WO2003089417A1 - Nouvelles formes cristallines de (s)-n-(1-carboxy-2-methyl-prop-1-yl) -n-pentanoyl-n- [2'-(1h-tetrazol-5-yl-)- biphenyl-4-yl methyl] amine (valsartan) - Google Patents

Nouvelles formes cristallines de (s)-n-(1-carboxy-2-methyl-prop-1-yl) -n-pentanoyl-n- [2'-(1h-tetrazol-5-yl-)- biphenyl-4-yl methyl] amine (valsartan) Download PDF

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Publication number
WO2003089417A1
WO2003089417A1 PCT/US2003/011712 US0311712W WO03089417A1 WO 2003089417 A1 WO2003089417 A1 WO 2003089417A1 US 0311712 W US0311712 W US 0311712W WO 03089417 A1 WO03089417 A1 WO 03089417A1
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methyl
valsartan
crystalline form
ketone
process according
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PCT/US2003/011712
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English (en)
Inventor
Buchi Reddy Reguri
Sudhakar Sunkari
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Dr. Reddy's Laboratories Limited
Cord,Janet, I.
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Priority to AU2003223637A priority Critical patent/AU2003223637A1/en
Publication of WO2003089417A1 publication Critical patent/WO2003089417A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • AMINE (VALSARTAN) The present invention relates to novel crystalline forms of (S)-N- (1- Carboxy-2-methyl-prop-l-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)- biphenyl-4-yl methyl amine (Valsartan) and to processes for their preparation.
  • Valsartan chemically described as (S)-N- (l-Carboxy-2-methyl-prop-l-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)- biphenyl-4-yl methyl amine, is represented by the following structural formula:
  • Valsartan a non-peptide angiotensin - II ATi antagonist, inhibits the action of angiotensin - II on its receptors, thus preventing the increase of blood pressure produced by the hormone-receptor interactions. Hence it is used in the treatment of cardiovascular complaints such as hypertension and heart failure.
  • U. S. Patent 5,399,578 discloses Valsartan, its pharmaceutically acceptable salts and process for their preparation.
  • WO patent application 02/06253 discloses crystalline, partly crystalline, amorphous and polymorphous forms of specific salts of Valsartan such as monopotassium salt, mono sodium salt, bis-diemethylammonium salt and others. There is a need for crystalline forms of Valsartan, for preparing pharmaceutical formulations useful for treatment of cardiovascular complaints such as hypertension and heart failure.
  • the present invention is directed to novel crystalline Forms of Valsartan.
  • the present invention essentially provides crystalline Form-I and Form-II of Valsartan.
  • the present invention also provides processes for the preparation of novel crystalline Form-I and Form-II of Valsartan by a commercially feasible process very well suited for scale up.
  • the process for the preparation of novel crystalline Form-I of Valsartan involves dissolution of Valsartan in C -C 6 straight or branched chain ketone solvent or a mixture thereof; precipitation from the so formed solution by adding an aliphatic hydrocarbon solvent or mixture thereof, accompanied by isolation and drying to obtain the desired crystalline Form-I of Valsartan.
  • the process for the preparation of novel crystalline Form-II of Valsartan comprises the dissolution of Valsartan in a ketone solvent and precipitation from the so formed solution by adding an aliphatic hydrocarbon solvent or mixture thereof accompanied by isolation and drying to obtain the desired crystalline polymorph Form-II of Valsartan.
  • Crystalline Form-I or Form-II of Valsartan of the present invention may exist in unsolvated as well as solvated forms. In general, both unsolvated as well as solvated forms are intended to be encompassed within the scope of the present invention.
  • Fig. 1 is a diagram showing the results of X-ray diffraction of crystalline Form-I of Valsartan.
  • Fig. 2 is a diagram showing the results of DSC of crystalline Form-I of Valsartan.
  • Fig. 3 is a diagram showing the results of X-ray diffraction of crystalline Form-II of Valsartan.
  • Fig. 4 is a diagram showing the results of DSC of crystalline Form-II of Valsartan.
  • Fig. 5 is a diagram showing the results of X-ray diffraction of the compound obtained by following the reference example.
  • the present invention provides novel crystalline Form-I and Form-II of Valsartan.
  • the present invention also provides processes for preparation of novel crystalline Form-I and Form-II of Valsartan.
  • the process for the preparation of crystalline Form-I of Valsartan comprises; a) dissolving Valsartan in a C 4 -C 6 straight or branched chain ketone solvent at 60 - 65 °C; b) adding an aliphatic hydrocarbon solvent accompanied by cooling; c) isolating and drying the product of step (b) to obtain crystalline Form-I of Valsartan.
