WO2005049587A1 - Procede de preparation de tetrazole de biphenyle - Google Patents

Procede de preparation de tetrazole de biphenyle Download PDF

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Publication number
WO2005049587A1
WO2005049587A1 PCT/IB2004/003733 IB2004003733W WO2005049587A1 WO 2005049587 A1 WO2005049587 A1 WO 2005049587A1 IB 2004003733 W IB2004003733 W IB 2004003733W WO 2005049587 A1 WO2005049587 A1 WO 2005049587A1
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WO
WIPO (PCT)
Prior art keywords
valsartan
barium
process according
salt
hydroxide
Prior art date
Application number
PCT/IB2004/003733
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English (en)
Inventor
Yatendra Kumar
Mohan Prasad
Saswata Lahiri
Nitin Maheshwari
Ira Saxena
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2005049587A1 publication Critical patent/WO2005049587A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • the present invention relates to processes for the preparation of pure valsartan. Also provided is a barium salt of valsartan, and a pharmaceutical composition thereof.
  • valsartan is (S)-N-(l-carboxy-2-methylprop-l-yl)N-pentanoyl-N-[2'- (lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine of Formula I,
  • U.S. Patent No. 5,399,578 has angiotensin II antagonist properties and is used for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the ATi receptor, such as high blood pressure and cardiac insufficiency.
  • the synthesis of valsartan is disclosed in U.S. Patent No. 5,399,578; CN 1317485; and U.S. Patent No. 6,271,375.
  • U.S. Patent No. 5,399,578 discloses recrystallization from diisopropyl ether to obtain valsartan after extracting reaction mixture with ethyl acetate. The preparation of several salts of valsartan has been reported in PCT application Nos.
  • PCT Application No. WO 02/06253 discloses valsartan salts including sodium, potassium, magnesium and calcium salts; ammonium salts; and salts of lysine and arginine in different solid state and hydrated forms.
  • Mono and poly hydrate valsartan salts of magnesium and calcium are disclosed in U.S. Patent Application No. US 2003/0171414. Summary of the Invention In one general aspect there is provided a process for preparation of pure valsartan.
  • the process includes dissolving crude valsartan in an inert solvent to form a mixture, adding an organic or inorganic base to the mixture to form a salt of valsartan, isolating the salt of valsartan in a solid state, and converting the salt of valsartan into pure valsartan.
  • Embodiments of the process may include one or more of the following features.
  • the inert solvent maybe one or more of water, alcohols, esters, nitriles, chlorinated hydrocarbons, cyclic ethers, dipolar aprotic solvents and mixtures thereof.
  • the alcohol may be one or more of methanol, ethanol, isopropanol, and mixtures thereof.
  • the organic base may be one or more of C1-C4 alkyl ammonia; mono, di or tri Cl-
  • the inorganic base may be one or more of metal carbonate, metal bicarbonate and metal hydroxide.
  • the metal carbonate may be one or more of lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate.
  • the metal bicarbonate may be one or more of sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate.
  • the metal hydroxide may be one or more of sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.
  • the process may further include the step of adding an antisolvent to precipitate out the salt of valsartan.
  • the antisolvent may include one or more of lower alkyl ethers, hydrocarbons, ketones and mixtures thereof.
  • the ketone may be one or more of acetone, methyl isobutyl ketone and mixtures thereof.
  • the conversion of salts of valsartan to pure valsartan may be achieved by the addition of an acid.
  • the acid may be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.
  • the pure valsartan obtained may have a chiral purity of greater than or equal to about 99%.
  • a barium salt of valsartan may be provided.
  • crystalline barium salt of valsartan may be characterized by X-ray peaks at about 5.40, 15.14, and 16.30 ⁇ 0.2 degrees two-theta.
  • the crystalline barium salt of valsartan may also be characterized by X-ray diffraction pattern as shown in Figure I.
  • the suitable solvent may include one or more of alcohols, esters, nitriles, chlorinated hydrocarbons, cyclic ethers, dipolar aprotic solvents and mixtures thereof.
  • the alcohol may be one or more of methanol, ethanol, isopropanol, and mixtures thereof.
