CN105461647A - Solid forms of Valsartan-Sacubitril trisodium compound, and preparation method and use thereof - Google Patents
Solid forms of Valsartan-Sacubitril trisodium compound, and preparation method and use thereof Download PDFInfo
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- CN105461647A CN105461647A CN201510618916.8A CN201510618916A CN105461647A CN 105461647 A CN105461647 A CN 105461647A CN 201510618916 A CN201510618916 A CN 201510618916A CN 105461647 A CN105461647 A CN 105461647A
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- valsartan
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- 0 CCCC*(/*(/CC1C=CC(C(CCC=C2)=C2/C(/N[N+])=N\N)=CC1)=C(\C(C)C)/C(O)=O)=O Chemical compound CCCC*(/*(/CC1C=CC(C(CCC=C2)=C2/C(/N[N+])=N\N)=CC1)=C(\C(C)C)/C(O)=O)=O 0.000 description 1
- PYNXFZCZUAOOQC-UTKZUKDTSA-N CCOC([C@H](C)C[C@@H](Cc(cc1)ccc1-c1ccccc1)NC(CCC(O)=O)=O)=O Chemical compound CCOC([C@H](C)C[C@@H](Cc(cc1)ccc1-c1ccccc1)NC(CCC(O)=O)=O)=O PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 description 1
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- 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
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- 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
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Abstract
The invention relates to a crystal form A and amorphous alpha, beta and gamma of a Valsartan-Sacubitril trisodium compound, and a preparation method thereof. The crystal form A and the amorphous alpha, beta and gamma have the advantages of simple preparation method, good stability and solubility, and suitableness for preparing various preparations. The invention also relates to a medicinal composition containing the crystal form or the amorphous substances, and a use of the compound in the preparation of drugs for preventing or treating chronic heart failure or hypertension.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, be specifically related to the crystal formation and preparation method thereof of the husky storehouse of valsartan than bent mixture, comprise the pharmaceutical composition of these crystal formations, and these crystal formations for the preparation of prevention treatment heart failure or hypertension drug in purposes.
Background technology
The husky storehouse of valsartan is by valsartan than bent mixture or its salt is bent with husky storehouse ratio or the mixture of its salt formation." mixture " refers to that valsartan or its salt and husky storehouse are combined by the effect of hydrogen bond or other non covalent bonds than bent or its salt and the compound with fixing stoichiometric ratio that coexists, such as, eutectic well known in the art is exactly one of concrete manifestation form of this mixture.This mixture also comprises its polycrystalline, amorphous, the form such as solvate, solvate polycrystalline, hydrate, hydrate polycrystalline further.
Valsartan; English popular name: valsartan, chemical name: (S)-N-pentanoyl-N-{ [2 '-(1H-tetrazole-5-base) [1,1 '-diphenyl]-4-base] methyl }-α-amino-isovaleric acid; structure, such as formula shown in I, is a kind of angiotensin receptor antagonist.
Sha Ku is than bent, English popular name: sacubitril, have another name called: AHU-377, chemical name: 4-{ [(2S, 4R)-1-([1,1 '-diphenyl]-4-base)-5-oxyethyl group-4-methyl-5-oxo penta-2-base] amino-4-ketobutyric acid, structure, such as formula shown in II, is a kind of enkephalinase inhibitor.
The husky storehouse of valsartan is more representational than bent mixture most is LCZ-696; its chemistry is by name: [4-{ [(2S; 4R)-1-([1; 1 '-diphenyl]-4-base)-5-oxyethyl group-4-methyl-5-oxo penta-2-base] amino-4-ketobutyric acid-(S)-N-pentanoyl-N-{ [2 "-(1H-tetrazole-5-base) [1 '; 1 "-diphenyl]-4 '-Ji] methyl }-α-amino-isovaleric acid] trisodium half pentahydrate, structure is as shown in formula III:
LCZ-696 is researched and developed by Novartis Co., Ltd; be used for the treatment of chronic heart failure or hypertension; it is a kind of molecule of dual function; enkephalinase and angiotensin receptor can be suppressed simultaneously; can act on renin-angiotensin system simultaneously and promote that brain natriuretic peptide circulates, this is a kind of pioneering new drug, in many ways cardioactive neuroendocrine system; block the acceptor applying harmful effect, promote protective mechanism simultaneously.Clinical study shows, LCZ-696 chronic heart failure and hypertensive Be very effective, security is good.Novartis Co., Ltd planned for the end of the year 2014 in the U.S., and the first quarter in 2015 submits to LCZ-696 to be used for the treatment of the new drug application of the heart failure that ejection fraction reduces in European Union, and this product is expected to become the granted first new drug for chronic heart failure in nearly 10 years.The new drug application that LCZ-696 is used for chronic heart failure that ejection fraction retains and essential hypertension also will in recent years submit applications.
LCZ-696 exists than the solid-state form of bent trisodium salt half pentahydrate eutectic with the husky storehouse of valsartan.Disclosing its powder x-ray diffraction feature (use Cu-K α radiation) in patent CN101098689A is: be that 4.5 °, 5.6 °, 12.8 °, 17.0 °, 19.8 °, 21.5 °, 27.4 ° positions are to having characteristic diffraction peak in 2 θ values.
LCZ-696 or the husky storehouse of valsartan generally use in the formulation in solid form than bent mixture, are therefore of great significance the research tool of its solid-state form.The present inventor is in the research process of the husky storehouse of valsartan than bent mixture solid-state form, surprisingly find the new solid-state form of the husky storehouse of valsartan than bent mixture, they have the powder x-ray diffraction TuPu method being significantly different from existing crystal formation, and preparation method is simple, crystal formation is easy to control, stability and favorable solubility, is applicable to several formulations.
Summary of the invention
One object of the present invention is the new solid-state form providing the husky storehouse of valsartan than bent trisodium salt mixture, and the husky storehouse of these valsartans is simpler than bent trisodium salt mixture new solid-state form preparation method, crystal formation is easy to control, stability and favorable solubility.
Another object of the present invention is to the preparation method providing the husky storehouse of valsartan than the new solid-state form of bent trisodium salt mixture.
Another object of the present invention is that providing package contains the pharmaceutical composition of the husky storehouse of the valsartan solid-state form newer for bent trisodium salt mixture for the treatment of significant quantity.
Another object of the present invention is to provide the husky storehouse of valsartan than the purposes of the new solid-state form of bent trisodium salt mixture at the medicine for the preparation of prevention or chronic heart failure or hypertension.
In order to realize foregoing invention object, the present invention provide firstly the husky storehouse of a kind of valsartan than bent trisodium salt mixture crystal form A.
Further, the invention provides the husky storehouse α more amorphous than bent trisodium salt mixture of a kind of valsartan.
Further, the invention provides the amorphous β of the bent trisodium salt mixture of a kind of valsartan-Sha Kubi.
Further, the invention provides the amorphous γ of the bent trisodium salt mixture of a kind of valsartan-Sha Kubi.
Further, the invention provides the preparation method of the husky storehouse of above-mentioned valsartan than bent trisodium salt mixture crystal form A and the husky storehouse of valsartan α, β, γ more amorphous than bent trisodium salt mixture.
Further, the invention provides the mixture containing the husky storehouse of above-mentioned valsartan α, β, γ more amorphous than bent trisodium salt mixture than bent trisodium salt mixture crystal form A, the husky storehouse of valsartan.