  • hexane is added to the ketone solvent of step a) and then more ketone solvent is added.
  • the hexane solvent is added at a temperature of 80 to 85 °C.
  • the ratio of hexane to total ketone solvent added in step a) is 2-1 :1-2 v/v.
  • the ketone solvent is selected from ethyl methyl ketone, methyl isobutyl ketone, methyl isopropyl ketone or di ethyl ketone or a mixture thereof.
  • the ratio of Valsartan to straight or branched chain ketone solvents in step a) is 1 : 1-5 w/v preferably 1 :2 w/v.
  • the aliphatic solvent is a straight or branched chain hydrocarbon or a cyclic hydrocarbon.
  • the aliphatic hydrocarbon is a C 4 -C 8 straight or branched chain hydrocarbon or C 4 -C 8 cyclic hydrocarbon.
  • the aliphatic solvent is selected from petroleum ether, n-hexane, hexane or cyclohexane or mixture thereof,
  • the ratio of Valsartan to aliphatic hydrocarbon solvent in step b) is 1:1-7 w/v, preferably 1:5 w/v and more preferably 1 :3 w/v.
  • Novel crystalline Form-I of Valsartan is characterized by its X-ray diffractogram.
  • the X-ray powder diffraction pattern of crystalline polymorph Form-I of Valsartan was measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha- 1 Radiation source.
  • the Crystalline Form-I of Valsartan has X-ray powder diffraction pattern essentially as shown in the Table- 1.
  • the X-ray powder diffraction pattern is expressed in the terms of 2 ⁇ (in degrees) and percentage intensity (in %).
  • the present invention also provides crystalline Form-I of Valsartan that is characterized by its X-Ray powder diffraction, substantially in accordance with Figure 1.
  • the present invention provides crystalline Form-I of Valsartan that is characterized by its Differential Scanning Calorimetry thermogram.
  • the Differential Scanning Calorimetry thermogram exhibits a significant endo peak at about 90.24°C.
  • the present invention also provides crystalline Form-I of Valsartan that is characterized by its Differential Scanning Calorimetry thermogram substantially in accordance with Figure 2.
  • the present invention further provides crystalline form-I of Valsartan having a visual melting point (capillary tube) in the range of about 80-91 °C.
  • the said crystalline form-I of Valsartan is stable white to off-white crystalline powder.
  • Another aspect of the present invention is to provide novel crystalline Form-II of Valsartan.
  • hexane is added to the ketone solvent of step i) and then more ketone solvent is added.
  • the hexane solvent is added at a temperature of 50 - 55 °C.
  • the ratio of hexane to total ketone solvent added in step i) is 2-1:1-2 v/v.
  • the ketone solvent employed in step i) comprises solvents such as methyl propyl ketone.
  • the ratio of Valsartan to ketone solvent in step i) is 1:1-5 w/v preferably 1 :2 w/v.
  • the aliphatic solvent is a straight or branched chain hydrocarbon or a cyclic hydrocarbon.
  • the aliphatic hydrocarbon is a C 4 -C 8 straight or branched chain hydrocarbon or C 4 -C 8 cyclic hydrocarbon.
  • the aliphatic hydrocarbon is selected from petroleum ether, n-hexane, hexane or cyclohexane or mixture thereof
  • the ratio of Valsartan to aliphatic hydrocarbon solvent in step ii) is 1:1-7 w/v, preferably 1 :5 w/v and more preferably 1 :3 w/v.
  • the solids can be separated by any conventional method, preferably by filtration, decanting or centrifugation; preferably by centrifugation.
  • Novel crystalline Form-II of Valsartan is characterized by its X-ray diffractogram.
  • the X-ray powder diffraction pattern of crystalline polymorph Form-II of Valsartan was measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha- 1 Radiation source.
  • the Crystalline Form-II of Valsartan has X-ray powder diffraction pattern essentially as shown in the Table-2.
  • the X-ray powder diffraction pattern is expressed in the terms of 20 (in degrees) and percentage intensity (in %).
  • the present invention also provides crystalline Form-II of Valsartan that is characterized by its X-Ray powder diffraction, substantially in accordance with Figure 3. Furthermore the present invention provides crystalline Form-II of Valsartan that is characterized by its Differential Scanning Calorimetry thermogram. The Differential Scanning Calorimetry thermogram exhibits a significant endo peak at about 92.91°C. The present invention also provides crystalline Form-II of Valsartan that is characterized by its Differential Scanning Calorimetry thermogram substantially in accordance with Figure 4.
  • the present invention further provides crystalline Form-II of Valsartan having a visual melting point (capillary tube) in the range of about 91-102°C.
  • the said crystalline Form-II of Valsartan is a stable white to off-white crystalline powder.
  • the Valsartan employed for the preparation of the novel crystalline Form I and Form-II may be obtained by processes disclosed in the prior art.
