CN102603663A - Polymorphism of valsartan and preparation method of polymorphism of valsartan - Google Patents
Polymorphism of valsartan and preparation method of polymorphism of valsartan Download PDFInfo
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 63
- 229960004699 valsartan Drugs 0.000 title claims abstract description 63
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000013078 crystal Substances 0.000 claims abstract description 74
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 66
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- 238000013019 agitation Methods 0.000 claims description 17
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 16
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
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- 238000000034 method Methods 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
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- 239000000203 mixture Substances 0.000 claims description 4
- -1 ethanol compound Chemical class 0.000 claims description 3
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 claims description 2
- 229940123413 Angiotensin II antagonist Drugs 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
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- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and discloses two new crystal forms E and F of valsartan and a preparation method of the two new crystal forms of valsartan. XRD (X-ray diffraction), Microscopes Raman spectrometer, infrared spectrum, DSC (differential scanning calorimeter), TGA (thermo gravimetric analyzer), DVS (dynamic vapor sorption instrument) and the like are adopted to perform comprehensive characterization on the new crystal forms. Good physicochemical properties and patent medicine performance of the new crystal forms are observed. The preparation method of new crystal forms of valsartan provided by the invention is simple, easy to control, and good in repeatability, and can obtain a target crystal form steadily.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to two kinds of new crystal E types and F type of valsartan and preparation method thereof.
Background technology
Polymorphism is meant the different spaces arrangement mode of solid matter with two or more, the phenomenon of the solid state with different physicochemical property of formation.In the drug research field, polymorphic has comprised polycomponent crystalline forms such as organic solvent thing, hydrate.The medicine heteromorphism extensively exists in drug discovery process, is organic micromolecule compound inherent characteristic.Small-molecule drug can have unlimited many crystal accumulation mode-polymorphics in theory, and research shows that the time and the resource of the research of the polymorphous discovery quantity of medicine and its input are in direct ratio.As the highest medicine-Lipitor of sales volume up to now in the world, just nearly 35 kinds of the crystal formations of patent protection.Polymorphism not only receives the space structure and the functional group performance of molecule itself; The control of internal factor such as intramolecularly and intermolecular interaction, the influence of aspects factors such as it also receives, and medicine synthesising process design, crystallization and purification condition, pharmaceutical adjunct are selected, preparation process route and method of granulating and condition of storage, wrapping material.Different crystal forms has distinct colors, fusing point, dissolving, dissolving out capability, chemicalstability, reactivity, mechanical stability etc., and these physical and chemical performances or processability directly have influence on safety, the effective performance of medicine sometimes.Therefore crystal formation research and control become the research content in the medicament research and development process.
Crystal formation research comprises crystal discovery and preferred two stages of crystal formation, finds the stage at crystal, mainly adopts multiple crystallization means; Like fusion-crystallization, solution evaporation, the crystallization method of cooling and suspendible method fast; Through changing crystallization condition; Solvent, temperature, speed and suspendible solvent ratios etc. influences the Externality of drug crystallization.Adopt high-throughput specimen preparation platform, prepare crystallization trial simultaneously hundreds of times, utilization micro-example technology of preparing and analytical test means.Preparation and find new crystal formation.In the preferred stage of crystal formation, grope for new amplification of crystal formation crystal formation technology and preparation condition, adopt multiple solid characterization method; Like X-ray diffraction, solid-state nuclear magnetic resonance, Raman spectrum; Means crystal formation crystal such as ir spectra characterize; In addition, adopt DSC, TGA, DVS, HPLC etc. that crystal formation is carried out physical and chemical performance research, relatively the water absorbability of different crystal forms, chemically stable, physical condition stability, workability etc. are studied.Select highly preferred solid form to develop at last.
The chemistry of valsartan (Valsartan) is by name: (S)-N-(1-pentanoyl)-N-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-L-Xie Ansuan, its chemical structural formula is following:
Valsartan is a kind of small-molecule drug with specificity Angiotensin II antagonistic activity of the AT1 of acting on receptor subtype, is widely used in treatment hypertension at present clinically.Valsartan has polymorphism, it is reported, has amorphous so far and 20 kinds of crystal formations.