Further, the invention provides containing the pharmaceutical composition of the husky storehouse of above-mentioned valsartan than bent trisodium salt mixture crystal form A or the husky storehouse of valsartan α, β, γ more amorphous than bent trisodium salt mixture.
Further, the invention provides the husky storehouse of above-mentioned valsartan than bent trisodium salt mixture crystal form A or the husky storehouse of valsartan than bent trisodium salt mixture amorphous α, β, γ purposes at the medicine for the preparation of prevention or chronic heart failure or hypertension.
the husky storehouse of valsartan is than bent trisodium salt mixture crystal form A
The husky storehouse of valsartan provided by the invention than the feature of the powder x-ray diffraction collection of illustrative plates (using Cu-K α radiation) of bent trisodium salt mixture crystal form A is: be that the position correspondence such as 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.6 ° ± 0.2 °, 12.5 ° ± 0.2 °, 16.9 ° ± 0.2 °, 20.0 ° ± 0.2 ° has characteristic diffraction peak in 2 θ values.
In one embodiment, the husky storehouse of valsartan of the present invention than the feature of the powder x-ray diffraction collection of illustrative plates (using Cu-K α radiation) of bent trisodium salt mixture crystal form A is: be 4.1 ° ± 0.2 ° in 2 θ values, 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 °, the position correspondence such as 29.1 ° ± 0.2 ° has characteristic diffraction peak.
In one embodiment, the husky storehouse of valsartan provided by the invention has as shown in Figure 1 representated by powder x-ray diffraction collection of illustrative plates than bent trisodium salt mixture crystal form A a feature.
In one embodiment, the husky storehouse of valsartan provided by the invention is generally greater than 70% than the crystal form purity (namely valsartan sand storehouse is than the mass percentage of bent trisodium salt mixture crystal form A) of bent trisodium salt mixture crystal form A, be preferably greater than 80%, be most preferably greater than 90%.This content can pass through powder x-ray diffraction method, means of differential scanning calorimetry (DSC) method or infrared spectroscopy etc. record.
Present invention also offers the preparation method of the husky storehouse of a kind of valsartan than bent trisodium salt mixture crystal form A, the method comprises:
(1) valsartan and Sha Ku are dissolved in ethanol than song;
(2) alkaline sodium compound is water-soluble;
(3) solution that solution step (2) obtained and step (1) obtain mixes, and adds anti-solvent and separates out solid;
(4) solid of separating out is separated;
(5) optional, step (4) isolated solid is dry at 20 ~ 50 DEG C.
In above-mentioned steps (1), described valsartan is the medicine gone on the market for many years, can commercialization buy, or can prepare according to known method.Such as, the preparation of valsartan is described in US5399578 and EP0443983, and these documents are incorporated in the application by way of reference.Described husky storehouse can obtain according to method disclosed in patent documentation US5217996A than song, and these documents are incorporated in the application by way of reference.
In above-mentioned steps (1), valsartan is generally 1:0.8 ~ 1.2, preferred 1:0.9 ~ 1.1 with husky storehouse than the bent mol ratio that feeds intake.
In above-mentioned steps (1), the weight proportion of ethanol and valsartan is generally 2:1 ~ 15:1, preferred 5:1 ~ 10:1.
In above-mentioned steps (2), alkaline sodium compound selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methylate or sodium ethylate etc., preferred sodium hydroxide, sodium methylate or sodium ethylate.
In above-mentioned steps (2), in alkaline sodium compound, the mol ratio that feeds intake of sodium and the middle valsartan of step (1) is generally 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), described " anti-solvent " refer to prepared mixture poor solubility and can and the solvent that dissolves each other of ethanol or water.These anti-solvent are selected from acetone, butanone, pentanone, pimelinketone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene etc. or their mixture, wherein preferred isopropyl acetate and ethyl acetate.The volume ratio of the mixed solvent of described anti-solvent and step (3) is generally 0.5:1 ~ 20:1.It can be standing for separating out solid process, also can be to stir.
In the step (4) of above-mentioned preparation method, described " separation " can adopt the ordinary method of filtering and waiting in the art.
In the step (5) of above-mentioned preparation method, the temperature of described " drying " is generally 20 ~ 50 DEG C; Can constant pressure and dry, also can drying under reduced pressure.
the husky storehouse α more amorphous than bent trisodium salt mixture of valsartan
The feature of the powder x-ray diffraction collection of illustrative plates (using Cu-K α radiation) of the husky storehouse α more amorphous than bent trisodium salt mixture of valsartan provided by the invention is: be have peak near 4.5 °, 20.5 ° and 31.6 ° in 2 θ values.Wherein " near " be generally ± scope of 0.5 ° for 4.5 °, the preferably ± scope of 0.3 °, the scope of more preferably ± 0.2 °; ± the scope of 2 ° is generally, the preferably ± scope of 1 °, the scope of more preferably ± 0.5 ° for 20.5 °; ± the scope of 0.5 ° is generally for 31.6 °.
In one embodiment, the husky storehouse of valsartan provided by the invention has as shown in Figure 2 representated by powder x-ray diffraction collection of illustrative plates than the amorphous α of bent trisodium salt mixture a feature.
In the bent trisodium salt composite mix of valsartan-Sha Kubi of preparation provided by the invention, the content (mass content) of the amorphous α of the bent trisodium salt mixture of valsartan-Sha Kubi is generally greater than 70%, is preferably greater than 80%, is most preferably greater than 90%.It will be appreciated by persons skilled in the art that the bent trisodium salt mixture of valsartan-Sha Kubi of the present invention refer to chemical synthesis process synthesis preparation containing impurity or bent trisodium salt other crystal formation of mixture of valsartan-Sha Kubi or the bent trisodium salt mixture of unbodied valsartan-Sha Kubi.
In one embodiment, the husky storehouse of valsartan is 0.2 ~ 20% than the water content in the amorphous α of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 2 ~ 15% than the water content in the amorphous α of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 4 ~ 15% than the water content in the amorphous α of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 5 ~ 15% than the water content in the amorphous α of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 6 ~ 15% than the water content in the amorphous α of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 7 ~ 15% than the water content in the amorphous α of bent trisodium salt mixture.
Present invention also offers the preparation method of the husky storehouse α more amorphous than bent trisodium salt mixture of a kind of valsartan, the method comprises:
(1) valsartan and Sha Ku are dissolved in ethanol than song;
(2) alkaline sodium compound is water-soluble;
(3) solution that solution step (2) obtained and step (1) obtain mixes, and adds anti-solvent and separates out solid;
(4) solid of separating out is separated and dry at 80 ~ 120 DEG C.
In the step (1) of above-mentioned preparation method, valsartan is generally 1:0.8 ~ 1.2, preferred 1:0.9 ~ 1.1 with husky storehouse than the bent mol ratio that feeds intake.
In the step (1) of above-mentioned preparation method, the weight proportion of ethanol and valsartan is generally 2:1 ~ 15:1, preferred 5:1 ~ 10:1.
In the step (2) of above-mentioned preparation method, alkaline sodium compound selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methylate or sodium ethylate etc., preferred sodium hydroxide, sodium methylate or sodium ethylate.
In the step (2) of above-mentioned preparation method, in alkaline sodium compound, the mol ratio that feeds intake of sodium and the middle valsartan of step (1) is generally 2.8 ~ 5:1, preferably 2.9 ~ 3.5:1.
In the step (2) of above-mentioned preparation method, the weight ratio of water and alkaline sodium compound is generally 0.5:1 ~ 10:1, preferably 0.5 ~ 5:1.