  • the method includes administering a pharmaceutical composition comprising valsartan barium.
  • a pharmaceutical composition which includes valsartan barium and one or more pharmaceutically acceptable excipients.
  • Crude valsartan may be prepared by methods known in the art including those described in U.S. Patent No. 5,399,578; CN 1317485; and U.S. Patent No. 6,271,375. Crude valsartan may contain isomeric impurities or any other impurity. Valsartan barium may also be obtained as a solution, for example from a reaction mixture resulting directly from a reaction in which valsartan is formed.
  • Suitable inert solvents for carrying out the processes include one or more of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide and dimethylformamide; esters, such as ethylacetate and isopropylacetate; cyclic ethers, such as dioxane and tetrahydrofuran; and mixtures thereof.
  • the mixture of crude valsartan and an inert solvent can be obtained by dissolving, suspending, slurrying, stirring or a combination thereof.
  • Suitable salts of valsartan include salts with an organic or inorganic base.
  • Valsartan salts with an inorganic base may include salts with alkali metal, such as lithium, sodium or potassium and alkaline earth metals salts, such as magnesium, calcium and barium.
  • Valsartan salts with an organic base may include salts with -C 4 alkyl ammonia; mono, di or tri C 1 -C 4 alkyl amine; mono, di or tri hydroxy C 1 -C 4 alkyl amine; morpholine; thiomorpholme; piperidine; and pyrrolidine.
  • the conversion of crude valsartan into salt of valsartan is achieved by adding the corresponding organic or inorganic base.
  • Suitable inorganic bases include one or more of alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof.
  • Suitable alkali metal carbonates include one or more of lithium carbonate, sodium carbonate and potassium carbonate.
  • Suitable alkali metal bicarbonates include one or more of sodium bicarbonate and potassium bicarbonate.
  • Suitable alkali metal hydroxides include one or more of sodium hydroxide and potassium hydroxide. Isolation of salt of valsartan may be accomplished by one or more of concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. The precipitation of salt of valsartan may be spontaneous, depending upon the solvent used and the conditions.
  • Precipitation may also occur with the addition of an antisolvent, i.e., a solvent in which the salt of valsartan is insoluble or sparingly soluble, to the inert solvent in which the salt of valsartan is prepared.
  • an antisolvent i.e., a solvent in which the salt of valsartan is insoluble or sparingly soluble
  • precipitation can be induced by concentrating and/or reducing the temperature of the inert solvent, particularly if the initial temperature is elevated.
  • the salts of valsartan may also be obtained from any of the methods described in
  • Suitable antisolvents that may be added to precipitate out a salt of valsartan include one or more of hydrocarbons, such as hexane, cyclohexane, toluene, heptane and octane; ketones, such as acetone and methyl isobutyl ketone; lower alkyl ethers, such as diethylether and diisopropylether; and mixtures thereof.
  • the amount of the solvent used varies depending on the type of solvent and lot size. Crystallization or precipitation may be conducted with or without stirring. The crystallization / precipitation time and temperature can vary.
  • the crystallization / precipitation may be performed at temperatures of from about 0°C to about 50°C for 30 minutes to 3 hours.
  • the conversion of salts of valsartan to pure valsartan may be achieved by addition of an acid in a suitable solvent. Suitable acids include one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.
  • the solvent used for the conversion of salts of valsartan to pure valsartan may be the same as those used for the preparation of valsartan salt as detailed above.
  • the reaction time and temperature also varies. For example, the reaction may be performed at temperatures of from about 20°C to about 50°C for 30 minutes to 2 hours.
  • Valsartan barium is a good crystalline solid. Crystalline valsartan barium may be characterized by a strong X-ray peak at about 5.40 ⁇ 0.2 degrees two-theta and peaks at 15.14 and 16.30 ⁇ 0.2 degrees two-theta. Crystalline valsartan barium may also be characterized by its IR spectra and DSC graph.
  • FIG. I is a powder X-ray diffraction pattern of valsartan barium.
  • FIG. II is a table of the X-ray diffraction peak values