I type and II type valsartan and preparation method thereof in patent WO03089417, have been reported; In patent WO2004083192, reported I-XIII type valsartan that percent crystallinity is not high and preparation method thereof, report I type and II type repeat name among I type wherein and II type and the patent WO03089417, but crystal formation is different; A type, Type B, C type and D type valsartan and preparation method thereof in patent WO2007017897, have been reported; In patent CN1763017, reported H type valsartan and preparation method thereof.
The present invention is comprehensively adopting on the basis of new crystallization nucleation mode and crystallization condition, the crystal formation of two kinds of novel valsartans of report: crystal formation E and crystal formation F.Discover that new crystal percent crystallinity is high, water absorbability is little, and forms regular crystal kenel, thereby helps the art breading of medicine and the improvement of physical and chemical performance, improves the patent medicine performance.
Summary of the invention
The present invention aims to provide two kinds of stable novel valsartan crystal forms.
First kind of new crystal of valsartan provided by the invention, this crystal formation called after E crystal formation.
The E crystal formation of valsartan is characterized in that, (island Feng 6000 is CuK) approximately: 9.46,10.86,11.78,14.00,15.24 for the X-ray powder diffraction of representing with 2 θ angles; 16.20,16.82,17.80,18.72,19.34,20.16,20.72,21.50; 21.74,22.12,23.06,24.26,24.76,25.20,26.48,27.08; 27.70 28.70,30.06,31.20,32.64,33.96,35.38,39.18 ° have characteristic peak.Its differential scanning calorimetric analysis (DSC) has the characteristic endotherm(ic)peak at about 140.2 ℃.
The preparation method of the E crystal formation of valsartan comprises the steps:
(1) suspendible: under room temperature to solvent boiling point temperature condition, with valsartan and solvent suspendible, wherein the mass volume ratio of valsartan and solvent (grams per liter) is 100: 1-1: 1;
(2) stir: above-mentioned suspension is stirred with magnetic agitation, and rotating speed is 60-600rpm, and churning time is 2-5 days;
(3) oven dry: above-mentioned suspension is filtered, behind the used solvent wash of a small amount of suspendible, promptly get valsartan E crystal formation in room temperature to 100 ℃ normal pressure or decompression oven dry;
Wherein, said solvent is selected from one or more the mixture in ether, acetone, butanone, MIBK, normal hexane, normal heptane, sherwood oil and the toluene.
Second kind of new crystal of valsartan provided by the invention, this crystal formation called after F crystal formation.
The F crystal formation of valsartan is characterized in that, (island Feng 6000 is CuK) approximately: 8.22,8.80,9.80,11.14,11.98 for the X-ray powder diffraction of representing with 2 θ angles; 12.42,14.22,14.52,14.94.15.86,16.94,17.34,18.00; 18.60,19.30,19.70,21.08,22.60,23.02,23.80; 24.14,24.70,26.18,27.26,27.56,30.46,35.28 ° have characteristic peak.Its differential scanning calorimetric analysis (DSC) has the characteristic endotherm(ic)peak at about 102.7 ℃.This N-type waferN is a rhombic system; Spacer is P2 (1) 2 (1) 2 (1), and unit cell parameters is:
unit cell volume is
The ethanol compound F crystalline structure formula of valsartan is as follows:
The preparation method of the ethanol compound F crystal formation of valsartan comprises the steps:
(1) suspendible: under room temperature to solvent boiling point temperature condition, with valsartan and solvent suspendible, wherein the mass volume ratio of valsartan and solvent (grams per liter) is 100: 1-10: 1;
(2) stir: above-mentioned suspension is stirred with magnetic agitation, and rotating speed is 60-600rpm, and churning time is 2-5 days;
(3) oven dry: above-mentioned suspension is filtered, behind the used solvent wash of a small amount of suspendible, promptly get valsartan F crystal formation in room temperature to 90 ℃ normal pressure or decompression oven dry;
Wherein, said solvent is the mixture that organic solvent such as ethanol or ethanol and methyl alcohol, acetone, acetonitrile, ether, THF, normal hexane, normal heptane or water form.