In the step (3) of above-mentioned preparation method, described " anti-solvent " refer to prepared mixture poor solubility and can and the solvent that dissolves each other of ethanol or water.These anti-solvent are selected from acetone, butanone, pentanone, pimelinketone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene etc. or their mixture, wherein preferred isopropyl acetate and ethyl acetate.The volume ratio of the mixed solvent of described anti-solvent and step (3) is generally 0.5:1 ~ 20:1.It can be standing for separating out solid process, also can be to stir.
In the step (4) of above-mentioned preparation method, described " separation " can adopt the ordinary method of filtering and waiting in the art.
In the step (4) of above-mentioned preparation method, the temperature of described " drying " is generally 80 ~ 150 DEG C, preferably 110 ~ 140 DEG C; Can constant pressure and dry, also can drying under reduced pressure.
the husky storehouse β more amorphous than bent trisodium salt mixture of valsartan
The feature of the powder x-ray diffraction collection of illustrative plates (using Cu-K α radiation) of the amorphous β of the bent trisodium salt mixture of valsartan-Sha Kubi provided by the invention is: be to having peak near 4.0 ° and 20.5 ° in 2 θ values, is the peak of nothing correspondence near 31.6 ° in 2 θ values.Wherein the particular location of " correspondence " is the summit at peak.Wherein " near " be generally ± scope of 0.5 ° for 4.0 °, the preferably ± scope of 0.3 °, the scope of more preferably ± 0.2 °; ± the scope of 2 ° is generally, the preferably ± scope of 1 °, the scope of more preferably ± 0.5 ° for 20.5 °; ± the scope of 0.5 ° is generally for 31.6 °.
In one embodiment, the amorphous β of the bent trisodium salt mixture of valsartan-Sha Kubi provided by the invention has the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 3.
In one embodiment, in the bent trisodium salt composite mix of valsartan-Sha Kubi of preparation provided by the invention, the content (mass content) of the amorphous β of the bent trisodium salt mixture of valsartan-Sha Kubi is generally greater than 70%, be preferably greater than 80%, be most preferably greater than 90%.
It will be appreciated by persons skilled in the art that the bent trisodium salt mixture of valsartan-Sha Kubi of the present invention refers to the bent trisodium salt mixture of valsartan-Sha Kubi containing impurity or other crystal formation of the bent trisodium salt mixture of valsartan-Sha Kubi with chemical synthesis process synthesis preparation.
In one embodiment, the husky storehouse of valsartan is 0.2 ~ 20% than the water content in the amorphous β of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 2 ~ 15% than the water content in the amorphous β of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 4 ~ 15% than the water content in the amorphous β of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 5 ~ 15% than the water content in the amorphous β of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 6 ~ 15% than the water content in the amorphous β of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 7 ~ 15% than the water content in the amorphous β of bent trisodium salt mixture.
Present invention also offers the preparation method of the amorphous β of the bent trisodium salt mixture of a kind of valsartan-Sha Kubi, the method comprises:
(1) valsartan and Sha Ku are dissolved in ethanol than song;
(2) alkaline sodium compound is water-soluble;
(3) solution that solution step (2) obtained and step (1) obtain mixes, and adds anti-solvent and separates out solid;
(4) solid of separating out is separated, lyophilize.
In the step (1) of above-mentioned preparation method, valsartan is generally 1:0.8 ~ 1.2, preferred 1:0.9 ~ 1.1 with husky storehouse than the bent mol ratio that feeds intake.
In the step (1) of above-mentioned preparation method, the weight proportion of ethanol and valsartan is generally 2:1 ~ 15:1, preferred 5:1 ~ 10:1.
In the step (2) of above-mentioned preparation method, alkaline sodium compound selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methylate or sodium ethylate etc., preferred sodium hydroxide, sodium methylate or sodium ethylate.
In the step (2) of above-mentioned preparation method, in alkaline sodium compound, the mol ratio that feeds intake of sodium and the middle valsartan of step (1) is generally 2.8 ~ 5:1, preferably 2.9 ~ 3.5:1.
In the step (2) of above-mentioned preparation method, the weight ratio of water and alkaline sodium compound is generally 0.5:1 ~ 10:1, preferably 0.5 ~ 5:1.
In the step (3) of above-mentioned preparation method, described " anti-solvent " refer to prepared mixture poor solubility and can and the solvent that dissolves each other of ethanol or water.These anti-solvent are selected from acetone, butanone, pentanone, pimelinketone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene etc. or their mixture, wherein preferred isopropyl acetate and ethyl acetate.The volume ratio of the mixed solvent of described anti-solvent and step (3) is generally 0.5:1 ~ 20:1.It can be standing for separating out solid process, also can be to stir.
In the step (4) of above-mentioned preparation method, described " separation " can adopt the ordinary method of filtering and waiting in the art.
In the step (4) of above-mentioned preparation method, the temperature of described " lyophilize " is generally-70 ~-10 DEG C, preferably-60 ~-40 DEG C; Pressure is generally 0 ~ 50Pa, preferably 1 ~ 10Pa.
the husky storehouse γ more amorphous than bent trisodium salt mixture of valsartan
The feature of the powder x-ray diffraction collection of illustrative plates (using Cu-K α radiation) of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi provided by the invention is: be to having peak near 4.5 ° and 20.5 ° in 2 θ values, is the peak of nothing correspondence near 31.6 ° in 2 θ values.Wherein the particular location of " correspondence " is the summit at peak.Wherein " near " be generally ± scope of 1 ° for 4.5 °, the preferably ± scope of 0.5 °, the scope of more preferably ± 0.2 °; ± the scope of 2 ° is generally, the preferably ± scope of 1 °, the scope of more preferably ± 0.5 ° for 20.5 °; ± the scope of 0.5 ° is generally for 31.6 °.
Further, the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi provided by the invention has the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 4.
The representational powder x-ray diffraction collection of illustrative plates of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi provided by the invention lists in (see Fig. 4) in accompanying drawing." representational powder x-ray diffraction collection of illustrative plates " refers to that the powder x-ray diffraction feature of this crystal formation meets the overall pattern of this collection of illustrative plates display, be understandable that in test process, due to be subject to many factors (as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc.) impact, the characteristic diffraction peak intensity of the powder x-ray diffraction collection of illustrative plates measured by same crystal formation has certain difference.
In the bent trisodium salt composite mix of valsartan-Sha Kubi of preparation provided by the invention, the content (mass content) of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi is generally greater than 70%, is preferably greater than 80%, is most preferably greater than 90%.It will be appreciated by persons skilled in the art that the bent trisodium salt mixture of valsartan-Sha Kubi of the present invention refer to chemical synthesis process synthesis preparation containing impurity or bent trisodium salt other crystal formation of mixture of valsartan-Sha Kubi or the bent trisodium salt mixture of unbodied valsartan-Sha Kubi.
The husky storehouse of valsartan provided by the invention is 0.2 ~ 20% than the water content in the amorphous γ of bent trisodium salt mixture, in one embodiment, the husky storehouse of valsartan is 0.2 ~ 6% than the water content in the amorphous γ of bent trisodium salt mixture, in one embodiment, the husky storehouse of valsartan is 0.2 ~ 4% than the water content in the amorphous γ of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 2 ~ 15% than the water content in the amorphous γ of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 4 ~ 15% than the water content in the amorphous γ of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 5 ~ 15% than the water content in the amorphous γ of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 6 ~ 15% than the water content in the amorphous γ of bent trisodium salt mixture, in another embodiment, the husky storehouse of valsartan is 7 ~ 15% than the water content in the amorphous γ of bent trisodium salt mixture.
