88g (4.60mmol) are mixed with acetone 40ml and are mixed conjunction by C1 Stirring, obtains clear solution；Into said mixture, the aqueous solution 1ml of sodium hydroxide 0.55g (13.8mmol) is added dropwise；It is spraying It does to obtain the final product.Obtain it is unformed, it is consistent with embodiment 1.

Embodiment 4

Crystalline state LCZ696 conversion

It takes 1 crystal form A sample of comparative example, respectively forced air drying and vacuum drying, investigates drying mode, temperature to the shadow of moisture It rings, is as follows:

4 LCZ696 sample drying mode result summary sheet of table

Drying means	Drying temperature DEG C	Drying time h	Moisture %^a
				Forced air drying	80	8	2.5059
It is dried in vacuo (P₂O₅)	80	8	2.8746
				Forced air drying	100	8	2.1874
Forced air drying	80	24	1.8239
				Forced air drying	90	48	1.3772

It can be seen that by upper table data, be dried in vacuo, preferably forced air drying almost the same with forced air drying moisture removal efficiency； Temperature is high, and moisture removal is high-efficient.Heat analysis (TGA/DSC) is carried out to 90 DEG C of dry 48h samples, attached drawing 7 is seen, is shown in 105 DEG C or less to lose a part of water be that 0.997% and 105-160 DEG C lose remaining water 0.352%, and melt, maximum melting peak is about 125 DEG C, and LCZ696 crystal form A (attached drawing 8), being shown in 105 DEG C or less and losing a part of water is 3.928% and 105-160 DEG C of mistake Remaining water 0.900% is removed, and is melted, maximum melting peak is at about 150 DEG C；The sample powder diffraction pattern such as attached drawing 4 and LCZ696 are brilliant Type A diffraction pattern (attached drawing 3) is significantly different, and also with the 1 unformed difference of gained of embodiment, related peak intensity, which compares, is not less than 2.0, For a kind of new crystal form, claim crystal form B.Calculate LCZ696 crystal form A peak intensity ratio related to crystal form B.

A variety of drying modes can not obtain unformed.

5 LCZ696 crystal form A peak intensity ratio of table

6 LCZ696 crystal form B peak intensity ratio of table

Crystal form A peak intensity ratio R_a2Less than 2.0, show since average range is too wide, lead to data distortion, peak intensity is than preferably and R And R_a1。

Embodiment 5 --- moisture and moisture absorption

90 are continued to sample after the 90 DEG C of dryings of method 3/7 in embodiment 1 and embodiment 2 and 4 crystalline state LCZ696 of embodiment DEG C forced air drying, measures moisture when different drying times, is detailed in following table:

7 different crystal forms sample drying mode result of table summarizes

Sample	Crystal form	Drying temperature DEG C	Drying time h	Moisture %
					4 crystal form B of embodiment	New crystallization	90	15、30	1.5052、1.3772
Embodiment 1	It is unformed	90	15、30	---、0.4778
					2 method 3 of embodiment	It is unformed	90	15、30	1.1586、0.6850
2 method 7 of embodiment	A	90	15、30	1.8270、1.3369

Under the conditions of 90 DEG C of forced air dryings, unformed moisture content can drop to 0.7% or less, thereby increases and it is possible to it is converted into crystal form B, it is brilliant The moisture of type B and and at any time extend moisture decline it is slower, 30h is not still 1.3% or so.Show it is of the invention unformed, more It is easy that more low-moisture sample is made.

Hygroscopicity test is carried out to above-mentioned sample, takes sample is naked to put or wrap using medicinal low density polyethylene (LDPE) valve bag (PE) Dress, or add the medicinal complex pocket of polyester/aluminium/polyethylene (PET/Al/PE) sealing again, it is placed in the environment of room temperature relative humidity 65% In, it increases weight in measurement moisture absorption in the 1/5th day.

Table 8 packs the influence to moisture absorption

The result shows that it is unformed it is naked put 5 days after moisture it is consistent with crystal form A moisture, it is also consistent with crystal form B moisture absorption rate；PE Packaging adds PET/Al/PE to can be very good isolation moisture content, and moisture absorption in 5 days is respectively less than 1%, unformed and crystal form B moisture absorption rate one It causes, is faster than that crystal form is different from the unformed moisture absorption of the technical knowledge in the field, and obtain small stable unformed of moisture absorption.

Powder diffraction is carried out to naked unformed (2 method 3 of embodiment) put and 4 crystal form B of embodiment, investigates transformation of crystal, The result shows that it is unformed it is naked put 5 days powder diagrams and initial consistent, be still it is unformed, show that unformed water suction can't turn Crystalline substance, the i.e. unformed form stable；And crystal form largely switchs to crystal form A after crystal form B moisture absorption, diffraction pattern and crystal form A are basic It is consistent and different from crystal form B, show to be dried made from crystal form B it is unstable.

