CN105461647B - Valsartan sand library is than solid-state form of bent trisodium salt composite and its preparation method and application - Google Patents
Valsartan sand library is than solid-state form of bent trisodium salt composite and its preparation method and application Download PDFInfo
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- CN105461647B CN105461647B CN201510618916.8A CN201510618916A CN105461647B CN 105461647 B CN105461647 B CN 105461647B CN 201510618916 A CN201510618916 A CN 201510618916A CN 105461647 B CN105461647 B CN 105461647B
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- valsartan
- bent
- trisodium salt
- salt composite
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- 229960004699 valsartan Drugs 0.000 title claims abstract description 148
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- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000011246 composite particle Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000576 food coloring agent Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- GTDHYNXLIKNVTJ-UHFFFAOYSA-N n-(1-hydroxy-2-methylpropan-2-yl)octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NC(C)(C)CO GTDHYNXLIKNVTJ-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 1
- 210000000607 neurosecretory system Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 229960003953 sacubitril Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to Valsartan sand libraries than crystal form A of bent trisodium salt composite and amorphous α, β, γ and preparation method thereof, the crystal form A and amorphous α, β, γ preparation method is simple, stability and favorable solubility, are suitable for preparing several formulations；The invention further relates to the pharmaceutical compositions containing above-mentioned crystal form or amorphous substance, can be used for prevention or chronic heart failure or hypertension drug.
Description
Technical field
The present invention relates to organic chemistry fileds and pharmaceutical field, and in particular to Valsartan sand library than bent compound crystal form and
Preparation method, comprising the pharmaceutical composition of these crystal forms and these crystal forms preparing for preventing or treat heart failure or height
Purposes in blood pressure medication.
Background technology
Valsartan sand library is than compound that bent or its salt is formed by Valsartan or its salt and husky library than bent compound.It is " multiple
Close object " refer to that Valsartan or its salt combine to coexist by the effect of hydrogen bond or other non-covalent bonds than bent or its salt with husky library
Compound with fixed stoichiometric ratio, for example, eutectic well known in the art is exactly the specific manifestation shape of the compound
One of formula.The compound still further comprise it polycrystalline, amorphous, solvate, solvate polycrystalline, hydrate, hydration
The forms such as object polycrystalline.
Valsartan, English common name：Valsartan, chemical name：(S)-N- valeryls-N- { [2 '-(1H- tetrazoles -5-
Base) [1,1 '-phenylbenzene] -4- bases] methyl }-valine, structure is a kind of angiotensin receptor antagonist shown in formula I.
Sha Ku is than bent, English common name：Sacubitril also known as：AHU-377, chemical name：4-{[(2S,4R)-1-([1,
1 '-phenylbenzene] -4- bases) the amyl- 2- yls of -5- ethyoxyl -4- methyl -5- oxos] amino } -4- ketobutyric acids, structure such as Formula II institute
Show, be a kind of enkephalinase inhibitor.
Valsartan sand library most more representative than bent compound is LCZ-696, and chemistry is entitled：[4-{[(2S,4R)-1-
The amyl- 2- yls of ([1,1 '-phenylbenzene] -4- bases) -5- ethyoxyl -4- methyl -5- oxos] amino } -4- ketobutyric acids-(S)-N- penta
Acyl group-N- { [2 "-(1H- tetrazole -5- bases) [1 ', 1 "-phenylbenzene] -4 '-yl] methyl }-valine] half pentahydrate of trisodium,
Structure is as shown in formula III：
LCZ-696 is researched and developed by Novartis Co., Ltd, and for chronic heart failure or hypertension, it is a kind of double action
Molecule can inhibit enkephalinase and angiotensin receptor simultaneously, can act on simultaneously renin-angiotensin system and
Promote brain natriuretic peptide cycle, this is a kind of pioneering new drug, in many ways cardioactive neuroendocrine system, blocks and applies
The receptor of adverse effect, while promote protective mechanism.Clinical research shows LCZ-696 chronic heart failures and high blood
The significant effect of pressure, good security.Novartis Co., Ltd planned for the end of the year 2014 in the U.S., and the first quarter in 2015 submits in European Union
LCZ-696 is used to treat the New Drug Application of the heart failure of ejection fraction reduction, and this product is expected to granted in becoming nearly 10 years be used for
The first new drug of chronic heart failure.The chronic heart failure and essential hypertension that LCZ-696 retains for ejection fraction
New Drug Application also will submit application middle in recent years.
LCZ-696 exists with solid-state form of the Valsartan sand library than bent half pentahydrate eutectic of trisodium salt.Patent
Its powder x-ray diffraction feature (being radiated using Cu-K α) is disclosed in CN101098689A is：2 θ values for 4.5 °, 5.6 °,
12.8 °, 17.0 °, 19.8 °, 21.5 °, 27.4 ° of positions be corresponding with characteristic diffraction peak.
LCZ-696 or Valsartan sand library generally use, therefore to its solid-state in solid form in the formulation than bent compound
The research of form has a very important significance.The present inventor is to research of the Valsartan sand library than bent compound solid-state form
Cheng Zhong is surprisingly found that new solid-state form of the Valsartan sand library than bent compound, they, which have, is significantly different from existing crystalline substance
The powder x-ray diffraction TuPu method of type, and preparation method is simple, crystal form is easily controllable, stability and favorable solubility,
Suitable for several formulations.
Invention content
It is an object of the present invention to provide new solid-state form of the Valsartan sand library than bent trisodium salt composite, these figured silk fabrics
Sha Tanshaku solid-state form preparation methods newer than bent trisodium salt composite are simple, crystal form is easily controllable, stability and dissolubility are good
It is good.
Another object of the present invention is to provide preparation of the Valsartan sand library than the new solid-state form of bent trisodium salt composite
Method.
It is newer than bent trisodium salt composite another object of the present invention is to provide the Valsartan sand library for including therapeutically effective amount
The pharmaceutical composition of solid-state form.
Another object of the present invention is to provide Valsartan sand library solid-state form newer than bent trisodium salt composite to prepare use
In prevention or the purposes of the drug of chronic heart failure or hypertension.
In order to achieve the above-mentioned object of the invention, present invention firstly provides a kind of Valsartan sand library than bent trisodium salt composite crystalline substance
Type A.
Further, the present invention provides a kind of Valsartan sand library is more amorphous α than bent trisodium salt composite.
Further, the present invention provides a kind of amorphous β of Valsartan-Sha Kubi songs trisodium salt composite.
Further, the present invention provides a kind of amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite.
Further, the present invention provides above-mentioned Valsartan sand library is more husky than bent trisodium salt composite crystal form A and Valsartan
The library preparation method more amorphous α, β, γ than bent trisodium salt composite.
Further, the present invention provides containing above-mentioned Valsartan sand library than bent trisodium salt composite crystal form A, Valsartan
Mixture more amorphous α, β, γ than bent trisodium salt composite Sha Ku.
Further, the present invention provides more husky than bent trisodium salt composite crystal form A or figured silk fabrics containing above-mentioned Valsartan sand library
Pharmaceutical composition more amorphous α, β, γ than bent trisodium salt composite Tan Shaku.
