WO2004076406A2 - Polymorphismes du losartan potassique et leur procede de preparation - Google Patents

Polymorphismes du losartan potassique et leur procede de preparation Download PDF

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Publication number
WO2004076406A2
WO2004076406A2 PCT/EP2004/001717 EP2004001717W WO2004076406A2 WO 2004076406 A2 WO2004076406 A2 WO 2004076406A2 EP 2004001717 W EP2004001717 W EP 2004001717W WO 2004076406 A2 WO2004076406 A2 WO 2004076406A2
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WO
WIPO (PCT)
Prior art keywords
losartan potassium
crystalline form
preparation
losartan
temperature
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PCT/EP2004/001717
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English (en)
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WO2004076406A3 (fr
Inventor
Andrea Boccignone
Luciana Malpezzi
Graziano Castaldi
Pietro Allegrini
Andrea Beltrame
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Dipharma S.P.A.
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Application filed by Dipharma S.P.A. filed Critical Dipharma S.P.A.
Publication of WO2004076406A2 publication Critical patent/WO2004076406A2/fr
Publication of WO2004076406A3 publication Critical patent/WO2004076406A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic 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

Definitions

  • the present invention relates to novel forms of Losartan potassium, in particular to a hydrated crystalline form, the amorphous form and a novel losartan potassium crystalline form, herein referred to as Form III. It also relates to a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Losartan potassium 2-n-Butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]- l-H-imidazole-5-methanol potassium salt is known as Losartan potassium.
  • Losartan potassium is a known hormone angiotensin II (All) inhibitor, useful in the treatment of angiotensin-induced hypertension.
  • Losartan potassium is also useful in the treatment of hypercholesterolemia, due to its ability to reduce total cholesterol, and in treating impaired cognitive performance.
  • Losartan potassium in combination with a diuretic, such as furosemide or hydrochlorotiazide, enhances the antihypertensive effect of Losartan potassium, while keeping the antiatherosclerotic and hypocholesterolemizing activities.
  • the administration of Losartan potassium can prevent renal failure sometimes induced by non steroidal anti-inflammatories.
  • US 5,138,069 and WO 93/10106 disclose Losartan potassium and its preparation. Two polymorphic forms of Losartan potassium, referred to as Form I and Form II, were described and characterized in US 5,608,075.
  • WO 03/048135 is directed to several Losartan potassium forms, including a tetrahydrate crystalline form therein defined as Form III. Such known Form III is different from the crystalline form provided by the present invention, also referred to as Form III.
  • Losartan potassium can exist, in addition to the known crystalline forms I and II, also in other forms stable at room temperature, in particular in the crystalline hydrated form, in the amorphous form and in a crystalline Form III.
  • the invention therefore relates to the polymorphic forms, herein referred to as hydrated crystalline form, amorphous form and crystalline Form
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Losartan potassium crystalline Form III, or a mixture thereof with at least one of Losartan potassium crystalline Form I, Losartan potassium crystalline Form II, Losartan potassium crystalline hydrate and amorphous Losartan potassium, as the active ingredient, together with a diluent and/or carrier, and to their use in therapy.
  • DSC thermograms were recorded with Perkin Elmer differential scansion calorimeter DSC7, subjecting the sample, placed in an open capsule, to a temperature increase of 10°/min. under nitrogen atmosphere.
  • IR spectra were recorded with a Perkin Elmer spectrophotometer FT-IR System 2000.
  • Fig. 1A XRPD (X-ray powder diffraction pattern) of Losartan potassium crystalline hydrate
  • Fig. IB XRPD (X-ray powder diffraction pattern) of Losartan potassium amorphous form
  • Fig. 2A DSC thermogram of Losartan potassium crystalline hydrate
  • Fig. 2B DSC thermogram of Losartan potassium amorphous form
  • Fig. 2C DSC thermogram of Losartan potassium crystalline Form III
  • Fig. 3A IR (Infrared Spectroscopy) of Losartan potassium crystalline hydrate
  • Fig. 3B IR (Infrared Spectroscopy) of Losartan potassium amorphous form
  • a first object of the invention is the hydrated crystalline form of Losartan potassium, typically containing approx. 3 to 14% by weight of water, in particular approx. 11 to 13% by weight of water.
  • An object of the invention is also the amorphous form of Losartan potassium, which can contain up to 10% by weight of water.
  • a further object of the invention is the crystalline Form III of Losartan potassium.
  • a further object of the invention is a novel process for the preparation of Losartan potassium crystalline Form II.
  • the Losartan potassium solution used to obtain Losartan potassium crystalline hydrate, amorphous Losartan potassium and Losartan potassium crystalline Form III can be prepared according to known methods.
  • Losartan can be obtained according to US 5,138,069 and WO 93/10106.
  • an aqueous solution of Losartan potassium can be prepared by dissolving it in a KOH aqueous solution, in equimolar ratio, and heating to approx. 60°C.
  • the resulting Losartan potassium aqueous solution is used for the preparations described in the following.
  • a Losartan potassium alcoholic solution for example a methanol or ethanol solution, for use in the preparations indicated in the following, can be prepared.