  • FIG. Ill is an infrared absorption spectrum of valsartan barium.
  • FIG. TV is a DSC graph of valsartan barium
  • the crude valsartan used in the preparation of valsartan barium may be prepared by any of the methods known in the art including those described U.S. Patent No. 5,399,578; CN 1317485; and U.S. Patent No. 6,271,375.
  • the starting valsartan may also be obtained as a solution directly from a reaction in which valsartan is formed and used as such without isolation.
  • the term "contacting" includes dissolving, slurrying, suspending, stirring or a combination thereof. Isolation may be accomplished by one or more of concentration, precipitation, cooling, filtration, centrifugation or a combination thereof, optionally followed by drying.
  • Solvents used for the preparation of valsartan barium may be similar to those used for the preparation of salts of valsartan as defined above.
  • the isolation of valsartan barium may be similar to the isolation of salts of valsartan as defined above.
  • Valsartan barium is useful for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the AT ! receptor.
  • the diseases or conditions include one or more of hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery, atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nepl ropathy, renal failure, e.g.
  • the salt is usually administered as part of a pharmaceutical composition.
  • a pharmaceutical composition that includes valsartan barium and one or more pharmaceutically acceptable excipients. Suitable excipients include one or more of carriers, diluents, lubricants, distingrants and glidants.
  • the pharmaceutical composition may optionally include other therapeutic ingredients.
  • the pharmaceutical composition may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.
  • Any suitable route of administration may be employed, for example, peroral or parental.
  • embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention.
  • the reaction was monitored by TLC. After completion of the reaction, it was filtered, concentrated and treated with a solution of sodium carbonate (8.25 g in 100 ml water). The aqueous layer was washed with dichloromethane, acidified and extracted with ethyl acetate. The organic layer was concentrated (HPLC Purity: 93.5%). It was dissolved in a mixture of ethanol (150 ml) and water (150 ml). This solution was treated with barium hydroxide (18.1 g) and stirred for 1 hour. It was then filtered and concentrated to about 150 ml at 55 to 65°C under reduced pressure. It was treated with acetone (150 ml) and stirred for 2 hours at 0 to 5°C. The solid obtained was filtered, washed with acetone (50 ml) and dried to obtain title salt as white crystalline solid.
  • Example 2 Preparation of N-[(2'-cyanobiphenyl -4-yl) methyl] -N-pentanoyl- (Q-valine methyl ester
  • a solution of N-[(2'-cyanobiphenyl-4-yl) methyl] -(L)-valine methyl ester hydrochloride (6 g, 16.7 mmol) in dichloromethane (50 ml), was treated with dusopropyl ethyl amine (7.6 g, 58.8 mmol) and valeryl chloride (4 g, 33.5 mmol) at 0 to 5 °C for 1 hour.
  • the reaction mixture was washed with water, 5% Sodium bicarbonate solution and 0.5N hydrochloric acid successively. The organic layer was then concentrated to afford the title compound as yellow-colored oil.
  • valsartan chiral purity: 96.07%, HPLC: purity 98.78%). It was then dissolved in ethanol (36ml) and water (36 ml) was added to it. Barium hydroxide octahydrate (5.28 g) was then added to the above mixture and stirred for 1 hour. The reaction mixture was filtered, concentrated to about 40ml at 50-55°C under reduced pressure, cooled and treated with acetone (36 ml). The reaction mixture was stirred for lhour, filtered and washed with acetone (12 ml). The solid obtained was dried to obtain valsartan barium.
  • Example 3 Preparation of (S)-N-(l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N- 2'(lH - tetrazol-5-yl)biphenyl-4-yl-methyl] amine barium salt (Valsartan Barium) Water (6 liters) was added to the solution of Valsartan (1 kg, HPLC Purity: 98.6%, Chiral purity: 96.5%) in ethanol (6 liters). It was then treated with barium hydroxide octahydrate (725 g)) and stirred for 1 hour. The reaction mixture was filtered and concentrated to about 6 liters at 55-60°C under reduced pressure. The reaction mixture was then treated with acetone (6 litres) and stirred for 2 hours at 0-5°C. The obtained solid was filtered, washed with acetone (2 liters) and dried to obtain valsartan barium