  • the invention likewise relates to the use of novel crystalline Form-I and Form-II of Valsartan as angiotensin II antagonist, active substance. In this connection, they can be used, preferably in the form of pharmaceutically acceptable preparations, in a method for the prophylactic and/or therapeutic treatment of the animal or human body, in particular as angiotensin II antagonists.
  • the invention likewise relates to pharmaceutical preparations which contain novel crystalline Form-I and Form-II of Valsartan as active ingredient and to processes for their preparation.
  • the pharmaceutical preparations according to the invention which contain the compound according to the invention are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • the daily dose of the active ingredient depends on the age and the individual condition and also on the manner of administration.
  • the novel pharmaceutical preparations contain, for example, from about
  • compositions according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, mefhylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, such as the above mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate; auxiliaries are primarily glidants, flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • fillers such as sugars, for example lactos
  • Sugar-coated tablet cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice- resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmefhylcellulose phthalate. Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may be added to the tablets or sugar-coated tablet coatings.
  • hard gelatin capsules and also soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard gelatin capsules may contain the active ingredient in the form of granules, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible to add stabilizers.
  • Suitable rectally utilizable pharmaceutical preparations are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which contain a combination of the active ingredient with a base substance may also be used.
  • Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity- increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.
  • suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides
  • viscosity- increasing substances for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.
  • the dose of the active ingredient depends on the warm-blooded animal species, the age and the individual condition and on the manner of administration. In the normal case, an approximate daily dose of about 10 mg to about 350 mg is to be estimated in the case of oral administration for a patient weighing approximately 75 kg. For other types of administration, the preferred daily dose is between 0.1 mg to 1000 mg per kilogram.
  • the following examples illustrate the invention described above; however, they are not intended to limit its extent in any manner.
  • tributyl tin chloride (61.9 kg), sodium azide (16.5 kg) were added to xylene (258 lit) and stirred for 1-2 hours at a temperature of 25-35°C then heated the mass to reflux and stirred till the reaction substantially completes. Cool the mass to 25-35°C and 10% sodium hydroxide solution (250 lit.) was added and further stirred for 24-30 hours.
  • the aqueous layer was separated from the resulting biphasic solution and washed with toluene (52 X 2 lit.). The pH of the aqueous layer was adjusted towards neutral with acetic acid (115 lit.) and washed with chloroform (52 X 2 lit.).
  • Valsartan (25.0 g) was dissolved in methyl isobutyl ketone (50.0ml) at a temperature of 60-65°C . Further hexane (60 ml) was slowly added at a temperature of 80 to 85 °C. The mixture was further heated to a temperature of 80-85°C followed by addition of Methyl isobutyl ketone (10.0 ml). The reaction mixture was then cooled to a temperature of 25-35°C and left overnight to crystallize to obtain a solid mass.
  • Fig-1 is characteristic X-ray powder diffraction pattern of Crystalline Form-I Valsartan. Vertical axis: Intensity (CPS); Horizontal axis: 29 (degrees). The sample was scanned between 0 to 45°. The significant 29 values (in degrees) obtained are at about 5.415, 13.145, 17.52, 14.213, 21.09, 14.894, 9.891, 22.1, 10.726 Fig-2 is Differential Scanning Calorimetry thermogram of crystalline
  • Fig: 3 is characteristic X-ray powder diffraction pattern of the novel crystalline Form-II of Valsartan. The sample was scanned between 0 to 45°. Vertical axis: Intensity (CPS); Horizontal axis: 2 ⁇ (degrees). The significant 29 values (in degrees) obtained are 5.48, 6.113 and 17.598 degrees.
  • Fig: 4 is Differential Scanning Calorimetric Thermogram of novel crystalline Form-II of Valsartan. The heating rate was 5°C/minute. The Differential Scanning Calorimetric Thermogram exhibits a significant endo peak at 92.91°C.
  • Fig-5 is characteristic X-ray powder diffraction pattern of Valsartan prepared as per reference example. It shows a plain halo with no peaks, which is a characteristic nature of amorphous form.