Present invention also offers the preparation method of the amorphous γ of the bent trisodium salt mixture of a kind of valsartan-Sha Kubi, the method comprises:
(1) valsartan, Sha Ku are dissolved in ethanol than bent and alkaline sodium compound;
(2) solution of enrichment step (1) gained, separates out solid;
(3) separating step (2) solid of separating out;
(4) optional, the solid obtained that drying step (3) is separated.
In the step (1) of above-mentioned preparation method, described valsartan is the medicine gone on the market for many years, can commercialization buy, or can prepare according to known method.Such as, the preparation of valsartan is described in US5399578 and EP0443983, and these documents are incorporated in the application by way of reference.Described husky storehouse can obtain according to method disclosed in patent documentation US5217996A than song, and these documents are incorporated in the application by way of reference.
In the step (1) of above-mentioned preparation method, described alkaline sodium compound selected from sodium hydroxide, sodium carbonate, sodium ethylate or sodium tert-butoxide etc., preferred sodium hydroxide or sodium ethylate.
In the step (1) of above-mentioned preparation method, described valsartan is generally 1:0.8 ~ 1.2, preferred 1:0.9 ~ 1.1 with husky storehouse than the bent mol ratio that feeds intake.
In the step (1) of above-mentioned preparation method, in described alkaline sodium compound, the mol ratio that feeds intake of sodium and valsartan is generally 2.8 ~ 5:1, preferably 2.9 ~ 3.5:1.
In the step (1) of above-mentioned preparation method, described valsartan, Sha Ku are comprised valsartan, Sha Ku to be dissolved in same ethanol than bent and alkaline sodium compound than bent and the alkaline sodium compound mode be dissolved in ethanol form ethanolic soln, or first valsartan, Sha Ku are partly or entirely dissolved in ethanol respectively than one or both materials in bent or alkaline sodium compound, and then mix, form ethanolic soln.
In the step (2) of above-mentioned preparation method, described concentrated mode comprises: directly concentrate; Or first concentrate, then add anti-solvent, reconcentration; Or first add anti-solvent, reconcentration etc.These concentrate can be alone, also can coupling.Wherein said anti-solvent refer to prepared mixture poor solubility and can and ethanolic moiety or the solvent that all dissolves each other, ether, isopropyl ether, n-butyl ether, t-butyl methyl ether, benzene,toluene,xylene, sherwood oil, normal hexane, normal heptane, octane-iso etc. or their mixture can be selected from, wherein preferred t-butyl methyl ether, toluene, normal hexane, normal heptane or octane-iso.The described mode adding anti-solvent comprises: disposablely add; Or add, concentrate after namely adding anti-solvent, after concentrated residue certain volume, again add anti-solvent, reconcentration, repeat this and add anti-solvent and concentrated operation. in batches
In the step (2) of above-mentioned preparation method, described concentrating can be carried out at ambient pressure, also can under reduced pressure carry out; Thickening temperature is generally 30 DEG C to solution boiling point.
In the step (3) of above-mentioned preparation method, described separation can adopt the ordinary method of filtering and waiting in the art.
In the step (4) of above-mentioned preparation method, the temperature of described drying is generally 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure.
In one embodiment, the invention provides a kind of husky storehouse of valsartan comprising treatment significant quantity than the pharmaceutical composition of bent trisodium salt mixture crystal form A and pharmaceutical excipient or preparation.
In one embodiment, the invention provides a kind of husky storehouse of valsartan comprising treatment significant quantity than the pharmaceutical composition of the amorphous α of bent trisodium salt mixture and pharmaceutical excipient or preparation.
In one embodiment, the invention provides a kind of pharmaceutical composition or the preparation that comprise the bent amorphous β of trisodium salt mixture of the valsartan-Sha Kubi treating significant quantity and pharmaceutical excipient.
In one embodiment, the invention provides a kind of pharmaceutical composition or the preparation that comprise the bent amorphous γ of trisodium salt mixture of the valsartan-Sha Kubi treating significant quantity and pharmaceutical excipient.
Aforementioned pharmaceutical compositions or preparation can per os or not oral administrations.Preferred oral formulation, comprises tablet, capsule, pill, granule, solution, syrup, dry suspensoid, suspensoid, powder, sustained release preparation or controlled release preparation etc.Wherein preferred tablet, capsule, granule, dry suspensoid and the solid orally ingestible such as sustained release preparation or controlled release preparation, wherein more preferably Tablet and Capsula agent.
The various formulations of aforementioned pharmaceutical compositions can be prepared according to the ordinary method of pharmaceutical field.Such as by the husky storehouse of valsartan for the treatment of significant quantity than bent trisodium salt mixture crystal form A or the husky storehouse of valsartan α, β, γ more amorphous than bent trisodium salt mixture, alternatively with activeconstituents that is another kind of or multiple treatment significant quantity, mix with one or more pharmaceutical excipients or contact, being then made into required formulation.
In one embodiment, the husky storehouse of valsartan provided by the invention to mix with one or more pharmaceutical excipients than the amorphous α of bent trisodium salt mixture, amorphous β, amorphous γ than bent trisodium salt mixture crystal form A or the husky storehouse of valsartan or contacts, then oral dosage form is made into, preferred tablet and capsule.In this oral dosage form, pharmaceutical excipient is selected from the pharmaceutical excipient of this area routine, comprises weighting agent, disintegrating agent, tackiness agent, dispersion agent, lubricant or retention aid and all types of coating materials etc.
Described weighting agent generally comprises pregelatinized Starch, starch, lactose, dextrin, secondary calcium phosphate, calcium carbonate, N.F,USP MANNITOL, Microcrystalline Cellulose, sorbyl alcohol, glucose etc., they can be used alone also can be used in combination, wherein preferred lactose, Microcrystalline Cellulose, pregelatinized Starch, N.F,USP MANNITOL.
Described disintegrating agent generally comprises cross-linked carboxymethyl cellulose sodium, Xylo-Mucine, sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose etc., they can be used alone also can be used in combination, is wherein preferably Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose.
Described tackiness agent generally comprises the ethanolic soln of Microcrystalline Cellulose, pre-paying starch, Vltra tears, hydroxypropylcellulose, polyvidone, polyvinylpolypyrrolidone, starch slurry, gum arabic, Macrogol 4000, polyvinyl alcohol, alginate, water, various concentration, they can be used alone also can be used in combination, wherein preferred polyvinylpolypyrrolidone, polyvidone, Vltra tears, hydroxypropylcellulose.
Described lubricant generally comprises Magnesium Stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid Potassium fumarate, palmitinic acid, silicon-dioxide, stearylamide, talcum powder, solid polyethylene glycol, vanay etc.They can be used alone also can be used in combination, wherein preferred silicon-dioxide, Magnesium Stearate, stearic acid, talcum powder.
If needed, other auxiliary materials can also be added in above-mentioned composition or preparation, as sweeting agent (as aspartame, Steviosin etc.), tinting material (medicinal or food dye as various in lemon yellow, ferric oxide etc.), stablizer (as calcium carbonate, Calcium hydrogen carbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, secondary calcium phosphate, glycine etc.), tensio-active agent (as tween 80, sodium lauryl sulphate etc.), coating material (as Opadry, Vltra tears, hydroxypropylcellulose, acrylic resin multipolymer etc.).