The present invention also provides described E crystal formation or F crystal formation preparing as the purposes in the medicine of Angiotensin II antagonist, more specifically is purposes in the hypertensive medicine of preparation treatment.
The present invention also provides a kind of pharmaceutical composition, and it comprises the described E crystal formation of claim 1 or described F crystal formation of claim 5 and pharmaceutically acceptable carrier.
Two kinds of novel valsartan crystal forms that the present invention relates to characterize through X-ray powder diffraction (XRPD), thermogravimetic analysis (TGA) (TG), differential scanning calorimetric analysis (DSC), infrared (IR), Raman (Raman) and water absorbability analysis solid-state approach such as (DVS).
The preparation method who the present invention relates to is simple to operate, and favorable reproducibility can be stablized acquisition target crystal formation.
Description of drawings
Fig. 1. X-ray powder diffraction (XRPD) figure of embodiment 1 valsartan E crystal formation.
Fig. 2. thermogravimetic analysis (TGA) (TG) figure of embodiment 1 valsartan E crystal formation.
Fig. 3. differential scanning calorimetric analysis (DSC) figure of embodiment 1 valsartan E crystal formation.
Fig. 4. ir spectra (IR) figure of embodiment 1 valsartan E crystal formation.
Fig. 5. Raman spectrum (Raman) figure of embodiment 1 valsartan E crystal formation.
Fig. 6. X-ray powder diffraction (XRPD) figure of embodiment 11 valsartan F crystal formations.
Fig. 7. thermogravimetic analysis (TGA) (TG) figure of embodiment 11 valsartan F crystal formations.
Fig. 8. differential scanning calorimetric analysis (DSC) figure of embodiment 11 valsartan F crystal formations.
Fig. 9. ir spectra (IR) figure of embodiment 11 valsartan F crystal formations.
Figure 10. Raman spectrum (Raman) figure of embodiment 11 valsartan F crystal formations.
Figure 11. water absorbability analysis (DVS) map of embodiment 1 valsartan E crystal formation and embodiment 11 valsartan F crystal formations
Embodiment
At ambient temperature, valsartan 10.0g is mixed the formation suspension with ether/normal heptane (volume ratio 1: 1) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 200rpm, and churning time is 3 days.Suspension filters, after the washing of a small amount of ether/normal heptane (volume ratio 1: 1) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 9.2g, productive rate is 92%.
10.0g valsartan places Erlenmeyer flask, adds ether/normal heptane (volume ratio 1: 2) mixed solvent 150mL.Add magnetic agitation and stir, form suspension.Rotating speed is 200rpm, keeps stirring at ambient temperature 3 days.Suspension filters, after the washing of a small amount of ether/normal heptane (volume ratio 1: 2) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 9.3g, productive rate is 93%.
The 10.0g valsartan is mixed the formation suspension with ether/normal hexane (volume ratio 1: 1) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 230rpm, keeps stirring at ambient temperature 4 days.Suspension filters, after the washing of a small amount of ether/normal hexane (volume ratio 1: 1) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 9.2g, productive rate is 92%.
At ambient temperature, valsartan 10.0g is mixed the formation suspension with ether/sherwood oil (volume ratio 1: 1) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 150rpm, and churning time is 5 days.Suspension filters, after the washing of a small amount of ether/sherwood oil (volume ratio 1: 1) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 9.3g, productive rate is 93%.
At ambient temperature, valsartan 10.0g is mixed the formation suspension with acetone/normal heptane (volume ratio 1: 5) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 120rpm, and churning time is 2 days.Suspension filters, after the washing of small amount of acetone/normal heptane (volume ratio 1: 5) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 8.3g, productive rate is 83%.
