CN109776441A - Unformed Valsartan Sha Kuba song sodium compound - Google Patents
Unformed Valsartan Sha Kuba song sodium compound Download PDFInfo
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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
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 (Ra1The 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 (Ra2The 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 °.
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 (Ra1The 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 (Ra2The 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.
Calculated result such as following table, no more than 1.8.Wherein R and Ra1Relatively, Ra2It 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 Ra1。
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 Ra2Less than 2.0, show since average range is too wide, lead to data distortion, peak intensity is than preferably and R
And Ra1。
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 (10)
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.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111253330A (en) * | 2020-02-29 | 2020-06-09 | 广州白云山天心制药股份有限公司 | Novel crystal form of sartan drug, preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461647A (en) * | 2014-09-28 | 2016-04-06 | 四川海思科制药有限公司 | Solid forms of Valsartan-Sacubitril trisodium compound, and preparation method and use thereof |
| CN105837464A (en) * | 2015-01-15 | 2016-08-10 | 四川海思科制药有限公司 | Sacubitril sodium crystal forms, preparation method and application thereof |
| CN106032361A (en) * | 2015-03-11 | 2016-10-19 | 齐鲁制药有限公司 | LCZ-696 novel crystal form and preparation method thereof |
| CN107510653A (en) * | 2016-06-17 | 2017-12-26 | 常州爱诺新睿医药技术有限公司 | It is a kind of containing unformed husky storehouse than bent and Valsartan Pharmaceutical composition of solid dispersions and preparation method thereof |
-
2019
- 2019-03-05 CN CN201910165492.2A patent/CN109776441B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461647A (en) * | 2014-09-28 | 2016-04-06 | 四川海思科制药有限公司 | Solid forms of Valsartan-Sacubitril trisodium compound, and preparation method and use thereof |
| CN105837464A (en) * | 2015-01-15 | 2016-08-10 | 四川海思科制药有限公司 | Sacubitril sodium crystal forms, preparation method and application thereof |
| CN106032361A (en) * | 2015-03-11 | 2016-10-19 | 齐鲁制药有限公司 | LCZ-696 novel crystal form and preparation method thereof |
| CN107510653A (en) * | 2016-06-17 | 2017-12-26 | 常州爱诺新睿医药技术有限公司 | It is a kind of containing unformed husky storehouse than bent and Valsartan Pharmaceutical composition of solid dispersions and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| 刘岳等: "沙库巴曲缬沙坦的药代动力学和药效学特点", 《中国循环杂志》 * |
| 李松等: "沙库巴曲缬沙坦钠的结晶溶剂研究", 《广东化工》 * |
| 白煜佳等: "沙库巴曲缬沙坦安全性回顾", 《中国循环杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253330A (en) * | 2020-02-29 | 2020-06-09 | 广州白云山天心制药股份有限公司 | Novel crystal form of sartan drug, preparation method and application thereof |
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