In one embodiment, in aforementioned pharmaceutical compositions or preparation, the husky storehouse of valsartan controls to be less than 100 μm 90% than the size distribution of bent trisodium salt mixture crystal form A or the husky storehouse of valsartan α, β, γ more amorphous than bent trisodium salt mixture, is preferably less than 50 μm, is more preferably less than 10 μm.
In one embodiment, in above-mentioned unitary pharmaceutical composition or preparation, the husky storehouse of valsartan is generally 1mg to 2g than the weight content of bent trisodium salt mixture crystal form A or the husky storehouse of valsartan α, β, γ more amorphous than bent trisodium salt mixture, preferred 10mg to 400mg, more preferably between 50mg to 200mg.
The present invention still further provides the husky storehouse of valsartan than bent trisodium salt mixture in the purposes becoming the medicine of the illness of feature for the preparation of prevention or chronic heart failure or hypertension, wherein chronic heart failure comprises the heart failure of ejection fraction minimizing and the chronic heart failure etc. of ejection fraction reservation, and hypertension comprises primary etc.
In one embodiment, the invention provides the husky storehouse of valsartan than bent trisodium salt mixture crystal form A or the husky storehouse of valsartan than bent trisodium salt mixture amorphous α, β, γ in the purposes for the preparation of prevention or chronic heart failure or hypertension being the medicine of the illness of feature.
The experiment proved that, the husky storehouse of valsartan provided by the invention than bent trisodium salt mixture crystal form A or the husky storehouse of valsartan easier than bent trisodium salt mixture amorphous α, β, γ preparation method, crystal formation is easy to control, stability and favorable solubility, is suitable for use in preparation.
The powder x-ray diffraction analysis of above-mentioned crystal of the present invention is under envrionment temperature and ambient moisture, and through the Cu-K α radiation of Dutch PANalytical X`PertPRO type Powder X-ray Diffractometer, (wavelength is
) measured." envrionment temperature " is generally 0 ~ 40 DEG C; " ambient moisture " is generally the relative humidity of 30% ~ 80%.Be understandable that in test process, due to be subject to many factors (as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc.) impact, characteristic diffraction peak position or the intensity of the powder x-ray diffraction collection of illustrative plates measured by same crystal formation have certain difference.Generally, in powder x-ray diffraction collection of illustrative plates the experimental error of characteristic diffraction peak 2 θ value can be ± 0.2 °.
Accompanying drawing explanation
Fig. 1 is the powder x-ray diffraction collection of illustrative plates of the husky storehouse of valsartan than bent trisodium salt mixture crystal form A.
Fig. 2 is the powder x-ray diffraction collection of illustrative plates of the husky storehouse α more amorphous than bent trisodium salt mixture of valsartan.
Fig. 3 is the powder x-ray diffraction collection of illustrative plates of the amorphous β of the bent trisodium salt mixture of valsartan-Sha Kubi.
Fig. 4 is the powder x-ray diffraction collection of illustrative plates of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi.
Embodiment
The embodiment of form by the following examples, foregoing invention content of the present invention is described in further details, but should not be construed as summary of the invention of the present invention and be only limitted to following examples, all inventions made based on foregoing of the present invention all belong to scope of the present invention.
In following examples
1hNMR test is using deuterated methanol as test solvent, and mark in doing with tetramethylsilane, at room temperature measures by BrukeAV-III400MHz nuclear magnetic resonance analyser.
In following examples, powder x-ray diffraction is measured by Dutch PANalytical X`PertPRO type Powder X-ray Diffractometer, and test condition is for being 4 °-40 ° with θ-θ configuration, sweep limit, and step-length is 0.0130 °, continuous sweep.Testing light source is copper target K α radiation, PIXcel detector; Voltage and current is respectively 40kV and 40mA.Method for making sample is: get with spoon the groove that appropriate sample is placed in glass load sample sheet at ambient conditions, suitably roll with slide glass, sample is evenly distributed in load sample sheet groove, then is struck off by sample surfaces with slide glass.Test period sample is non rotating in himself plane.
In following examples, lyophilize carries out in the FD-1A-50 freeze drier of Beijing Bo Yikang laboratory apparatus company limited production.
Embodiment 1: the husky storehouse of valsartan is than the preparation of bent trisodium salt mixture crystal form A
Under room temperature, by valsartan 2.00g (4.60mmol), Sha Ku than bent 1.88g (4.60mmol) and dehydrated alcohol (10ml) mix and blend, obtain settled solution.To in said mixture, add the aqueous solution 1ml of sodium hydroxide 0.55g (13.8mmol).Heat above-mentioned system to 30 ~ 50 DEG C, drip isopropyl acetate 100ml in about 10 minutes, to adularescent Precipitation.Leave standstill, cooling.Adularescent solid is separated out, and filters, washing with acetone filter cake, and filter cake is dry at 30 ~ 40 DEG C, obtains the husky storehouse of valsartan than bent trisodium salt mixture crystal form A.
1HNMR(400MHz,CD
3OD)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 result, δ: 7.035-7.619, have 17 fragrant hydrogen, can judge that in this title product, valsartan and husky storehouse are 1:1 than bent molar composition ratio.
Fig. 1 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, its observed value is following (gets observed value corresponding to diffraction peak that relative intensity within the scope of 4 °-40 °, 2 θ angle is greater than 1%, three decimals are got in the observed value round off of 2 θ and d, and a decimal is got in the round off of relative intensity measure value):
Embodiment 2: the preparation of the husky storehouse α more amorphous than bent trisodium salt mixture of valsartan
Under room temperature, valsartan 2.00g (4.60mmol), Sha Ku, than bent 1.88g (4.60mmol) and dehydrated alcohol (10ml) mix and blend, obtain settled solution.To in said mixture, drip the aqueous solution 1ml of sodium methylate 0.75g (13.8mmol).Heat above-mentioned system to 30 ~ 50 DEG C, drip isopropyl acetate 50ml in about 5 minutes, to adularescent Precipitation.Stir cooling.Adularescent solid is separated out, and filters, washing with acetone filter cake.Filter cake, at 120 ~ 130 DEG C of drying under reduced pressure, obtains the husky storehouse α more amorphous than bent trisodium salt mixture of valsartan.
1HNMR(400MHz,CD
3OD)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 result, δ: 7.034-7.619, have 17 fragrant hydrogen, can judge that in this title product, valsartan and husky storehouse are 1:1 than bent molar composition ratio.
Fig. 2 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, and its observed value is as follows:
| 2θ(°) | Peak type | Relative intensity (%) |
| 4.5 near | More sharp-pointed peak | 100 |
| Near 20.5 | Broad peak | — |
| Near 31.6 | More sharp-pointed peak | 32 |
Embodiment 3: containing the husky storehouse of 50mg valsartan than the tablet of bent trisodium salt mixture crystal form A and preparation thereof
Prescription:
Preparation: after being progressively increased mix than bent trisodium salt mixture crystal form A, Microcrystalline Cellulose, Zeparox, polyvinylpolypyrrolidone equivalent in husky for valsartan in upper table storehouse, add Magnesium Stearate and silicon-dioxide, mix.Use dry granulating machine is granulated, and adopts 30 eye mesh screen screening particles.Then the particle after screening is mixed rear compressing tablet with polyvinylpolypyrrolidone, Magnesium Stearate.Use Opadry dressing, obtain coating tablet.