Further, the present invention provides above-mentioned Valsartan sand library is more husky than bent trisodium salt composite crystal form A or Valsartan
Library it is more amorphous α, β, γ than bent trisodium salt composite preparing for preventing or chronic heart failure or hypertension
The purposes of drug.
Valsartan sand library is than bent trisodium salt composite crystal form A
Powder x-ray diffraction collection of illustrative plates of the Valsartan sand library provided by the invention than bent trisodium salt composite crystal form A (uses
Cu-K α radiate) feature be：It it is 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.6 ° ± 0.2 °, 12.5 ° in 2 θ values
± 0.2 °, 16.9 ° ± 0.2 °, 20.0 ° ± 0.2 ° is waited positions to be corresponding with characteristic diffraction peak.
In one embodiment, Valsartan sand library of the present invention is than the powder of bent trisodium salt composite crystal form A
The feature of X-ray diffracting spectrum (being radiated using Cu-K α) is：2 θ values for 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 ° is waited positions
It is corresponding with characteristic diffraction peak.
In one embodiment, Valsartan sand library provided by the invention has such as than bent trisodium salt composite crystal form A
Feature representated by powder x-ray diffraction collection of illustrative plates shown in FIG. 1.
In one embodiment, Valsartan sand library provided by the invention is than the crystal form of bent trisodium salt composite crystal form A
Purity (i.e. Valsartan sand library is than the mass percentage of bent trisodium salt composite crystal form A) is generally higher than 70%, preferably greater than
80%, most preferably greater than 90%.The content can pass through powder x-ray diffraction method, differential scanning calorimetry (DSC) method or infrared
Absorption spectrometry etc. measures.
The present invention also provides a kind of preparation method of Valsartan sand library than bent trisodium salt composite crystal form A, this method packets
It includes：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated is detached；
(5) optionally, solid step (4) isolated is dry at 20~50 DEG C.
In above-mentioned steps (1), the Valsartan is the drug listed for many years, commercially viable to buy or be according to
It is prepared by the method known.For example, the preparation of Valsartan is described in US5399578 and EP0443983, these documents pass through reference
Mode is incorporated into the application.The sand library can be made than song according to the method disclosed in patent document US5217996A, this
A little documents are incorporated into the application by reference.
In above-mentioned steps (1), Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~1.2, preferably 1:
0.9~1.1.
In above-mentioned steps (1), the weight proportion of ethyl alcohol and Valsartan is generally 2:1~15:1, preferably 5:1~10:1.
In above-mentioned steps (2), alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide or ethyl alcohol
Sodium etc., preferably sodium hydroxide, sodium methoxide or sodium ethoxide.
In above-mentioned steps (2), the mol ratio that feeds intake of sodium and Valsartan in step (1) is generally in alkaline sodium compound
2.8~5:1, preferably 2.9~3.5:1.
In above-mentioned steps (2), the weight ratio of water and alkaline sodium compound is generally 0.5:1~10:1, preferably 0.5~5:1.
In above-mentioned steps (3), " anti-solvent " refers to prepared compound poor solubility and can be mutual with ethyl alcohol or water
Molten solvent.These anti-solvents are selected from acetone, butanone, pentanone, cyclohexanone, Ethyl formate, methyl acetate, ethyl acetate, acetic acid
Isopropyl ester, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, first
Benzene, dimethylbenzene etc. or their mixture, wherein it is preferred that isopropyl acetate and ethyl acetate.The anti-solvent and step (3)
The volume ratio of mixed solvent is generally 0.5:1~20:1.It can be standing or stirring that solid process, which is precipitated,.
In the step of above-mentioned preparation method (4), the routine side in the art such as filtering may be used in " separation "
Method.
In the step of above-mentioned preparation method (5), the temperature of " drying " is generally 20~50 DEG C；Can with constant pressure and dry,
It can also be dried under reduced pressure.
Valsartan sand library is more amorphous α than bent trisodium salt composite
The Valsartan sand library provided by the invention powder x-ray diffraction collection of illustrative plates more amorphous α than bent trisodium salt composite (makes
With Cu-K α radiate) feature be：Nearby there is peak for 4.5 °, 20.5 ° and 31.6 ° in 2 θ values.Wherein " near " general for 4.5 °
Range for the range of ± 0.5 ° of range, preferably ± 0.3 °, more preferably ± 0.2 °；The range for being generally ± 2 ° for 20.5 °,
It is preferred that the range of ± 1 ° of range, more preferably ± 0.5 °；For 31.6 ° generally ± 0.5 ° of range.
In one embodiment, Valsartan sand library provided by the invention is more amorphous α than bent trisodium salt composite has
Feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 2.
Valsartan-Sha Kubi is bent in the Valsartan-Sha Kubi song trisodium salt composite mix of preparation provided by the invention
The content (mass content) of the amorphous α of trisodium salt composite is generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be appreciated by persons skilled in the art that Valsartan-Sha Kubi songs trisodium salt composite of the present invention is referred to change
What synthetic method was synthetically prepared contains impurity or the Valsartan other crystal forms of-Sha Kubi song trisodium salt composites or unbodied figured silk fabrics
Sha Tan-Sha Kubi song trisodium salt composites.
In one embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 0.2~
20%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 2~
15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 4~
15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 5~
15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 6~
15%, in another embodiment, water content during Valsartan sand library is more amorphous α than bent trisodium salt composite for 7~
15%.
The present invention also provides the preparation method that a kind of Valsartan sand library is more amorphous α than bent trisodium salt composite, this method
Including：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated and the drying at 80~120 DEG C are detached.
In the step of above-mentioned preparation method (1), Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~
1.2, preferably 1:0.9~1.1.
In the step of above-mentioned preparation method (1), the weight proportion of ethyl alcohol and Valsartan is generally 2:1~15:1, preferably 5:1
~10:1.
In the step of above-mentioned preparation method (2), alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, first
Sodium alkoxide or sodium ethoxide etc., preferably sodium hydroxide, sodium methoxide or sodium ethoxide.
In the step of above-mentioned preparation method (2), sodium mole is matched with feeding intake for Valsartan in step (1) in alkaline sodium compound
Than being generally 2.8~5:1, preferably 2.9~3.5:1.
In the step of above-mentioned preparation method (2), the weight ratio of water and alkaline sodium compound is generally 0.5:1~10:1, it is excellent
Select 0.5~5:1.
In the step of above-mentioned preparation method (3), " anti-solvent " refers to prepared compound poor solubility and can be with
The solvent that ethyl alcohol or water dissolve each other.These anti-solvents are selected from acetone, butanone, pentanone, cyclohexanone, Ethyl formate, methyl acetate, acetic acid
Ethyl ester, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, tertiary butyl
Methyl ether, toluene, dimethylbenzene etc. or their mixture, wherein it is preferred that isopropyl acetate and ethyl acetate.The anti-solvent with
The volume ratio of the mixed solvent of step (3) is generally 0.5:1~20:1.Be precipitated solid process can be stand or
Stirring.
In the step of above-mentioned preparation method (4), the routine side in the art such as filtering may be used in " separation "
Method.
In the step of above-mentioned preparation method (4), the temperature of " drying " is generally 80~150 DEG C, preferably 110~140
℃；It can also be dried under reduced pressure with constant pressure and dry.