At ambient temperature, valsartan 10.0g is mixed the formation suspension with acetone/normal hexane (volume ratio 1: 5) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 300rpm, and churning time is 3 days.Suspension filters, after the washing of small amount of acetone/normal hexane (volume ratio 1: 5) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 8.3g, productive rate is 83%.
Embodiment 7
At ambient temperature, valsartan 10.0g is mixed the formation suspension with acetone/sherwood oil (volume ratio 1: 5) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 200rpm, and churning time is 4 days.Suspension filters, after the washing of small amount of acetone/sherwood oil (volume ratio 1: 5) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 8.3g, productive rate is 83%.
At ambient temperature, valsartan 10.0g is mixed the formation suspension with butanone/normal heptane (volume ratio 1: 5) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 400rpm, and churning time is 4 days.Suspension filters, after the washing of a small amount of butanone/normal heptane (volume ratio 1: 5) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 8.5g, productive rate is 85%.
Embodiment 9
At ambient temperature, valsartan 10.0g is mixed the formation suspension with butanone/normal hexane (volume ratio 1: 5) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 200rpm, and churning time is 4 days.Suspension filters, after the washing of a small amount of butanone/normal hexane (volume ratio 1: 5) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 8.5g, productive rate is 85%.
At ambient temperature, valsartan 10.0g is mixed the formation suspension with butanone/sherwood oil (volume ratio 1: 5) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 240rpm, and churning time is 3 days.Suspension filters, after the washing of a small amount of butanone/sherwood oil (volume ratio 1: 5) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (E type) 8.4g, productive rate is 84%.
Embodiment 11
The 10.0g valsartan is placed Erlenmeyer flask, mix forming suspension with ethanol/water (volume ratio 2: 1) mixed solvent 150mL.Add magnetic agitation and stir, rotating speed is 150rpm, keeps stirring at ambient temperature 2 days.Suspension filters, after the washing of small amount of ethanol/water (volume ratio 2: 1) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (F type) 7.5g, productive rate is 75%.
10.0g mixing with ethanol/water (volume ratio 1: 1) mixed solvent 150mL, valsartan forms suspension.Add magnetic agitation and stir, rotating speed is 200rpm, keeps stirring at ambient temperature 3 days.Suspension filters, after the washing of small amount of ethanol/water (volume ratio 1: 1) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (F type) 8.1g, productive rate is 81%.
Embodiment 13
The 10.0g valsartan is placed Erlenmeyer flask, add ethanol/water (volume ratio 1: 3) mixed solvent 150mL, magnetic agitation stirs, and rotating speed is 100rpm, remains under 50 ℃ of conditions to stir 3 days.Suspension filters, after the washing of small amount of ethanol/water (volume ratio 1: 3) mixed solvent, in reduced pressure at room temperature.Obtain white crystalline powder (F type) 8.6g, productive rate is 86%.
Claims (11)
1. the E crystal formation of a valsartan is characterized in that, is making an appointment with the X-ray powder diffraction that 2 θ angles are represented: 9.46,10.86,11.78,14.00,15.24,16.20; 16.82,17.80,18.72,19.34,20.16,20.72,21.50,21.74; 22.12,23.06,24.26,24.76,25.20,26.48,27.08,27.70; 28.70,30.06,31.20,32.64,33.96,35.38,39.18 ° have characteristic peak.
2. E crystal formation according to claim 1 is characterized in that, differential scanning calorimetric analysis has the characteristic endotherm(ic)peak at about 140.2 ℃.
3. the preparation method of E crystal formation according to claim 1 is characterized in that this method comprises the steps:
(1) suspendible: under room temperature to solvent boiling point temperature condition, with valsartan and solvent suspendible;
(2) stir: above-mentioned suspension is stirred with magnetic agitation, and rotating speed is 60-600rpm, and churning time is 2-5 days;
(3) oven dry: above-mentioned suspension is filtered, behind solvent wash, promptly get the crystallization of E type valsartan in room temperature to 100 ℃ normal pressure or decompression oven dry.