Embodiment 4: containing tablet and the preparation thereof of the husky storehouse α more amorphous than bent trisodium salt mixture of 100mg valsartan
Prescription:
Preparation: after being progressively increased mix than the amorphous α of bent trisodium salt mixture, Microcrystalline Cellulose, Zeparox, polyvinylpolypyrrolidone equivalent in husky for valsartan in upper table storehouse, add Magnesium Stearate and silicon-dioxide, mix.Use dry granulating machine is granulated, and adopts 30 eye mesh screen screening particles.Then the particle after screening is mixed rear compressing tablet with polyvinylpolypyrrolidone, Magnesium Stearate.Use Opadry dressing, obtain coating tablet.
Embodiment 5: the preparation of the amorphous β of the bent trisodium salt mixture of valsartan-Sha Kubi
Under room temperature, by valsartan 2.00g (4.60mmol), Sha Ku than bent 1.88g (4.60mmol) and dehydrated alcohol 10ml mix and blend, obtain settled solution; To in said mixture, drip the aqueous solution 1ml of sodium hydroxide 0.55g (13.8mmol); Heat above-mentioned system to 40 ~ 50 DEG C, in about 5 minutes, drip isopropyl acetate 50ml; Stir cooling, adularescent solid is separated out, and filters, and filter cake, through washing with acetone, about-54 DEG C, lyophilize under 10Pa condition, obtains the amorphous β of the bent trisodium salt mixture of valsartan-Sha Kubi.
1HNMR(400MHz,CD
3OD)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)。
Above-mentioned
1in H-NMR result, δ: 7.034-7.618, have 17 fragrant hydrogen, can judge that in this title product, valsartan and husky storehouse are 1:1 than bent molar composition ratio.
Fig. 3 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, and its observed value is as follows:
| 2θ(°) | Peak type | Relative intensity (%) |
| 4.0 near | More sharp-pointed peak | 100.0 |
| Near 20.5 | Broad peak | — |
The amorphous β of the bent trisodium salt mixture of gained above-mentioned crystal formation called after valsartan-Sha Kubi.
Embodiment 6: containing tablet and the preparation thereof of the amorphous β of the bent trisodium salt mixture of 50mg valsartan-Sha Kubi
Prescription:
| Component | Content (mg/ sheet) |
| In particle | |
| The bent amorphous β of the trisodium salt mixture (preparing by the method for embodiment 5) of valsartan-Sha Kubi | 56.5 |
| Microcrystalline Cellulose | 7.5 |
| Zeparox | 22.5 |
| Polyvinylpolypyrrolidone | 5 |
| Silicon-dioxide | 0.5 |
| Magnesium Stearate | 0.5 |
| Outside particle | |
| Polyvinylpolypyrrolidone | 5 |
| Magnesium Stearate | 0.5 |
| Opadry | 1.1 |
Preparation: the amorphous β of bent for valsartan-Sha Kubi in upper table trisodium salt mixture, Microcrystalline Cellulose, Zeparox, polyvinylpolypyrrolidone equivalent are progressively increased after mixing, add Magnesium Stearate and silicon-dioxide, mix.Use dry granulating machine is granulated, and adopts 30 eye mesh screen screening particles.Then the particle after screening is mixed rear compressing tablet with polyvinylpolypyrrolidone, Magnesium Stearate.Use Opadry dressing, obtain coating tablet.
Embodiment 7: containing tablet and the preparation thereof of the amorphous β of the bent trisodium salt mixture of 100mg valsartan-Sha Kubi
Prescription:
| Component | Content (mg/ sheet) |
| In particle | |
| The bent amorphous β of the trisodium salt mixture (preparing by the method for embodiment 5) of valsartan-Sha Kubi | 113.0 |
| Microcrystalline Cellulose | 15.0 |
| Zeparox | 45.0 |
| Polyvinylpolypyrrolidone | 5.0 |
| Silicon-dioxide | 1.0 |
| Magnesium Stearate | 1.0 |
| Outside particle | |
| Polyvinylpolypyrrolidone | 10 |
| Magnesium Stearate | 1.0 |
| Opadry | 2.2 |
Preparation: the amorphous β of bent for valsartan-Sha Kubi in upper table trisodium salt mixture, Microcrystalline Cellulose, Zeparox, polyvinylpolypyrrolidone equivalent are progressively increased after mixing, add Magnesium Stearate and silicon-dioxide, mix.Use dry granulating machine is granulated, and adopts 30 eye mesh screen screening particles.Then the particle after screening is mixed rear compressing tablet with polyvinylpolypyrrolidone, Magnesium Stearate.Use Opadry dressing, obtain coating tablet.
Embodiment 8: the preparation of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi
Sodium hydroxide 0.55g (13.8mmol) is dissolved in dehydrated alcohol 10ml; Valsartan 2.00g (4.60mmol) and husky storehouse are dissolved in dehydrated alcohol 10ml than bent 1.88g (4.60mmol).Under stirring, the ethanolic soln of above-mentioned sodium hydroxide is dropped in valsartan and the ethanolic soln of Sha Ku than song, obtain settled solution.When decompression concentrated solution volume is to about 5ml at 30 ~ 40 DEG C, add normal heptane 15ml, reconcentration to about 5ml, then repeats, with normal heptane 15ml and the operation 10 times being concentrated into about 5ml, have a large amount of solid to separate out in system.Filter, filter cake washs through normal heptane, drying under reduced pressure at 40 ~ 45 DEG C, obtains the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi.
1HNMR(400MHz,CD
3OD)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)。
Above-mentioned
1in H-NMR result, δ: 7.034-7.618, have 17 fragrant hydrogen, can judge that in this title product, valsartan and husky storehouse are 1:1 than bent molar composition ratio.
Fig. 4 is shown in by the powder x-ray diffraction collection of illustrative plates surveyed, and its observed value is as follows:
| 2θ(°) | Peak type | Relative intensity (%) |
| 4.5 near | More sharp-pointed peak | 100.0 |
| Near 20.5 | Broad peak | — |
The amorphous γ of the bent trisodium salt mixture of gained above-mentioned crystal formation called after valsartan-Sha Kubi.
Embodiment 9: the preparation of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi
Sodium ethylate 1.10g (16.1mmol) is dissolved in dehydrated alcohol 10ml; Valsartan 2.00g (4.60mmol) and husky storehouse are dissolved in dehydrated alcohol 10ml than bent 1.88g (4.60mmol).Under stirring, the ethanolic soln of above-mentioned sodium ethylate is dropped to by valsartan and Sha Ku in the ethanolic soln 10ml than song, obtain settled solution.When decompression concentrated solution volume is to about 5ml at 35 ~ 40 DEG C, add toluene 15ml, reconcentration to about 5ml, then repeats the operation that adds toluene 15ml and be concentrated into about 5ml 5 times, has a large amount of solid to separate out in system.Filter, filter cake is through toluene wash, and drying under reduced pressure at 65 ~ 70 DEG C, obtains the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi.
Embodiment 10: the preparation of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi
Valsartan 2.20g (5.06mmol) and husky storehouse are dissolved in dehydrated alcohol 20ml than bent 1.88g (4.60mmol), add sodium hydroxide 0.55g (13.8mmol), stir clearly molten.Add methyl tertiary butyl ether 400ml, at 35 ~ 40 DEG C, be evaporated to a large amount of solid separate out.Filter, obtain the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi.
Embodiment 11: the preparation of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi
Valsartan 1.80g (4.14mmol) and husky storehouse are dissolved in dehydrated alcohol 50ml than bent 1.88g (4.60mmol), add sodium ethylate 0.94g (13.8mmol), stir clearly molten.At 35 ~ 40 DEG C, decompression concentrated solution is separated out to there being solid.Filter, filter cake is drying under reduced pressure at 50 ~ 55 DEG C, obtains the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi.