Valsartan sand library is more amorphous β than bent trisodium salt composite
The powder x-ray diffraction collection of illustrative plates of the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention (makes
With Cu-K α radiate) feature be：Peak nearby is corresponding with for 4.0 ° and 20.5 ° in 2 θ values, in 2 θ values for 31.6 ° nearby without correspondence
Peak.Wherein the specific location of " correspondence " is the vertex at peak.Wherein " near " for 4.0 ° of generally ± 0.5 ° of ranges, preferably
The range of ± 0.3 ° of range, more preferably ± 0.2 °；It is more excellent for the range of 20.5 ° generally ± 2 ° of range, preferably ± 1 °
The range of ± 0.5 ° of choosing；For 31.6 ° generally ± 0.5 ° of range.
In one embodiment, the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention has
Feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 3.
In one embodiment, the Valsartan-Sha Kubi song trisodiums salt composite mixing of preparation provided by the invention
The content (mass content) of the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite is generally higher than 70% in object, preferably greater than
80%, most preferably greater than 90%.
It will be appreciated by persons skilled in the art that Valsartan-Sha Kubi songs trisodium salt composite of the present invention refers to
Be the figured silk fabrics containing impurity or the other crystal forms of Valsartan-Sha Kubi song trisodium salt composites being synthetically prepared with chemical synthesis process
Sha Tan-Sha Kubi song trisodium salt composites.
In one embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 0.2~
20%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 2~
15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 4~
15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 5~
15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 6~
15%, in another embodiment, water content during Valsartan sand library is more amorphous β than bent trisodium salt composite for 7~
15%.
The present invention also provides the preparation method of the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite a kind of, this method
Including：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated, freeze-drying are detached.
In the step of above-mentioned preparation method (1), Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8~
1.2, preferably 1:0.9~1.1.
In the step of above-mentioned preparation method (1), the weight proportion of ethyl alcohol and Valsartan is generally 2:1~15:1, preferably 5:1
~10:1.
In the step of above-mentioned preparation method (2), alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, first
Sodium alkoxide or sodium ethoxide etc., preferably sodium hydroxide, sodium methoxide or sodium ethoxide.
In the step of above-mentioned preparation method (2), sodium mole is matched with feeding intake for Valsartan in step (1) in alkaline sodium compound
Than being generally 2.8~5:1, preferably 2.9~3.5:1.
In the step of above-mentioned preparation method (2), the weight ratio of water and alkaline sodium compound is generally 0.5:1~10:1, it is excellent
Select 0.5~5:1.
In the step of above-mentioned preparation method (3), " anti-solvent " refers to prepared compound poor solubility and energy
The solvent to dissolve each other with ethyl alcohol or water.These anti-solvents are selected from acetone, butanone, pentanone, cyclohexanone, Ethyl formate, methyl acetate, second
Acetoacetic ester, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, glycol dimethyl ether, tertiary fourth
Ylmethyl ether, toluene, dimethylbenzene etc. or their mixture, wherein it is preferred that isopropyl acetate and ethyl acetate.The anti-solvent
0.5 is generally with the volume ratio of the mixed solvent of step (3):1~20:1.It can stand that solid process, which is precipitated, can also
It is stirring.
In the step of above-mentioned preparation method (4), the routine side in the art such as filtering may be used in " separation "
Method.
In the step of above-mentioned preparation method (4), generally -70~-10 DEG C of the temperature of " freeze-drying ", preferably -60
~-40 DEG C；Pressure is generally 0~50Pa, preferably 1~10Pa.
Valsartan sand library is more amorphous γ than bent trisodium salt composite
The powder x-ray diffraction collection of illustrative plates of the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention
The feature of (being radiated using Cu-K α) is：Peak nearby is corresponding with for 4.5 ° and 20.5 ° in 2 θ values, in 2 θ values for 31.6 ° nearby without right
The peak answered.Wherein the specific location of " correspondence " is the vertex at peak.Wherein " near " for 4.5 ° of generally ± 1 ° of ranges, preferably
The range of ± 0.5 ° of range, more preferably ± 0.2 °；It is more excellent for the range of 20.5 ° generally ± 2 ° of range, preferably ± 1 °
The range of ± 0.5 ° of choosing；For 31.6 ° generally ± 0.5 ° of range.
Further, the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention has such as Fig. 4 institutes
The feature representated by powder x-ray diffraction collection of illustrative plates shown.
The representative powder X-ray of the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite provided by the invention spreads out
Collection of illustrative plates is penetrated to be listed in attached drawing (referring to Fig. 4)." representative powder x-ray diffraction collection of illustrative plates " refers to the powder X-ray of this crystal form
Diffractive features meet this collection of illustrative plates display whole pattern, it is to be appreciated that during the test, due to by many factors (such as
Processing method, instrument, test parameter, test operation of sample etc. when the granularity of test sample, test) influence, same crystalline substance
The characteristic diffraction peak intensity of powder x-ray diffraction collection of illustrative plates measured by type has certain difference.
Valsartan-Sha Kubi is bent in the Valsartan-Sha Kubi song trisodium salt composite mix of preparation provided by the invention
The content (mass content) of the amorphous γ of trisodium salt composite is generally higher than 70%, preferably greater than 80%, most preferably greater than 90%.
It will be appreciated by persons skilled in the art that Valsartan-Sha Kubi songs trisodium salt composite of the present invention is referred to change
What synthetic method was synthetically prepared contains impurity or the Valsartan other crystal forms of-Sha Kubi song trisodium salt composites or unbodied figured silk fabrics
Sha Tan-Sha Kubi song trisodium salt composites.
Water content during Valsartan sand library provided by the invention is more amorphous γ than bent trisodium salt composite is 0.2~20%,
In one embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 0.2~6%,
In one specific embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 0.2~4%, another
In one specific embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 2~15%, another
In specific embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 4~15%, in another tool
In body embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 5~15%, another specific
In embodiment, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 6~15%, in another specific reality
It applies in scheme, the water content during Valsartan sand library is more amorphous γ than bent trisodium salt composite is 7~15%.
The present invention also provides the preparation method of the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite a kind of, the party
Method includes：
(1) Valsartan, Sha Ku are dissolved in than bent and alkaline sodium compound in ethyl alcohol；
(2) solid is precipitated in the solution obtained by concentration step (1)；
(3) solid that separating step (2) is precipitated；
(4) optionally, the separated solid obtained of drying steps (3).
In the step of above-mentioned preparation method (1), the Valsartan is the drug listed for many years, it is commercially viable buy or
It can be prepared according to known method.For example, the preparation of Valsartan is described in US5399578 and EP0443983, these documents
It is incorporated into the application by reference.The sand library can be according to the side disclosed in patent document US5217996A than song
Method is made, these documents are incorporated into the application by reference.
In the step of above-mentioned preparation method (1), the alkaline sodium compound may be selected from sodium hydroxide, sodium carbonate, sodium ethoxide
Or sodium tert-butoxide etc., preferably sodium hydroxide or sodium ethoxide.
In the step of above-mentioned preparation method (1), the Valsartan is generally 1 with husky library than the bent mol ratio that feeds intake:0.8
~1.2, preferably 1:0.9~1.1.