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Abstract

La présente invention a trait à de nouvelles formes cristallines de (S)-N- (1-Carboxy-2-méthyl-prop-1-yl) -N-pentanoyl-N- [2'-(1H-tétrazol-5-yl)- biphényl-4-yl méthyl amine (Valsartan) et à leurs procédés de préparation. Valsartan, de désignation chimique (S)-N- (1-Carboxy-2-méthyl-prop-1-yl) -N-pentanoyl-N- [2'-(1H-tétrazol-5-yl)- biphényl-4-yl méthyl amine, est représenté par la formule structurelle (I).
PCT/US2003/011712 2002-04-15 2003-04-15 Nouvelles formes cristallines de (s)-n-(1-carboxy-2-methyl-prop-1-yl) -n-pentanoyl-n- [2'-(1h-tetrazol-5-yl-)- biphenyl-4-yl methyl] amine (valsartan) WO2003089417A1 (fr)

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AU2003223637A AU2003223637A1 (en) 2002-04-15 2003-04-15 Novel crystalline forms of (s)-n-(1-carboxy-2-methyl-prop-1-yl) -n-pentanoyl-n- (2'-(1h-tetrazol-5-yl-)- biphenyl-4-yl methyl) amine (valsartan)

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IN287CH2002 2002-04-15
IN287/MAS/2002 2002-04-15
IN322CH2002 2002-04-26
IN322/MAS/2002 2002-04-26

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004083192A1 (fr) * 2003-03-17 2004-09-30 Teva Pharmaceutical Industries Ltd. Formes polymorphes de valsartan
WO2004094391A3 (fr) * 2003-04-21 2005-03-24 Teva Pharma Procede de preparation du valsartan et de ses intermediaires
WO2005049588A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede d'isolement de valsartan
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle
EP1661891A1 (fr) * 2004-11-30 2006-05-31 KRKA, D.D., Novo Mesto Procédé de prépartion de valsartan
US7199144B2 (en) 2003-04-21 2007-04-03 Teva Pharmaceuticals Industries, Ltd. Process for the preparation of valsartan and intermediates thereof
WO2007054965A2 (fr) * 2005-09-23 2007-05-18 Alembic Limited Procede de preparation de tetrazoles a partir de derives cyano aromatiques
WO2007088558A2 (fr) * 2006-02-02 2007-08-09 Alembic Limited Procédé de purification du valsartan
US7378531B2 (en) 2003-04-21 2008-05-27 Teva Pharmaceutical Industries Ltd Process for the preparation of valsartan
WO2007017897A3 (fr) * 2005-05-25 2009-10-15 Ipca Laboratories Ltd. Nouvelles formes cristallines de (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine
KR101009404B1 (ko) 2008-04-30 2011-01-19 켐젠주식회사 (에스)-엔-(1-카르복시-2-메틸-프로-1-필)-엔-펜타노일-엔-[2'-(1에이취-테트라졸-5-일)비페닐-4-일-메틸]아민화합물의 고순도 제조방법
WO2012016969A1 (fr) 2010-08-03 2012-02-09 Novartis Ag Valsartan hautement cristallin
CN104610185A (zh) * 2014-03-10 2015-05-13 杭州领业医药科技有限公司 缬沙坦母液的回收方法
US9388134B2 (en) 2005-11-09 2016-07-12 Novartis, Ag Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl)-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
CN105777660A (zh) * 2016-03-29 2016-07-20 潍坊盛瑜药业有限公司 缬沙坦晶型e的诱导结晶工艺及应用
WO2017012600A1 (fr) 2015-07-20 2017-01-26 Zentiva, K.S. Composition pharmaceutique contenant du valsartan et du sacubitril et procédés de préparation et de stabilisation correspondants
WO2018002673A1 (fr) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Nouvelles formulations d'antagonistes du récepteur de l'angiotensine ii
EP3067043B1 (fr) 2007-11-06 2022-11-30 Novartis AG Compositions pharmaceutiques basées sur des superstructures d'antagoniste/bloqueur du récepteur de l'angiotensine (arb) et de l'inhibiteur de l'endopeptidase neutre (nep)