Embodiment 12: the tablet of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi and preparation thereof
Prescription:
| Component | Content (mg/ sheet) |
| In particle | |
| The bent amorphous γ of the trisodium salt mixture (preparing by the method for embodiment 8) of valsartan-Sha Kubi | 53.9 (by anhydrides) |
| Microcrystalline Cellulose | 7.5 |
| Zeparox | 22.5 |
| Polyvinylpolypyrrolidone | 5 |
| Silicon-dioxide | 0.5 |
| Magnesium Stearate | 0.5 |
| Outside particle | |
| Polyvinylpolypyrrolidone | 5 |
| Magnesium Stearate | 0.5 |
| Opadry | 1.1 |
Preparation: the amorphous γ of bent for valsartan-Sha Kubi in upper table trisodium salt mixture, Microcrystalline Cellulose, Zeparox, polyvinylpolypyrrolidone equivalent are progressively increased after mixing, add Magnesium Stearate and silicon-dioxide, mix.Use dry granulating machine is granulated, and adopts 30 eye mesh screen screening particles.Then the particle after screening is mixed rear compressing tablet with polyvinylpolypyrrolidone, Magnesium Stearate.Use Opadry dressing, obtain coating tablet.
Embodiment 13: the tablet of the amorphous γ of the bent trisodium salt mixture of valsartan-Sha Kubi and preparation thereof
Prescription:
| Component | Content (mg/ sheet) |
| In particle | |
| The bent amorphous γ of the trisodium salt mixture (preparing by the method for embodiment 8) of valsartan-Sha Kubi | 107.8 (by anhydrides) |
| Microcrystalline Cellulose | 15.0 |
| Zeparox | 45.0 |
| Polyvinylpolypyrrolidone | 5.0 |
| Silicon-dioxide | 1.0 |
| Magnesium Stearate | 1.0 |
| Outside particle | |
| Polyvinylpolypyrrolidone | 10 |
| Magnesium Stearate | 1.0 |
| Opadry | 2.2 |
Preparation: the amorphous γ of bent for valsartan-Sha Kubi in upper table trisodium salt mixture, Microcrystalline Cellulose, Zeparox, polyvinylpolypyrrolidone equivalent are progressively increased after mixing, add Magnesium Stearate and silicon-dioxide, mix.Use dry granulating machine is granulated, and adopts 30 eye mesh screen screening particles.Then the particle after screening is mixed rear compressing tablet with polyvinylpolypyrrolidone, Magnesium Stearate.Use Opadry dressing, obtain coating tablet.
Embodiment 14: stability study
Get LCZ696 (by the preparation of method disclosed in patent documentation CN101098689A), the husky storehouse of valsartan is than bent trisodium salt mixture crystal form A (preparing by the method for embodiment 1), the husky storehouse of valsartan α (by the method for embodiment 2 prepare) more amorphous than bent trisodium salt mixture, the husky storehouse of valsartan carries out stability test than the amorphous γ (preparing by the method for embodiment 8) of bent trisodium salt mixture than the amorphous β of bent trisodium salt mixture (prepare by the method for embodiment 5) and valsartan sand storehouse under 40 DEG C ± 2 DEG C conditions, detect after 30 days, result is as follows:
Above-mentioned research shows: the husky storehouse of valsartan provided by the invention is more suitable with LCZ696 than the stability of the amorphous γ of bent trisodium salt mixture with the husky storehouse of valsartan than the amorphous β of bent trisodium salt mixture than the amorphous α of bent trisodium salt mixture, the husky storehouse of valsartan than bent trisodium salt mixture crystal form A, the husky storehouse of valsartan.
Embodiment 15: solubility study
Get LCZ696 (by the preparation of method disclosed in patent documentation CN101098689A), the husky storehouse of valsartan than bent trisodium salt mixture crystal form A (prepare by the method for embodiment 1), the husky storehouse of valsartan than the amorphous α of bent trisodium salt mixture (prepare by the method for embodiment 2), valsartan sand storehouse than the amorphous β of bent trisodium salt mixture (preparing by the method for embodiment 5) and valsartan sand storehouse γ (by the method for embodiment 8 prepare) more amorphous than bent trisodium salt mixture, measure their solvabilities in different pH medium respectively, result is as follows:
| Medium | LCZ696 | Crystal form A | Amorphous α | Amorphous β | Amorphous γ |
| PH of buffer 1 | Almost insoluble or insoluble | 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 | Yi Rong | Yi Rong | Yi Rong | Yi Rong | Yi Rong |
| PH of buffer 6.8 | Dissolve | Dissolve | Dissolve | Dissolve | Dissolve |
Above-mentioned research shows: the husky storehouse of valsartan provided by the invention than bent trisodium salt mixture crystal form A, the husky storehouse of valsartan than the amorphous α of bent trisodium salt mixture, the husky storehouse of valsartan than the solvability of the amorphous β of bent trisodium salt mixture and the husky storehouse of valsartan γ more amorphous than bent trisodium salt mixture and LCZ696 quite or better.
Embodiment 16: Study on Hygroscopicity
Under getting LCZ696 (by the preparation of method disclosed in patent documentation CN101098689A) and valsartan sand storehouse being placed on the environment of relative humidity about 75% than bent trisodium salt mixture crystal form A (preparing by the method for embodiment 1), observe its proterties, result is as follows:
| Sample | Moisture absorption situation under relative humidity about 75% |
| LCZ696 | Place and become sticky for about 30 minutes |
| Crystal form A | Without considerable change |
Above-mentioned research shows: the husky storehouse of valsartan provided by the invention than the water absorbability of bent trisodium salt mixture crystal form A lower than LCZ696.The water absorbability that the husky storehouse of valsartan is improved than bent trisodium salt mixture crystal form A, be conducive to the raising of its bulk drug and preparation stability, also can reduce the control overflow to its bulk drug and preparation preparation manipulation and storage requirement, contribute to the raising of production efficiency and the reduction of production cost.
The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should limit with claims is as the criterion.
Claims (15)
1. the husky storehouse of valsartan is than bent trisodium salt mixture, it is characterized in that, it is crystal form A, and powder x-ray diffraction collection of illustrative plates is that 4.1 ° ± 0.2 °, 4.9 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.6 ° ± 0.2 °, 12.5 ° ± 0.2 °, 16.9 ° ± 0.2 °, 20.0 ° ± 0.2 ° place is to having characteristic diffraction peak in 2 θ values.Preferably 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 ° position to should characteristic diffraction peak be had, more preferably there is the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 1.
2. the husky storehouse of valsartan as claimed in claim 1 is than bent trisodium salt mixture, and it is characterized in that, crystal form purity is greater than 70%, is preferably greater than 80%, is most preferably greater than 90%.
3. the husky storehouse of valsartan is than a bent trisodium salt mixture, and it is characterized in that, it is amorphous α, and powder x-ray diffraction collection of illustrative plates is have peak near 4.5 °, 20.5 ° and 31.6 ° in 2 θ values.Wherein " near " be the scope of ± 0.5 ° for 4.5 °, the preferably ± scope of 0.3 °, the scope of more preferably ± 0.2 °; Be the scope of ± 2 ° for 20.5 °, the preferably ± scope of 1 °, the scope of more preferably ± 0.5 °; It is the scope of ± 0.5 ° for 31.6 °; Preferably, there is the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 2.