4. the preparation method of E crystal formation according to claim 3, it is to be selected from ether, acetone, butanone, MIBK, normal hexane, normal heptane, sherwood oil and the toluene one or more that wherein said and valsartan are made into the used solvent of suspension.
5. the ethanol compound F crystal formation of a valsartan is characterized in that, is making an appointment with the X-ray powder diffraction that 2 θ angles are represented: 8.22,8.80,9.80,11.14,11.98; 12.42,14.22,14.52,14.94.15.86,16.94,17.34,18.00; 18.60,19.30,19.70,21.08,22.60,23.02,23.80; 24.14,24.70,26.18,27.26,27.56,30.46,35.28 ° have charateristic avsorption band.
6. F crystal formation according to claim 5 is characterized in that, differential scanning calorimetric analysis has the characteristic endotherm(ic)peak at about 102.7 ℃.
7. F crystal formation according to claim 5; It is characterized in that; This N-type waferN is a rhombic system; Spacer is P2 (1) 2 (1) 2 (1); Unit cell parameters is:
α=β=γ=90 °, unit cell volume is
8. the preparation method of F crystal formation according to claim 5 is characterized in that this method comprises the steps:
(1) suspendible: under room temperature to solvent boiling point temperature condition, with valsartan and solvent suspendible;
(2) stir: above-mentioned suspension is stirred with magnetic agitation, and rotating speed is 60-600rpm, and churning time is 2-5 days;
(3) oven dry: above-mentioned suspension is filtered, behind solvent wash, promptly get the crystallization of F type valsartan in room temperature to 90 ℃ normal pressure or decompression oven dry.
9. the preparation method of F crystal formation according to claim 8, it is ethanol that wherein said and valsartan is made into the used solvent of suspension; Perhaps, the mixture of ethanol and methyl alcohol, acetone, acetonitrile, ether, THF, normal hexane, normal heptane or water formation.
10. the described F crystal formation of E crystal formation according to claim 1 or claim 5 is preparing as the purposes in the medicine of Angiotensin II antagonist.
11. a pharmaceutical composition, it comprises the described E crystal formation of claim 1 or described F crystal formation of claim 5 and pharmaceutically acceptable carrier.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN105777660A (en) * | 2016-03-29 | 2016-07-20 | 潍坊盛瑜药业有限公司 | Induced crystallization process and application of valsartan crystal form E |
| CN105801506A (en) * | 2014-12-30 | 2016-07-27 | 天津法莫西医药科技有限公司 | New crystal form of valsartan and preparation method thereof |
| JP2016150917A (en) * | 2015-02-17 | 2016-08-22 | 株式会社トクヤマ | Method for producing crystal of valsartan |
| CN106243056A (en) * | 2016-07-29 | 2016-12-21 | 陈欣怡 | A kind of novel solid form of valsartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104610185A (en) * | 2014-03-10 | 2015-05-13 | 杭州领业医药科技有限公司 | Recovery method of valsartan mother liquor |
| CN104610185B (en) * | 2014-03-10 | 2017-06-27 | 杭州领业医药科技有限公司 | The recovery method of valsartan mother liquid |
| CN105801506A (en) * | 2014-12-30 | 2016-07-27 | 天津法莫西医药科技有限公司 | New crystal form of valsartan and preparation method thereof |
| JP2016150917A (en) * | 2015-02-17 | 2016-08-22 | 株式会社トクヤマ | Method for producing crystal of valsartan |
| CN105777660A (en) * | 2016-03-29 | 2016-07-20 | 潍坊盛瑜药业有限公司 | Induced crystallization process and application of valsartan crystal form E |
| CN106243056A (en) * | 2016-07-29 | 2016-12-21 | 陈欣怡 | A kind of novel solid form of valsartan |
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| CN102603663B (en) | 2014-09-10 |
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