Embodiment 6 --- dissolubility test

And comparative example 1 gained crystal form A unformed to embodiment 1 tests solubility.About 0.1g is respectively taken, corresponding be situated between is added in segmentation Matter 0.1ml, 0.9ml (total 1ml), 2ml (total 3ml), 7ml (total 10ml), 90ml (total 100ml), 900ml are (total 1000ml), determined according to Chinese Pharmacopoeia, dissolved clarification is then respectively easily to dissolve, is readily soluble, dissolution, slightly molten, slightly soluble, soluble,very slightly, such as It is still insoluble, it is determined as almost insoluble.As a result such as following table.

9 crystal form A of table and unformed dissolubility compare

* CN105461647A data are derived from

It can be seen that it is of the invention it is unformed be easily to dissolve, and crystal form A is several in pH1.2 hydrochloric acid under various aqueous mediums Insoluble, unformed solubility is 10000 times or more of crystal form A solubility；Compare CN105461647A in unformed α, β, γ data, it is unformed not increase than crystal form A solubility, and the unformed dissolubility of the present invention is significantly better than unformed α, β, γ, Especially in pH1.2 hydrochloric acid, solubility improves 1000~10000 times.

Embodiment 7 --- tablet preparation

Valsartan Sha Kuba song sodium unformed (preparation of 1 method of embodiment) 100g, microcrystalline cellulose 50g, crospovidone 10g, silica 3.2g, magnesium stearate 1.6g are uniformly mixed.Using dry granulating machine (believing that friendship is special in the Shenzhen DC-5) granulation, adopt Particle is sieved with 30 mesh screens.Then by after screening particle and magnesium stearate 1.0g tabletting after mixing.Use stomach dissolution type Film coating pre-mix dose coating, weight gain 4% obtain coating tablet.

Finally, it should be noted that above embodiments are only to illustrate the present invention and not limit technology described in the invention Scheme；Those skilled in the art should understand that still can modify to the present invention or equivalent replacement；And all are not It is detached from the technical solution and its improvement of the spirit and scope of the present invention, should all be covered within the scope of the claims of the present invention.

Claims

1. unformed Valsartan Sha Kuba song sodium compound, it is characterised in that: radiated using Cu-K α, powder x-ray diffraction Figure, 1) the obvious sharp peak of nothing or narrow peak within the scope of 2 θ values is 4.0-40.0 °；2) have in 2 θ values for 4.2-5.0 ° of range 0 ~ 1 wide Peak or steamed bun peak KFA are that the corresponding 2 θ values of 10-30 ° of range 1 broad peak of formation or the peak steamed bun peak KFC, KFC arc top are in 2 θ values 19.5-21.5°；3) it is not more than when in the peak intensity ratio that 2 θ values are KFA and KFC when 4.2-5.0 ° of range has 1 broad peak or steamed bun peak 1.8。

2. compound described in claim 1, it is characterised in that: the peak intensity ratio of KFA and KFC is not more than 1.5.

3. compound as claimed in claim 2, it is characterised in that: the peak intensity ratio of KFA and KFC is not more than 1.2.

4. compound described in claim 1, it is characterised in that: its infrared spectroscopy is in following wave number cm^-1There is an absorption peak: 1724 ± 2。

5. compound as claimed in claim 2, it is characterised in that: its infrared spectroscopy is in following wave number cm^-1There is an absorption peak: 1724 ± 2,1582 ± 2,1487 ± 2,1460 ± 2.

6. compound described in claim 1, it is characterised in that: without the crystallization water and moisture content is not more than 10%.

7. the preparation method of compound described in claim 1 takes Valsartan Sha Kuba song sodium composite solids or Valsartan sodium The solid for being 1:1 with Sha Kuba song sodium molar ratio, is dissolved in good solvent, and then direct solvent evaporated, which is made or is added anti-solvent, makes it It is precipitated and is made；Good solvent is selected from methanol, ethyl alcohol, isopropanol, acetone.

8. the preparation method of compound described in claim 1 takes Valsartan and Sha Kuba bent, molar ratio 1:1 is dissolved in good molten Agent is slowly added to the solution of the alkaline sodium compound of molar equivalent, by then directly solvent evaporated is made or addition anti-solvent makes It, which is precipitated, is made；Good solvent is selected from methanol, ethyl alcohol, isopropanol, acetone；Alkaline sodium compound is selected from sodium hydroxide, sodium carbonate, carbon Sour hydrogen sodium, sodium methoxide or sodium ethoxide；Anti-solvent is selected from Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetic acid fourth Ester, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene or it Mixture.

9. the composition of compound described in claim 1, comprising the described in any item compounds of claim 1 ~ 6 and pharmaceutically Acceptable carrier.

10. the application that compound described in claim 1 is applicable in following disease medicament in preparation: hypertension, heart failure are left Ventricular insufficiency, hypertrophic cardiomyopathy, diabetes cardiomyopathy, supraventricular and ventricular arrhythmia, auricular fibrillation, atrium is flutterred It is dynamic, harmful vascular remodeling, myocardial infarction, atherosclerosis, angina pectoris, renal insufficiency, diabetes, secondary aldosterone Increase disease/primary and condary pulmonary hypertension and/or kidney failure.