  • a Losartan potassium aqueous solution is concentrated by distillation. The solution is then left to cool spontaneously to room temperature. The resulting solid is filtered and dried in a static dryer to approx. 40-50°C, to give a product identified as Losartan potassium crystalline hydrate.
  • Said hydrate crystalline form has a water content typically ranging from approx. 3 to 14% by weight, in particular approx. from 11 to 13% by weight.
  • the Losartan potassium solution is concentrated by evaporation of the solvent at a temperature ranging from approx. 60 to 100°C. The solution is then left to cool spontaneously to room temperature. The resulting solid is filtered and dried in a static dryer at approx. 40-50°C, to give a product identified as Losartan potassium crystalline hydrate.
  • the resulting hydrate crystalline form has water content typically ranging from approx. 3 to 14% by weight, in particular from approx. 11 to 13% by weight.
  • the hydrate crystalline form of Losartan potassium has the following characteristics: a) X-ray powder diffraction spectrum, Fig. 1A, comprising diffraction peaks at approx. 5.7, 6.9, 8.9, 13.2, 13.9 14.2, 14.9, 15.8, 16.2, 16.3, 17.1, 17.4, 19.9, 20.8, 21.0, 21.6, 21.9, 22.2, 23.3, 23.6, 24.1, 24.8, 25.2, 26.6, 27.5, 28.5 p 0.2 degrees in 2-theta. b) DSC thermogram, Fig. 2 A, having 3 characteristic peaks: a first endothermal peak at an extrapolated onset temperature of approx.
  • Amorphous Losartan potassium is obtained by heating Losartan potassium crystalline hydrate at a temperature of approx. 120-150°C, in a static dryer. After reaching this temperature, the solid is left to cool to room temperature, thereby obtaining amorphous Losartan potassium.
  • the amorphous form can contain water up to approx. 10% by weight.
  • Losartan potassium amorphous form can be obtained starting from a Losartan potassium aqueous solution.
  • the solution is first concentrated by distillation of the solvent, then concentrated to a residue under vacuum, while hot.
  • the resulting solid is dried in a static dryer, optionally under vacuum, at approx. 45-50°C, thereby obtaining directly amorphous Losartan potassium.
  • this amorphous form can contain water up to approx. 10% by weight.
  • the Losartan potassium amorphous form obtainable by the process of the invention has the following characteristics: a) X-ray powder diffraction spectrum, Fig. IB, without single diffraction peaks but with the characteristic halo typical of an amorphous substance, having a maximum approx. between 18 and 24° in 2T; b) DSC thermogram, Fig. 2B, having an exothermic peak at an extrapolated onset temperature ranging from 185 to 200°C, corresponding to the transition from the amorphous to crystalline anhydrous phase identified at point D, and an endothermal peak at an extrapolated onset temperature of approx. 272°C, corresponding to complete melting of the product; and c) IR spectrum, Fig. 3B, which shows a broadened band characteristic of the O-H bond stretching, ranging from the frequencies approx. between 3050 and 3650 cm "1 .
  • a Losartan potassium solution is prepared providing a solution of Losartan potassium in methanol at room temperature.
  • the Losartan potassium methanol solution is heated to approx. 50-60°C and kept at this temperature, under stirring, until complete evaporation of the solvent.
  • the resulting solid is left to dry, for instance in the open air or alternatively in a static dryer at approx. 45-50°C, thereby obtaining crystalline Losartan potassium, identified as Form III.
  • a Losartan potassium crystalline Form III can be prepared starting from losartan free acid, by reacting it with potassium bicarbonate, preferably in 4-5 volumes of methanol. The mixture is stirred at a temperature ranging from 30°C to reflux, preferably at reflux temperature, until complete dissolution of the potassium bicarbonate. The losartan potassium methanol solution, thus obtained, is concentrated, optionally under vacuum, to residue which contains the product and an amount of solvent equal to half the weight of the product. Under these conditions the polymorph Form III crystallizes.
  • Losartan potassium crystalline Form III as obtainable by the process of the invention, has the following characteristics: a) X-ray powder diffraction spectrum, Fig. 1C, comprising a very strong diffraction peak at 7.2 p 0.2 degrees in 2-theta and diffraction peaks of average intensity at approx. 7.6, 8.0, 12.5, 13.2, 13.9, 15.3, 16.1, 17.2, 17.8, 18.5, 19.3, 19.6, 20.7, 21.6, 24.2, 24.9, 26.1, 27.8, 28.9, 29.5 p 0.2 degrees in 2-theta.
  • Losartan crystalline Form II (known from US 5,608.075) It has been found that Losartan potassium crystalline Form II can be obtained from amorphous Losartan potassium, as obtainable according to invention, by heating at a temperature approx. ranging from 220 to 240°C.
  • Losartan potassium crystalline Form II prepared according to the process of the invention, has the following characteristics: a) X-ray powder diffraction spectrum having the same sequences angular and peaks intensities as that reported in US 5,608,075 for Losartan potassium Form II; and b) DSC thermogram having an endothermal peak at an extrapolated onset temperature of approx. 271°C, similar to that reported in US 5,608,075 for Losartan potassium Form II.
  • the Form II was identified and confirmed by X-rays powder diffraction, whereas thermal analysis gives no indications. In fact the conversion from Form III to Form II is not clearly evidenced in the DSC thermogram of the Form III, Fig. 2C.
  • the importance of the novel Losartan potassium forms of the invention resides mainly in their useful application in the pharmaceutical technique, in particular in processes such as filtration, drying, sieving, formulation, and the like.