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des procédés de préparation de valsartan pur, ainsi qu'un sel de baryum de valsartan et une composition pharmaceutique de ces composés.
PCT/IB2004/003733 2003-11-21 2004-11-15 Procede de preparation de tetrazole de biphenyle WO2005049587A1 (fr)

Applications Claiming Priority (2)

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IN1447/DEL/2003 2003-11-21
IN1447DE2003 2003-11-21

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007032019A3 (fr) * 2005-08-22 2007-06-14 Alembic Ltd Procede de preparation de valsartan
WO2007069271A2 (fr) * 2005-10-31 2007-06-21 Alembic Limited Procede de purification d'une (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine
WO2007071750A1 (fr) * 2005-12-22 2007-06-28 Enantia, S.L. Intermédiaires et procédés de synthèse du valsartan
WO2007088558A2 (fr) * 2006-02-02 2007-08-09 Alembic Limited Procédé de purification du valsartan
WO2008018843A1 (fr) * 2006-08-08 2008-02-14 Ulkar Kimya Sanayi Ve Ticaret As Procédé de production de formes de sel utiles de composés de biphényl-tétrazole
EP2090567A2 (fr) 2008-02-13 2009-08-19 Ranbaxy Laboratories, Ltd. Processus pour la préparation d'intermédiaires de valsartan
KR100995734B1 (ko) 2008-05-28 2010-11-19 일동제약주식회사 발사르탄의 개선된 제조방법
US7880015B2 (en) 2006-07-03 2011-02-01 Aurobindo Pharma Ltd. Process for the preparation of angiotensin II antagonist
WO2015056219A1 (fr) 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Procédé de séchage et de micronisation simultanés de valsartan
WO2021022516A1 (fr) * 2019-08-07 2021-02-11 浙江华海药业股份有限公司 Procédé d'affinage de valsartan
US10975111B2 (en) * 2018-06-26 2021-04-13 Signpath Pharma, Inc. Cardiopathy-reducing phosphodiester lipids
EP3939967A1 (fr) 2020-07-15 2022-01-19 KRKA, d.d., Novo mesto Procédé continu pour la préparation de (s)-méthyl n-((2'-cyano-[1,1'-biphényl]-4-yl)méthyl)-n-pentanoylvalinate dans un réacteur à écoulement
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
WO2023148748A1 (fr) * 2022-02-04 2023-08-10 Iol Chemicals And Pharmaceuticals Limited Procédé sûr amélioré pour la préparation de médicaments sartan de formule i

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5399578A (en) * 1990-02-19 1995-03-21 Ciba-Geigy Corp Acyl compounds
WO1999001459A1 (fr) * 1997-06-30 1999-01-14 Zambon Group S.P.A. Procede d'ortho-metallation permettant de synthetiser des 2-substitue-1-(tetrazol-5-yl)benzenes
WO2002006253A1 (fr) * 2000-07-19 2002-01-24 Novartis Ag Sels de valsartan
WO2003066606A1 (fr) * 2002-02-04 2003-08-14 Novartis Ag Sels de valsartan
WO2003089417A1 (fr) * 2002-04-15 2003-10-30 Dr. Reddy's Laboratories Limited 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)
WO2004083192A1 (fr) * 2003-03-17 2004-09-30 Teva Pharmaceutical Industries Ltd. Formes polymorphes de valsartan
WO2004094391A2 (fr) * 2003-04-21 2004-11-04 Teva Pharmaceutical Industries Ltd. Procede de preparation du valsartan et de ses intermediaires