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WO2002006253A1 (fr) * 2000-07-19 2002-01-24 Novartis Ag Sels de valsartan

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US5399578A (en) * 1990-02-19 1995-03-21 Ciba-Geigy Corp Acyl compounds
US6071931A (en) * 1995-10-06 2000-06-06 Novartis Ag AT1 -receptor antagonists for preventing and treating postischemic renal failure and for protecting ischemic kidneys
WO2002006253A1 (fr) * 2000-07-19 2002-01-24 Novartis Ag Sels de valsartan

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105557B2 (en) 2003-03-17 2006-09-12 Teva Pharmaceutical Industries, Ltd. Polymorphs of valsartan
WO2004083192A1 (fr) * 2003-03-17 2004-09-30 Teva Pharmaceutical Industries Ltd. Formes polymorphes de valsartan
US7378531B2 (en) 2003-04-21 2008-05-27 Teva Pharmaceutical Industries Ltd Process for the preparation of valsartan
US7199144B2 (en) 2003-04-21 2007-04-03 Teva Pharmaceuticals Industries, Ltd. Process for the preparation of valsartan and intermediates thereof
WO2004094391A3 (fr) * 2003-04-21 2005-03-24 Teva Pharma Procede de preparation du valsartan et de ses intermediaires
WO2005049587A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede de preparation de tetrazole de biphenyle
WO2005049588A1 (fr) * 2003-11-21 2005-06-02 Ranbaxy Laboratories Limited Procede d'isolement de valsartan
EP1661891A1 (fr) * 2004-11-30 2006-05-31 KRKA, D.D., Novo Mesto Procédé de prépartion de valsartan
WO2006058701A1 (fr) * 2004-11-30 2006-06-08 Krka, D.D. Novo Mesto Procede de synthese du valsartan
WO2007017897A3 (fr) * 2005-05-25 2009-10-15 Ipca Laboratories Ltd. Nouvelles formes cristallines de (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine
WO2007054965A2 (fr) * 2005-09-23 2007-05-18 Alembic Limited Procede de preparation de tetrazoles a partir de derives cyano aromatiques
WO2007054965A3 (fr) * 2005-09-23 2007-11-01 Alembic Ltd Procede de preparation de tetrazoles a partir de derives cyano aromatiques
US11096918B2 (en) 2005-11-09 2021-08-24 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
EP2340828B1 (fr) 2005-11-09 2020-07-15 Novartis AG Combiaisons pharmaceutiques d'un antagoniste du recepteur de l'angiotensine et un inhibiteur de nep
US11642329B2 (en) 2005-11-09 2023-05-09 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
US9388134B2 (en) 2005-11-09 2016-07-12 Novartis, Ag Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl)-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
WO2007088558A2 (fr) * 2006-02-02 2007-08-09 Alembic Limited Procédé de purification du valsartan
WO2007088558A3 (fr) * 2006-02-02 2007-10-25 Alembic Ltd Procédé de purification du valsartan
EP3067043B1 (fr) 2007-11-06 2022-11-30 Novartis AG Compositions pharmaceutiques basées sur des superstructures d'antagoniste/bloqueur du récepteur de l'angiotensine (arb) et de l'inhibiteur de l'endopeptidase neutre (nep)
KR101009404B1 (ko) 2008-04-30 2011-01-19 켐젠주식회사 (에스)-엔-(1-카르복시-2-메틸-프로-1-필)-엔-펜타노일-엔-[2'-(1에이취-테트라졸-5-일)비페닐-4-일-메틸]아민화합물의 고순도 제조방법
WO2012016969A1 (fr) 2010-08-03 2012-02-09 Novartis Ag Valsartan hautement cristallin
CN103052630A (zh) * 2010-08-03 2013-04-17 诺华有限公司 高度结晶的缬沙坦
CN104610185A (zh) * 2014-03-10 2015-05-13 杭州领业医药科技有限公司 缬沙坦母液的回收方法
WO2017012600A1 (fr) 2015-07-20 2017-01-26 Zentiva, K.S. Composition pharmaceutique contenant du valsartan et du sacubitril et procédés de préparation et de stabilisation correspondants
CN105777660A (zh) * 2016-03-29 2016-07-20 潍坊盛瑜药业有限公司 缬沙坦晶型e的诱导结晶工艺及应用
WO2018002673A1 (fr) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Nouvelles formulations d'antagonistes du récepteur de l'angiotensine ii

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