  • Losartan potassium crystalline hydrate, amorphous Losartan potassium and Losartan potassium crystalline Form III can be used in human and veterinary medicine in the treatment of those pathologies which can be treated with Losartan potassium, and with the known crystalline forms Losartan forms I and II.
  • they can be used in the treatment of hypertension in both humans and warm-blooded animals having homeostatic mechanisms, myocardial infarction and impaired cognitive performance.
  • the treatment as indicated above, can be also carried out in combination with other medicaments commonly used in the treatment of said pathologies.
  • the present invention therefore also relates to Losartan potassium crystalline Form III, or a mixture thereof with at least one of Losartan potassium crystalline hydrate and amorphous Losartan potassium, for use as a medicament, in particular in the treatment of hypertension, myocardial infarction and in treating impaired cognitive performance.
  • the invention also relates to a method for the treatment of hypertension, myocardial infarction and impaired cognitive performance in a patient in need of said treatment, comprising administering to said patient a therapeutically effective amount of a product selected from Losartan potassium crystalline Form III, or a mixture thereof with at least one of Losartan potassium crystalline hydrate and amorphous Losartan potassium; more preferably Losartan potassium crystalline Form III.
  • a product selected from Losartan potassium crystalline Form III, or a mixture thereof with at least one of Losartan potassium crystalline hydrate and amorphous Losartan potassium; more preferably Losartan potassium crystalline Form III.
  • the dosage will depend on the conditions of the patient or animal to be treated, and on other factors such as age, severity of the disease and weight. As a rule, the daily dosage will range approx. from 1 to 500 mg, preferably approx. from 10 to 100 mg, in single or repeated administrations, according to the physician's indications.
  • Losartan potassium crystalline hydrate, amorphous Losartan and Losartan potassium crystalline Form III can be formulated according to known methods, in a pharmaceutical form suitable for the oral or parenteral use. Examples of said forms are solutions, suspensions and emulsions for the oral or parenteral use, tablets, pills, capsules, mixtures of powders, syrups and suppositories.
  • Losartan potassium crystalline hydrate A Losartan potassium solution is poured into deionized water in a 50 ml round-bottom flask (33 g; cone. 45.5%). The volume of the solution is halved by distillation. The solution is then left to cool spontaneously to room temperature. The resulting solid is filtered and dried in a static dryer at approx. 45-50°C for about 5 hours, and, after cooling to room temperature, is identified as Losartan potassium crystalline hydrate.
  • a Losartan potassium solution is poured into deionized water in a 50 ml round-bottom flask (27 g; cone. 37%). The solution is kept under magnetic stirring at 75°C until evaporation of approx. half the solvent. The solution is then left to cool spontaneously to room temperature. The resulting solid is filtered and dried in a static dryer at approx. 45-50°C for about 4 hours, and, after cooling to room temperature, is identified as Losartan potassium crystalline hydrate. Its water content is approx. 11.7% w/w.
  • Losartan potassium crystalline hydrate obtained as described in Example 1
  • 5 g of Losartan potassium crystalline hydrate obtained as described in Example 1
  • the solid is kept at this temperature for 5 minutes and then left to cool spontaneously to room temperature.
  • the resulting solid was identified as amorphous Losartan potassium.
  • the same preparation of amorphous Losartan potassium can be carried out following the procedure described above, but heating the product in the Petri dish to a temperature of 140°C. Its water content is approx. 4.7% w/w.
  • a Losartan potassium solution is poured into deionized water in a 50 ml round-bottom flask (35 g; cone. 42.9%). The solution is concentrated by distilling off approx. 16.0 ml of solvent and then concentrated to a residue under vacuum while still hot. The resulting solid is then dried in a static dryer at 45-50°C for approx. 24 hours, to give, after cooling to room temperature, amorphous Losartan potassium. Its water content is approx. 5.1% w/w. EXAMPLE 5
  • amorphous Losartan potassium is obtained having water content lower than 0.5% w/w.
  • Losartan potassium crystalline Form III obtained as described in Example 6 or Example 9, are placed in a covered Petri dish and heated in a static dryer at 10°C/min. to approx. 240°C. The solid is kept at this temperature for approx. 3 minutes and then left to cool spontaneously to room temperature. The resulting solid is identified as Losartan potassium crystalline Form II.
  • Capsules for the oral administration are prepared by filling two-piece standard hard gelatine capsules with 100 mg each of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des polymorphismes du losartan potassique, identifiés comme un hydrate cristallin de losartan potassique, du losartan potassique amorphe et du losartan potassique modifié sous sa forme cristalline III, leur procédé de préparation, des compositions pharmaceutiques contenant ceux-ci et leur utilisation en thérapie.
PCT/EP2004/001717 2003-02-25 2004-02-20 Polymorphismes du losartan potassique et leur procede de preparation WO2004076406A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000328A ITMI20030328A1 (it) 2003-02-25 2003-02-25 Polimorfi di losartan potassio e procedimento per la loro preparazione.
ITMI2003A000328 2003-02-25