In the step of above-mentioned preparation method (1), the mol ratio one that feeds intake of sodium and Valsartan in the alkaline sodium compound
As be 2.8~5:1, preferably 2.9~3.5:1.
It is described to be dissolved in Valsartan, Sha Ku in ethyl alcohol than bent and alkaline sodium compound in the step of above-mentioned preparation method (1)
Mode include by Valsartan, Sha Ku than song and alkaline sodium compound be dissolved in same ethyl alcohol and form ethanol solution or first by figured silk fabrics
Sha Tan, Sha Ku are partly or entirely dissolved in ethyl alcohol respectively than one or both of bent or alkaline sodium compound substance, then mix again
It closes, forms ethanol solution.
In the step of above-mentioned preparation method (2), the mode of the concentration includes：Directly concentrate；Or first concentrate, it adds anti-
Solvent, then concentrate；Or anti-solvent is first added in, then concentrate.These concentrations can be applied alone, and can also be combined.It is wherein described anti-molten
Agent refers to, to prepared compound poor solubility and the solvent that can dissolve each other with ethanolic moiety or all, may be selected from ether, isopropyl
Ether, n-butyl ether, t-butyl methyl ether, benzene,toluene,xylene, petroleum ether, n-hexane, normal heptane, isooctane etc. or theirs is mixed
Object is closed, wherein it is preferred that t-butyl methyl ether, toluene, n-hexane, normal heptane or isooctane.The mode packet for adding in anti-solvent
It includes：It is disposable to add in；Or be added portionwise, that is, it is concentrated after adding in anti-solvent, after concentrating remaining certain volume, is added in again anti-
Solvent, then concentrate, repeat the operation for adding anti-solvent and concentration.
In the step of above-mentioned preparation method (2), the concentration can carry out under normal pressure, can also carry out under reduced pressure；
Thickening temperature is generally 30 DEG C to solution boiling point.
In the step of above-mentioned preparation method (3), the conventional method in the art such as filtering may be used in the separation.
In the step of above-mentioned preparation method (4), the temperature of the drying is generally 30~70 DEG C；Can with constant pressure and dry,
It can be dried under reduced pressure.
In one embodiment, the present invention provides a kind of Valsartan sand libraries comprising therapeutically effective amount to answer than bent trisodium salt
Close the pharmaceutical composition or preparation of object crystal form A and pharmaceutic adjuvant.
In one embodiment, the present invention provides a kind of Valsartan sand libraries comprising therapeutically effective amount to answer than bent trisodium salt
Close the pharmaceutical composition or preparation of the amorphous α of object and pharmaceutic adjuvant.
In one embodiment, the present invention provides a kind of Valsartan-Sha Kubi song trisodium salts comprising therapeutically effective amount
The pharmaceutical composition or preparation of the amorphous β of compound and pharmaceutic adjuvant.
In one embodiment, the present invention provides a kind of Valsartan-Sha Kubi song trisodium salts comprising therapeutically effective amount
The pharmaceutical composition or preparation of the amorphous γ of compound and pharmaceutic adjuvant.
Aforementioned pharmaceutical compositions or preparation can orally or not oral administrations.It is preferred that peroral dosage form, including tablet, capsule,
Pill, granule, solution, syrup, dry suspensoid agent, suspension, powder, sustained release preparation or controlled release preparation etc..Wherein preferably
The solid orally ingestibles such as tablet, capsule, granule, dry suspensoid agent and sustained release preparation or controlled release preparation, wherein more preferable piece
Agent and capsule.
The various dosage forms of aforementioned pharmaceutical compositions can be prepared according to the conventional method of pharmaceutical field.Such as it will treat effective
The Valsartan sand library of amount is more amorphous α, β, γ than bent trisodium salt composite than bent trisodium salt composite crystal form A or Valsartan sand library,
Optionally with the active constituent of one or more therapeutically effective amounts, mix or contact with one or more pharmaceutic adjuvants, then
It is made into required dosage form.
In one embodiment, Valsartan sand library provided by the invention is more husky than bent trisodium salt composite crystal form A or figured silk fabrics
Tan Shaku is more amorphous α than bent trisodium salt composite, amorphous β, amorphous γ are mixed or contacted with one or more pharmaceutic adjuvants,
Then peroral dosage form, preferred tablet and capsule are made into.In the peroral dosage form, pharmaceutic adjuvant is selected from this field routine
Pharmaceutic adjuvant, including filler, disintegrant, adhesive, dispersant, lubricant or retention agent and all types of coating materials
Deng.
The filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium monohydrogen phosphate, calcium carbonate, mannitol, micro-
Crystalline cellulose, sorbierite, glucose etc., they, which can be used alone, to be used in mixed way, wherein it is preferred that lactose, microcrystalline cellulose
Element, pregelatinized starch, mannitol.
The disintegrant generally comprises cross-linked carboxymethyl cellulose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, is crosslinked and gathers
Vinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose etc., they, which can be used alone, to mix
It uses, wherein preferably microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low
Replace hydroxypropyl cellulose.
Described adhesive generally comprises microcrystalline cellulose, pre-paying starch, hydroxypropyl methyl cellulose, hydroxy propyl cellulose
Element, povidone, crospovidone, starch slurry, Arabic gum, Macrogol 4000, polyvinyl alcohol, alginates, water, various concentration
Ethanol solution, they, which can be used alone, to be used in mixed way, wherein it is preferred that crospovidone, povidone, hydroxypropyl first
Base cellulose, hydroxypropylcellulose.
The lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid richness horse
Sour potassium, palmitic acid, silica, stearmide, talcum powder, solid polyethylene glycol, glyceryl triacetate etc..They can be independent
Using that can also be used in mixed way, wherein it is preferred that silica, magnesium stearate, stearic acid, talcum powder.
If desired, other auxiliary materials can also be added into above-mentioned composition or preparation, as sweetener (such as aspartame,
Steviosin etc.), colorant (such as lemon yellow, iron oxide various medicinal or food coloring), stabilizer (such as calcium carbonate, bicarbonate
Calcium, sodium bicarbonate, sodium carbonate, calcium phosphate, calcium monohydrogen phosphate, glycine etc.), surfactant (such as Tween 80, dodecyl sulphate
Sodium etc.), coating material (such as Opadry, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin copolymer etc.).
In one embodiment, in aforementioned pharmaceutical compositions or preparation, Valsartan sand library is than bent trisodium salt composite
Crystal form A or Valsartan sand library it is more amorphous α, β, γ than bent trisodium salt composite particle diameter distribution control 90% be less than 100 μm, it is excellent
Choosing is less than 50 μm, more preferably less than 10 μm.
In one embodiment, in above-mentioned unitary pharmaceutical composition or preparation, Valsartan sand library is answered than bent trisodium salt
It closes object crystal form A or Valsartan sand the library weight content more amorphous α, β, γ than bent trisodium salt composite and is generally 1mg to 2g, preferably
10mg to 400mg, more preferable 50mg is between 200mg.
It is slower for preventing or treating preparing than bent trisodium salt composite that the present invention still further provides Valsartan sand library
Heart failure or hypertension become the purposes of the drug of the illness of feature, and wherein chronic heart failure is reduced including ejection fraction
Heart failure and the chronic heart failure etc. that retains of ejection fraction, hypertension is including primary etc..