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5399578A (en) * 1990-02-19 1995-03-21 Ciba-Geigy Corp Acyl compounds
WO1999001459A1 (fr) * 1997-06-30 1999-01-14 Zambon Group S.P.A. Procede d'ortho-metallation permettant de synthetiser des 2-substitue-1-(tetrazol-5-yl)benzenes
WO2002006253A1 (fr) * 2000-07-19 2002-01-24 Novartis Ag Sels de valsartan
WO2003066606A1 (fr) * 2002-02-04 2003-08-14 Novartis Ag Sels de valsartan
WO2003089417A1 (fr) * 2002-04-15 2003-10-30 Dr. Reddy's Laboratories Limited 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)
WO2004083192A1 (fr) * 2003-03-17 2004-09-30 Teva Pharmaceutical Industries Ltd. Formes polymorphes de valsartan
WO2004094391A2 (fr) * 2003-04-21 2004-11-04 Teva Pharmaceutical Industries Ltd. Procede de preparation du valsartan et de ses intermediaires

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007032019A3 (fr) * 2005-08-22 2007-06-14 Alembic Ltd Procede de preparation de valsartan
WO2007069271A2 (fr) * 2005-10-31 2007-06-21 Alembic Limited Procede de purification d'une (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine
WO2007069271A3 (fr) * 2005-10-31 2008-10-02 Alembic Ltd Procede de purification d'une (s)-n-(1-carboxy-2-methyl-prop-1-yl)-n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine
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
WO2007071750A1 (fr) * 2005-12-22 2007-06-28 Enantia, S.L. Intermédiaires et procédés de synthèse du valsartan
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
US7880015B2 (en) 2006-07-03 2011-02-01 Aurobindo Pharma Ltd. Process for the preparation of angiotensin II antagonist
WO2008018843A1 (fr) * 2006-08-08 2008-02-14 Ulkar Kimya Sanayi Ve Ticaret As Procédé de production de formes de sel utiles de composés de biphényl-tétrazole
EP2090567A2 (fr) 2008-02-13 2009-08-19 Ranbaxy Laboratories, Ltd. Processus pour la préparation d'intermédiaires de valsartan
US7943794B2 (en) 2008-02-13 2011-05-17 Ranbaxy Laboratories Limited Processes for the preparation of intermediates of valsartan
KR100995734B1 (ko) 2008-05-28 2010-11-19 일동제약주식회사 발사르탄의 개선된 제조방법
WO2015056219A1 (fr) 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Procédé de séchage et de micronisation simultanés de valsartan
US10975111B2 (en) * 2018-06-26 2021-04-13 Signpath Pharma, Inc. Cardiopathy-reducing phosphodiester lipids
US11643424B2 (en) 2018-06-26 2023-05-09 Signpath Pharma, Inc. Cardiopathy-reducing phosphodiester lipids
US11746119B2 (en) 2018-06-26 2023-09-05 Signpath Pharma, Inc. Cardiopathy-reducing phosphodiester lipids
WO2021022516A1 (fr) * 2019-08-07 2021-02-11 浙江华海药业股份有限公司 Procédé d'affinage de valsartan
EP3939967A1 (fr) 2020-07-15 2022-01-19 KRKA, d.d., Novo mesto Procédé continu pour la préparation de (s)-méthyl n-((2'-cyano-[1,1'-biphényl]-4-yl)méthyl)-n-pentanoylvalinate dans un réacteur à écoulement
WO2023148748A1 (fr) * 2022-02-04 2023-08-10 Iol Chemicals And Pharmaceuticals Limited Procédé sûr amélioré pour la préparation de médicaments sartan de formule i

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