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WO2004076406A2 true WO2004076406A2 (fr) 2004-09-10
WO2004076406A3 WO2004076406A3 (fr) 2005-01-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076097A2 (fr) * 2004-12-07 2006-07-20 Nektar Therapeutics Preparation non cristalline stable contenant du losartan

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US5608075A (en) * 1993-12-23 1997-03-04 Merck & Co., Inc. Polymorphs of losartan and the process for the preparation of form II of losartan
WO2002094816A1 (fr) * 2001-05-18 2002-11-28 Aurobindo Pharma Limited Procede de cristallisation du losartan potassium
WO2003048135A1 (fr) * 2001-11-14 2003-06-12 Teva Pharmaceutical Industries Ltd. Formes cristallines amorphes de losartan potassique et leur procede de preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US5608075A (en) * 1993-12-23 1997-03-04 Merck & Co., Inc. Polymorphs of losartan and the process for the preparation of form II of losartan
WO2002094816A1 (fr) * 2001-05-18 2002-11-28 Aurobindo Pharma Limited Procede de cristallisation du losartan potassium
WO2003048135A1 (fr) * 2001-11-14 2003-06-12 Teva Pharmaceutical Industries Ltd. Formes cristallines amorphes de losartan potassique et leur procede de preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076097A2 (fr) * 2004-12-07 2006-07-20 Nektar Therapeutics Preparation non cristalline stable contenant du losartan
WO2006076097A3 (fr) * 2004-12-07 2006-09-14 Nektar Therapeutics Preparation non cristalline stable contenant du losartan

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WO2004076406A3 (fr) 2005-01-13
ITMI20030328A1 (it) 2004-08-26

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