In one embodiment, the present invention provides Valsartan sand library is more husky than bent trisodium salt composite crystal form A or figured silk fabrics
Tan Shaku is more amorphous α, β, γ than bent trisodium salt composite to be for prevention or chronic heart failure or hypertension in preparation
The purposes of the drug of the illness of feature.
The experiment proved that Valsartan sand library provided by the invention is than bent trisodium salt composite crystal form A or Valsartan sand library ratio
Amorphous α, β, γ preparation method of bent trisodium salt composite is easy, and crystal form is easily controllable, stability and favorable solubility, suitable for use
In preparation.
The powder x-ray diffraction analysis of the above-mentioned crystal of the present invention is under environment temperature and ambient humidity, through Dutch pa
Receiving the Cu-K α radiation of section's X`Pert PRO type Powder X-ray Diffractometers, (wavelength is) measure what is completed." environment temperature "
Usually 0~40 DEG C；" ambient humidity " is usually 30%~80% relative humidity.It is appreciated that during the test,
Due to by many factors (processing method of sample, instrument, test parameter, test operation when the granularity of such as test sample, test
Deng) influence, the characteristic diffraction peak position of the powder x-ray diffraction collection of illustrative plates measured by same crystal form or intensity have centainly
Difference.Under normal circumstances, the experimental error of 2 θ values of characteristic diffraction peak can be ± 0.2 ° in powder x-ray diffraction collection of illustrative plates.
Description of the drawings
Fig. 1 is powder x-ray diffraction collection of illustrative plates of the Valsartan sand library than bent trisodium salt composite crystal form A.
Fig. 2 is the Valsartan sand library powder x-ray diffraction collection of illustrative plates more amorphous α than bent trisodium salt composite.
Fig. 3 is the powder x-ray diffraction collection of illustrative plates of the amorphous β of Valsartan-Sha Kubi song trisodium salt composites.
Fig. 4 is the powder x-ray diffraction collection of illustrative plates of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites.
Specific embodiment
The specific embodiment of form by the following examples does further specifically the foregoing invention content of the present invention
It is bright, but the invention content that should not be construed as the present invention is only limitted to following embodiment, it is all to be made based on the above of the present invention
Invention all belongs to the scope of the present invention.
In following embodiment1H NMR tests are using deuterated methanol as test solvent, make internal standard with tetramethylsilane,
It is measured at room temperature with Bruke AV-III 400MHz Nuclear Magnetic Resonance.
Powder x-ray diffraction is by Dutch Panaco X`Pert PRO type Powder X-ray Diffractometers in following embodiment
It measures, test condition is using θ-θ configurations, scanning range as 4 ° -40 °, and step-length is 0.0130 °, continuous scanning.Testing light source is
Copper target K α radiation, PIXcel detectors；Voltage and current is respectively 40kV and 40mA.Method for making sample is：It uses at ambient conditions
Spoon takes appropriate sample to be placed in the groove of glass load sample piece, is suitably rolled with glass slide, sample is made to be evenly distributed on load sample piece
In groove, then with glass slide sample surfaces are struck off.Sample does not rotate in its own plane during test.
Freeze-drying is the FD-1A-50 freezings produced in Beijing Bo Yikang laboratory apparatus Co., Ltd in following embodiment
It is carried out in drying machine.
Embodiment 1：Valsartan sand library is than the preparation of bent trisodium salt composite crystal form A
At room temperature, by Valsartan 2.00g (4.60mmol), Sha Ku than bent 1.88g (4.60mmol) and absolute ethyl alcohol
(10ml) is mixed, and obtains clear solution.Into said mixture, the water-soluble of sodium hydroxide 0.55g (13.8mmol) is added in
Liquid 1ml.Above-mentioned system is heated to dropwise addition isopropyl acetate 100ml in 30~50 DEG C, about 10 minutes, until there is white precipitate precipitation.
It stands, cooling.There is white solid precipitation, filter, acetone washing filter cake, filter cake is dry at 30~40 DEG C, obtains Valsartan sand
Library is than bent trisodium salt composite crystal form A.
1H NMR(400MHz,CD3OD)δ:0.643-0.660(d,2H),0.811-0.847(m,2H),0.945-1.018
(m,5H),1.144-1.162(d,3H),1.207-1.243(t,3H),1.382-1.526(m,3H),1.630-1.670(m,
1H),1.886-1.955(m,1H),2.093-2.273(m,2H),2.393-2.441(m,4H),2.511-2.690(m,2H),
2.741-2.836(m,2H),3.901-3.928(d,1H),4.060-4.155(m,3H),4.539-4.583(m,1H),
4.911-4.956(m,1H),7.035-7.055(d,1H),7.101-7.121(d,1H),7.155-7.210(m,2H),
7.288-7.333(m,3H),7.372-7.443(m,4H),7.462-7.520(m,2H),7.540-7.560(d,2H),
7.596-7.619(m,2H)。
In above-mentioned 1H-NMR results, δ:7.035-7.619 shares 17 fragrant hydrogen, it can be determined that figured silk fabrics in the title product
Sha Tan is 1 than bent molar composition ratio with husky library:1.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 1, and measured value (takes relative intensity in the range of 4 ° -40 ° of 2 θ angles as follows
The measured value round off of measured value corresponding more than 1% diffraction maximum, 2 θ and d take three decimals, relative intensity measure value
Round off takes a decimal)：
Embodiment 2：The preparation more amorphous α than bent trisodium salt composite of Valsartan sand library
At room temperature, Valsartan 2.00g (4.60mmol), Sha Ku are than bent 1.88g (4.60mmol) and absolute ethyl alcohol (10ml)
It is mixed, obtains clear solution.Into said mixture, the aqueous solution 1ml of sodium methoxide 0.75g (13.8mmol) is added dropwise.Add
The above-mentioned system of heat is to dropwise addition isopropyl acetate 50ml in 30~50 DEG C, about 5 minutes, until there is white precipitate precipitation.Stirring cooling.Have
White solid is precipitated, filtering, acetone washing filter cake.Filter cake is dried under reduced pressure at 120~130 DEG C, obtains Valsartan sand library than song three
The amorphous α of sodium salt compound.