4. the husky storehouse of valsartan as claimed in claim 3 is than bent trisodium salt mixture, and it is characterized in that, its water content is 0.2 ~ 20%, or is 0.5 ~ 6%, or be 1 ~ 4%, or be 2 ~ 18%, or be 4 ~ 16%, or be 5 ~ 15%, or be 6 ~ 12%, or be 7 ~ 11%; Preferably, the content (mass content) of described amorphous α is generally greater than 70%, is preferably greater than 80%, is most preferably greater than 90%.
5. the bent trisodium salt mixture of valsartan-Sha Kubi, it is characterized in that, it is amorphous β, and powder x-ray diffraction collection of illustrative plates is to having peak near 4.0 °, 20.5 ° in 2 θ values, is without corresponding peak near 31.6 ° in 2 θ values.Wherein " near " be the scope of ± 0.5 ° for 4.0 °, the preferably ± scope of 0.3 °, the scope of more preferably ± 0.2 °; Be the scope of ± 2 ° for 20.5 °, the preferably ± scope of 1 °, the scope of more preferably ± 0.5 °; It is the scope of ± 0.5 ° for 31.6 °; Preferably, there is the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 3.
6. the bent trisodium salt mixture of valsartan-Sha Kubi as claimed in claim 5, it is characterized in that, water content is 0.2 ~ 20%, or be 0.5 ~ 6%, or be 1 ~ 4%, or be 2 ~ 18%, or be 4 ~ 16%, or be 5 ~ 15%, or be 6 ~ 12%, or be 7 ~ 11%, preferably, the content (mass content) of described amorphous β is generally greater than 70%, is preferably greater than 80%, is most preferably greater than 90%.
7. the bent trisodium salt mixture of valsartan-Sha Kubi, it is characterized in that, it is amorphous γ, powder x-ray diffraction collection of illustrative plates is to having peak near 4.5 °, 20.5 ° in 2 θ values, at the peak that 2 θ values are without correspondence near 31.6 °, wherein " near " be the scope of ± 1 ° for 4.5 °, the preferably ± scope of 0.5 °, the scope of more preferably ± 0.2 °; Be the scope of ± 2 ° for 20.5 °, the preferably ± scope of 1 °, the scope of more preferably ± 0.5 °; It is the scope of ± 0.5 ° for 31.6 °; Preferably, there is the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 4.
8. the bent trisodium salt mixture of valsartan-Sha Kubi as claimed in claim 7, it is characterized in that, water content is 0.2 ~ 20%, or be 0.5 ~ 6%, or be 1 ~ 4%, or be 2 ~ 18%, or be 4 ~ 16%, or be 5 ~ 15%, or be 6 ~ 12%, or be 7 ~ 11%, preferably, the content (mass content) of described amorphous γ is generally greater than 70%, is preferably greater than 80%, is most preferably greater than 90%.
9. the husky storehouse of the valsartan described in claim 1 or 2, than the preparation method of bent trisodium salt mixture, is characterized in that comprising:
(1) valsartan and Sha Ku are dissolved in ethanol than song;
(2) alkaline sodium compound is water-soluble;
(3) solution that solution step (2) obtained and step (1) obtain mixes, and adds anti-solvent and separates out solid;
(4) solid of separating out is separated;
(5) optional, step (4) isolated solid is dry at 20 ~ 50 DEG C.
10. the husky storehouse of the valsartan described in claim 3 or 4, than the preparation method of bent trisodium salt mixture, is characterized in that comprising:
(1) valsartan and Sha Ku are dissolved in ethanol than song;
(2) alkaline sodium compound is water-soluble;
(3) solution that solution step (2) obtained and step (1) obtain mixes, and adds anti-solvent and separates out solid;
(4) solid of separating out is separated and dry at 80 ~ 150 DEG C.
The preparation method of the bent trisodium salt mixture of the valsartan-Sha Kubi described in 11. claims 5 or 6, the method comprises:
(1) valsartan and Sha Ku are dissolved in ethanol than song;
(2) alkaline sodium compound is water-soluble;
(3) solution that solution step (2) obtained and step (1) obtain mixes, and adds anti-solvent and separates out solid;
(4) solid of separating out is separated, lyophilize.
Preferably, in step (4), cryodesiccated temperature is-70 ~-10 DEG C, and preferably-60 ~-40 DEG C, pressure is 0 ~ 50Pa, is preferably 1 ~ 10Pa.
12. preparation methods as described in any one of claim 9-11, is characterized in that step (2) neutral and alkali sodium compound is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methylate or sodium ethylate, are preferably selected from sodium hydroxide, sodium methylate or sodium ethylate; In step (3), anti-solvent is selected from acetone, butanone, pentanone, pimelinketone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, glycol dimethyl ether, t-butyl methyl ether, toluene, dimethylbenzene or their mixture, is preferably selected from isopropyl acetate or ethyl acetate.
The preparation method of the bent trisodium salt mixture of the valsartan-Sha Kubi described in 13. claims 7 or 8, the method comprises:
(1) by valsartan, Sha Ku is dissolved in ethanol than bent and alkaline sodium compound;
(2) solution of enrichment step (1) gained, separates out solid;
(3) separating step (2) solid of separating out;
(4) optional, the solid that drying step (3) is separated.
Preferably, step (1) neutral and alkali sodium compound is selected from sodium hydroxide, sodium carbonate, sodium ethylate or sodium tert-butoxide, preferred sodium hydroxide or sodium ethylate;
Preferably, in step (2), condensing mode comprises: directly concentrate; Or first concentrate, then add anti-solvent, reconcentration; Or first add anti-solvent, reconcentration;
Preferably, anti-solvent is selected from ether, isopropyl ether, n-butyl ether, t-butyl methyl ether, benzene,toluene,xylene, sherwood oil, normal hexane, normal heptane, octane-iso or their mixture, preferred t-butyl methyl ether, toluene, normal hexane, normal heptane or octane-iso;
Preferably, in step (4), drying temperature is 30 ~ 70 DEG C.
14. 1 kinds of pharmaceutical compositions, the husky storehouse of the valsartan that its husky storehouse of the valsartan according to any one of claim 1 ~ 8 comprising treatment significant quantity obtains than preparation method any one of bent trisodium salt mixture or claim 9 ~ 13 is than bent trisodium salt mixture, and pharmaceutical excipient.
The husky storehouse of the valsartan that the husky storehouse of valsartan according to any one of 15. claims 1 ~ 8 obtains than the preparation method described in bent trisodium salt mixture or any one of claim 9 ~ 13 than bent trisodium salt mixture in the purposes for the preparation of prevention or chronic heart failure or hypertension being the medicine of the illness of feature.
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| 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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| CN201410633511 | 2014-11-12 | ||
| 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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| 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 |
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| CN107935958B (en) * | 2017-11-30 | 2021-02-09 | 中国药科大学 | Valsartan puerarin sodium salt compound and preparation method thereof |
| CN107935958A (en) * | 2017-11-30 | 2018-04-20 | 中国药科大学 | A kind of Valsartan Puerarin sodium salt compound and preparation method thereof |
| CN109776441A (en) * | 2018-05-24 | 2019-05-21 | 合肥合源药业有限公司 | Unformed Valsartan Sha Kuba song sodium compound |
| CN109776441B (en) * | 2018-05-24 | 2022-08-19 | 合肥合源药业有限公司 | Amorphous valsartan-sabotargol sodium compound |
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | 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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