1H NMR(400MHz,CD3OD)δ:0.649-0.6665(d,2H),0.811-0.847(m,2H),0.945-1.019
(m,5H),1.145-1.256(d,3H),1.382-1.527(t,3H),1.382-1.527(m,3H),1.610-1685(m,
1H),1.887-1.957(m,1H),2.062-2.288(m,2H),2.393-2.440(m,4H),2.511-2.692(m,2H),
2.742-2.836(m,2h),3.903-3.929(d,1H),4.060-4.156(m,3H),4.535-4.581(m,1H),
4.905-4.959(m,1H),7.034-7.055(d,1H),7.101-7.121(d,1H),7.155-7.208(m,2H),
7.288-7.336(m,3H),7.373-7.443(m,4H),7.463-7.521(m,2H),7.540-7.561(d,2H),
7.598-7.619(m,2H)。
In above-mentioned 1H-NMR results, δ:7.034-7.619 shares 17 fragrant hydrogen, it can be determined that figured silk fabrics in the title product
Sha Tan is 1 than bent molar composition ratio with husky library:1.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 2, and measured value is as follows：
| 2θ(°) | Peak type | Relative intensity (%) |
| Near 4.5 | More sharp peak | 100 |
| Near 20.5 | Broad peak | — |
| Near 31.6 | More sharp peak | 32 |
Embodiment 3：Tablet of the sand library of Valsartan containing 50mg than bent trisodium salt composite crystal form A and its preparation
Prescription：
It prepares：By Valsartan sand library in upper table than bent trisodium salt composite crystal form A, microcrystalline cellulose, lactose monohydrate, crosslinking
Povidone equivalent is progressively increased after mixing, adds in magnesium stearate and silica, is uniformly mixed.It is pelletized using dry granulating machine,
Particle is sieved using 30 mesh screens.Then by the particle after screening and the tabletting after mixing of crospovidone, magnesium stearate.Make
It is coated with Opadry, obtains coating tablet.
Embodiment 4：The sand library of Valsartan containing the 100mg tablet more amorphous α than bent trisodium salt composite and its preparation
Prescription：
It prepares：By Valsartan sand library in upper table is more amorphous α than bent trisodium salt composite, microcrystalline cellulose, lactose monohydrate, friendship
Connection povidone equivalent is progressively increased after mixing, adds in magnesium stearate and silica, is uniformly mixed.Use dry granulation mechanism
Grain sieves particle using 30 mesh screens.Then the particle after screening and crospovidone, magnesium stearate are pressed after mixing
Piece.It is coated using Opadry, obtains coating tablet.
Embodiment 5：The preparation of the amorphous β of Valsartan-Sha Kubi song trisodium salt composites
At room temperature, by Valsartan 2.00g (4.60mmol), Sha Ku than bent 1.88g (4.60mmol) and absolute ethyl alcohol 10ml
It is mixed, obtains 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 dropwise addition isopropyl acetate 50ml in 40~50 DEG C, about 5 minutes；Stirring cooling, there is white solid precipitation, mistake
Filter, filter cake are washed through acetone, are freeze-dried under the conditions of about -54 DEG C, 10Pa, obtain Valsartan-Sha Kubi song trisodium salt composites
Amorphous β.
1H NMR(400MHz,CD3OD)δ:0.658-0.675(d,2H),0.811-0.849(m,2H),0.947-1.021
(m,5H),1.145-1.163(d,3H),1.206-1.241(d,3H),1.383-1.528(t,3H),1.633-1.654(m,
1H),1.889-1.959(m,1H),2.082-2.274(m,2H),2.405-2.420(m,4H),2.505-2.657(m,2H),
2.759-2.803(m,2h),3.908-3.935(d,1H),4.060-4.140(m,3H),4.534-4.582(m,1H),
4.897-4.911(m,1H),7.034-7.055(d,1H),7.100-7.121(d,1H),7.154-7.204(m,2H),
7.288-7.337(m,3H),7.394-7.443(m,4H),7.468-7.506(m,2H),7.540-7.560(d,2H),
7.595-7.618(m,2H)。
It is above-mentioned1In H-NMR results, δ:7.034-7.618 shares 17 fragrant hydrogen, it can be determined that figured silk fabrics in the title product
Sha Tan is 1 than bent molar composition ratio with husky library:1.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 3, and measured value is as follows：
| 2θ(°) | Peak type | Relative intensity (%) |
| Near 4.0 | More sharp peak | 100.0 |
| Near 20.5 | Broad peak | — |
The above-mentioned crystal form of gained is named as the amorphous β of Valsartan-Sha Kubi song trisodium salt composites.
Embodiment 6：The tablet of the amorphous β of-Sha Kubi song trisodium salt composites of Valsartan containing 50mg and its preparation
Prescription：
| Component | Content (mg/ pieces) |
| In particle | |
| Valsartan-Sha Kubi amorphous the β of song trisodium salt composite (preparing as described in Example 5) | 56.5 |
| Microcrystalline cellulose | 7.5 |
| Lactose monohydrate | 22.5 |
| Crospovidone | 5 |
| Silica | 0.5 |
| Magnesium stearate | 0.5 |
| Outside particle | |
| Crospovidone | 5 |
| Magnesium stearate | 0.5 |
| Opadry | 1.1 |
It prepares：By the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite in upper table, microcrystalline cellulose, lactose monohydrate,
Crospovidone equivalent is progressively increased after mixing, adds in magnesium stearate and silica, is uniformly mixed.Use dry granulation mechanism
Grain sieves particle using 30 mesh screens.Then the particle after screening and crospovidone, magnesium stearate are pressed after mixing
Piece.It is coated using Opadry, obtains coating tablet.
Embodiment 7：The tablet of the amorphous β of-Sha Kubi song trisodium salt composites of Valsartan containing 100mg and its preparation
Prescription：
| Component | Content (mg/ pieces) |
| In particle | |
| Valsartan-Sha Kubi amorphous the β of song trisodium salt composite (preparing as described in Example 5) | 113.0 |
| Microcrystalline cellulose | 15.0 |
| Lactose monohydrate | 45.0 |
| Crospovidone | 5.0 |
| Silica | 1.0 |
| Magnesium stearate | 1.0 |
| Outside particle | |
| Crospovidone | 10 |
| Magnesium stearate | 1.0 |
| Opadry | 2.2 |
It prepares：By the amorphous β of Valsartan-Sha Kubi songs trisodium salt composite in upper table, microcrystalline cellulose, lactose monohydrate,
Crospovidone equivalent is progressively increased after mixing, adds in magnesium stearate and silica, is uniformly mixed.Use dry granulation mechanism
Grain sieves particle using 30 mesh screens.Then the particle after screening and crospovidone, magnesium stearate are pressed after mixing
Piece.It is coated using Opadry, obtains coating tablet.
Embodiment 8：The preparation of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites
Sodium hydroxide 0.55g (13.8mmol) is dissolved in absolute ethyl alcohol 10ml；By Valsartan 2.00g (4.60mmol) and
Sha Ku is dissolved in than bent 1.88g (4.60mmol) in absolute ethyl alcohol 10ml.Under stirring, the ethanol solution of above-mentioned sodium hydroxide is added dropwise
To Valsartan and Sha Ku than in bent ethanol solution, obtaining clear solution.Decompression concentrated solution volume is to about at 30~40 DEG C
During 5ml, normal heptane 15ml is added in, is further concentrated to about 5ml, then repeat to add normal heptane 15ml and be concentrated into the operation 10 of about 5ml
It is secondary, there are a large amount of solids to be precipitated in system.Filtering, filter cake are washed through normal heptane, are dried under reduced pressure at 40~45 DEG C, obtain Valsartan-sand
Library is more amorphous γ than bent trisodium salt composite.
1H NMR(400MHz,CD3OD)δ:0.665-0.681(d,2H),0.817-0.853(m,2H),0.947-1.022
(m,5H),1.123-1.144(d,3H),1.205-1.241(d,3H),1.383-1.541(m,3H),1.614-1.675(m,
1H),1.889-1.959(m,1H),2.084-2.288(m,2H),2.389-2.472(m,4H),2.510-2.677(m,2H),
2.743-2.837(m,2H),3.916-3.943(d,1H),4.080-4.161(m,3H),4.551-4.590(d,1H),
4.796-4.925(m,1H),7.034-7.054(d,1H),7.101-7.122(d,1H),7.152-7.202(m,2H),
7.287-7.334(m,3H),7.382-7.443(m,4H),7.472-7.513(m,2H),7.5439-7.559(d,2H),
7.596-7.614(d,2H)。
It is above-mentioned1In H-NMR results, δ:7.034-7.618 shares 17 fragrant hydrogen, it can be determined that figured silk fabrics in the title product
Sha Tan is 1 than bent molar composition ratio with husky library:1.
The powder x-ray diffraction collection of illustrative plates surveyed is shown in Fig. 4, and measured value is as follows：
| 2θ(°) | Peak type | Relative intensity (%) |
| Near 4.5 | More sharp peak | 100.0 |
| Near 20.5 | Broad peak | — |
The above-mentioned crystal form of gained is named as the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites.
Embodiment 9：The preparation of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites
Sodium ethoxide 1.10g (16.1mmol) is dissolved in absolute ethyl alcohol 10ml；By Valsartan 2.00g (4.60mmol) and sand
Library is dissolved in than bent 1.88g (4.60mmol) in absolute ethyl alcohol 10ml.Under stirring, by the ethanol solution of above-mentioned sodium ethoxide be added dropwise to by
Valsartan and Sha Ku are than in bent ethanol solution 10ml, obtaining clear solution.Decompression concentrated solution volume is extremely at 35~40 DEG C
During about 5ml, toluene 15ml is added in, is further concentrated to about 5ml, then repeated plus toluene 15ml and the operation 5 times for being concentrated into about 5ml,
There are a large amount of solids to be precipitated in system.Filtering, filter cake are washed through toluene, are dried under reduced pressure at 65~70 DEG C, obtain Valsartan-Sha Kubi
The bent amorphous γ of trisodium salt composite.
Embodiment 10：The preparation of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites
Valsartan 2.20g (5.06mmol) and husky library are dissolved in than song 1.88g (4.60mmol) in absolute ethyl alcohol 20ml, added
Enter sodium hydroxide 0.55g (13.8mmol), stir dissolved clarification.Methyl tertiary butyl ether(MTBE) 400ml is added in, is concentrated under reduced pressure at 35~40 DEG C
It is precipitated to there is a large amount of solids.Filtering, obtains the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites.
Embodiment 11：The preparation of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites
Valsartan 1.80g (4.14mmol) and husky library are dissolved in than song 1.88g (4.60mmol) in absolute ethyl alcohol 50ml, added
Enter sodium ethoxide 0.94g (13.8mmol), stir dissolved clarification.Decompression concentrated solution is to there is solid precipitation at 35~40 DEG C.Filtering, filter
Cake is dried under reduced pressure at 50~55 DEG C, obtains the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites.
Embodiment 12：The tablet of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites and its preparation
Prescription：
| Component | Content (mg/ pieces) |
| In particle | |
| Valsartan-Sha Kubi amorphous the γ of song trisodium salt composite (preparing as described in Example 8) | 53.9 (based on anhydrides) |
| Microcrystalline cellulose | 7.5 |
| Lactose monohydrate | 22.5 |
| Crospovidone | 5 |
| Silica | 0.5 |
| Magnesium stearate | 0.5 |
| Outside particle | |
| Crospovidone | 5 |
| Magnesium stearate | 0.5 |
| Opadry | 1.1 |
It prepares：By the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite in upper table, microcrystalline cellulose, lactose monohydrate,
Crospovidone equivalent is progressively increased after mixing, adds in magnesium stearate and silica, is uniformly mixed.Use dry granulation mechanism
Grain sieves particle using 30 mesh screens.Then the particle after screening and crospovidone, magnesium stearate are pressed after mixing
Piece.It is coated using Opadry, obtains coating tablet.
Embodiment 13：The tablet of the amorphous γ of Valsartan-Sha Kubi song trisodium salt composites and its preparation
Prescription：
| Component | Content (mg/ pieces) |
| In particle | |
| Valsartan-Sha Kubi amorphous the γ of song trisodium salt composite (preparing as described in Example 8) | 107.8 (based on anhydrides) |
| Microcrystalline cellulose | 15.0 |
| Lactose monohydrate | 45.0 |
| Crospovidone | 5.0 |
| Silica | 1.0 |
| Magnesium stearate | 1.0 |
| Outside particle | |
| Crospovidone | 10 |
| Magnesium stearate | 1.0 |
| Opadry | 2.2 |
It prepares：By the amorphous γ of Valsartan-Sha Kubi songs trisodium salt composite in upper table, microcrystalline cellulose, lactose monohydrate,
Crospovidone equivalent is progressively increased after mixing, adds in magnesium stearate and silica, is uniformly mixed.Use dry granulation mechanism
Grain sieves particle using 30 mesh screens.Then the particle after screening and crospovidone, magnesium stearate are pressed after mixing
Piece.It is coated using Opadry, obtains coating tablet.
Embodiment 14：Stability study
LCZ696 (being prepared by the method disclosed in patent document CN101098689A), Valsartan sand library are taken than bent trisodium salt
Compound crystal form A (preparing as described in Example 1), Valsartan sand library are more amorphous α than bent trisodium salt composite (by embodiment 2
Method prepare), Valsartan sand library (preparing as described in Example 5) amorphous β than bent trisodium salt composite and Valsartan sand
Library (preparing as described in Example 8) more amorphous γ than bent trisodium salt composite carries out stability examination under the conditions of 40 DEG C ± 2 DEG C
It tests, is detected after 30 days, it is as a result as follows：
The studies above shows：Valsartan sand library provided by the invention is than bent trisodium salt composite crystal form A, Valsartan sand library ratio
The amorphous α of bent trisodium salt composite, Valsartan sand library is more amorphous β than bent trisodium salt composite and Valsartan sand library is than song trisodium salt
The stability of the amorphous γ of compound is suitable with LCZ696.
Embodiment 15：Solubility study
LCZ696 (being prepared by the method disclosed in patent document CN101098689A), Valsartan sand library are taken than bent trisodium salt
Compound crystal form A (preparing as described in Example 1), Valsartan sand library are more amorphous α than bent trisodium salt composite (by embodiment 2
Method prepare), Valsartan sand library (preparing as described in Example 5) amorphous β than bent trisodium salt composite and Valsartan sand
Library is more amorphous γ than bent trisodium salt composite (preparing as described in Example 8), measures them respectively in different pH medium
Dissolubility is as a result as follows：
| Medium | LCZ696 | Crystal form A | Amorphous α | Amorphous β | Amorphous γ |
| PH of buffer 1 | It is almost insoluble or insoluble | It is almost insoluble or insoluble | Soluble,very slightly | Soluble,very slightly | Soluble,very slightly |
| PH of buffer 3 | Soluble,very slightly | Soluble,very slightly | Slightly soluble | Slightly soluble | Slightly soluble |
| PH of buffer 5 | Slightly soluble | Slightly soluble | Slightly soluble | Slightly soluble | Slightly soluble |
| Water | It is readily soluble | It is readily soluble | It is readily soluble | It is readily soluble | It is readily soluble |
| PH of buffer 6.8 | Dissolving | Dissolving | Dissolving | Dissolving | Dissolving |
The studies above shows：Valsartan sand library provided by the invention is than bent trisodium salt composite crystal form A, Valsartan sand library ratio
The amorphous α of bent trisodium salt composite, Valsartan sand library is more amorphous β than bent trisodium salt composite and Valsartan sand library is than song trisodium salt
The dissolubility of the amorphous γ of compound is suitable with LCZ696 or more preferable.
Embodiment 16：Study on Hygroscopicity
LCZ696 (being prepared by the method disclosed in patent document CN101098689A) and Valsartan sand library are taken than song trisodium
Salt composite crystal form A (preparing as described in Example 1) is placed in the environment of relative humidity about 75%, observes its character, knot
Fruit is as follows：
| Sample | Moisture absorption situation under relative humidity about 75% |
| LCZ696 | It places about 30 minutes and becomes sticky |
| Crystal form A | Without significant change |
The studies above shows：Valsartan sand library provided by the invention is less than than the hygroscopicity of bent trisodium salt composite crystal form A
LCZ696.Valsartan sand library is conducive to its bulk pharmaceutical chemicals and preparation stability than the hygroscopicity that bent trisodium salt composite crystal form A improves
Raising, can also reduce the control requirement to its bulk pharmaceutical chemicals and preparation preparation manipulation and storage requirement, contribute to production efficiency
Improve the reduction with production cost.
The above description is merely a specific embodiment, but protection scope of the present invention is not limited thereto, any
Those skilled in the art disclosed herein technical scope in, can without the variation that creative work is expected or
It replaces, should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be limited with claims
Subject to fixed protection domain.
Claims (11)
1. a kind of Valsartan sand library is than bent trisodium salt composite, which is characterized in that it is crystal form A, powder x-ray diffraction collection of illustrative plates
2 θ values for 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.6 ° ± 0.2 °, 12.5 ° ± 0.2 °, 16.9 ° ± 0.2 °,
Characteristic diffraction peak is corresponding at 20.0 ° ± 0.2 °.
2. Valsartan sand library as described in claim 1 is than bent trisodium salt composite, which is characterized in that powder x-ray diffraction figure
Spectrum 2 θ values for 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 ° of ± 0.2 ° of positions be corresponding with characteristic diffraction peak.
3. Valsartan sand library as described in claim 1 is than bent trisodium salt composite, which is characterized in that the crystal has as schemed
The feature representated by powder x-ray diffraction collection of illustrative plates shown in 1.
4. Valsartan sand library as described in claim 1 is than bent trisodium salt composite, which is characterized in that crystal form purity is more than
70%.
5. Valsartan sand library as described in claim 1 is than bent trisodium salt composite, which is characterized in that crystal form purity is more than
80%.
6. Valsartan sand library as described in claim 1 is than bent trisodium salt composite, which is characterized in that crystal form purity is more than
90%.
7. claim 1-6 any one of them Valsartan sand library is than the preparation method of bent trisodium salt composite, it is characterised in that
Including：
(1) Valsartan and Sha Ku ratio songs are dissolved in ethyl alcohol；
(2) alkaline sodium compound is dissolved in water；
(3) solution that step (2) obtains with the solution that step (1) obtains is mixed, adds in anti-solvent and solid is precipitated；
(4) solid be precipitated is detached；
(5) optionally, solid step (4) isolated is dry at 20~50 DEG C.
8. preparation method as claimed in claim 7, which is characterized in that step (2) neutral and alkali sodium compound be selected from sodium hydroxide,
Sodium carbonate, sodium bicarbonate, sodium methoxide or sodium ethoxide；Anti-solvent is selected from acetone, butanone, pentanone, cyclohexanone, formic acid in step (3)
Ethyl ester, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, second
Glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene or their mixture.
9. preparation method as claimed in claim 7, which is characterized in that anti-solvent is selected from isopropyl acetate or second in step (3)
Acetoacetic ester.
10. a kind of pharmaceutical composition, it includes the Valsartan sand libraries according to any one of claims 1 to 6 of therapeutically effective amount
It is more compound than bent trisodium salt than any one of bent trisodium salt composite or claim 7~9 Valsartan sand library made from preparation method
Object and pharmaceutic adjuvant.
11. Valsartan sand library according to any one of claims 1 to 6 is any than bent trisodium salt composite or claim 7~9
Valsartan sand library made from preparation method described in is than bent trisodium salt composite in preparation for preventing or treat chronic mental and physical efforts
The purposes of the drug for the illness that failure or hypertension are characterized.
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| CN201510002956 | 2015-01-05 | ||
| CN201510002956X | 2015-01-05 | ||
| CN201510618916.8A CN105461647B (en) | 2014-09-28 | 2015-09-24 | Valsartan sand library is than solid-state form of bent trisodium salt composite and its preparation method and application |
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| EP3253740A1 (en) * | 2015-02-06 | 2017-12-13 | Mylan Laboratories Ltd. | Amorphous trisodium sacubitril valsartan and a process for the preparation thereof |
| KR102569599B1 (en) | 2015-08-28 | 2023-08-21 | 헤테로 랩스 엘티디. | Process for the preparation of dual-acting angiotensin receptor-neprilysin inhibitor compounds |
| 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 |
| WO2017191620A1 (en) * | 2016-05-06 | 2017-11-09 | Sun Pharmaceutical Industries Limited | A crystalline form of a salt of sacubitril and a process of its preparation |
| CN107468685B (en) * | 2016-06-08 | 2021-06-01 | 科贝源(北京)生物医药科技有限公司 | Pharmaceutical composition and compound for treating hypertension and heart failure |
| CN105902506A (en) * | 2016-06-12 | 2016-08-31 | 佛山市腾瑞医药科技有限公司 | Sacubitril/valsartan preparation and application thereof |
| EP3522886A4 (en) * | 2016-10-10 | 2020-02-19 | Laurus Labs Limited | STABLE AMORPHE FORM OF THE SACUBITRIL VALSARTAN TRINATRIUM COMPLEX AND METHOD FOR THE PRODUCTION THEREOF |
| AU2017349757A1 (en) | 2016-10-28 | 2019-05-30 | Biocon Limited | Amorphous trisodium sacubitril valsartan and process for its preparation |
| CN106518709A (en) * | 2016-11-07 | 2017-03-22 | 济南益新医药技术有限公司 | Preparation method of amorphous sacubitri valsartan sodium salt composite |
| CN107674038A (en) * | 2017-01-03 | 2018-02-09 | 上海博志研新药物技术有限公司 | ARB NEPi compounds, crystal formation, preparation method and application |
| CN107935958B (en) * | 2017-11-30 | 2021-02-09 | 中国药科大学 | Valsartan puerarin sodium salt compound and preparation method thereof |
| CN109776441B (en) * | 2018-05-24 | 2022-08-19 | 合肥合源药业有限公司 | Amorphous valsartan-sabotargol sodium compound |
| US20210177803A1 (en) | 2018-08-23 | 2021-06-17 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
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