WO2010046804A2 - A process for preparation of losartan potassium form i - Google Patents
A process for preparation of losartan potassium form i Download PDFInfo
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- WO2010046804A2 WO2010046804A2 PCT/IB2009/054485 IB2009054485W WO2010046804A2 WO 2010046804 A2 WO2010046804 A2 WO 2010046804A2 IB 2009054485 W IB2009054485 W IB 2009054485W WO 2010046804 A2 WO2010046804 A2 WO 2010046804A2
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- Prior art keywords
- losartan potassium
- losartan
- preparation
- suspension
- potassium
- Prior art date
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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
Definitions
- the present invention relates to a process for preparation of Losartan potassium
- Losartan is used as Antihypertensive. It is non-peptide angiotensin II receptor antagonist. It is used in the treatment of hypertension. It is also used in the treatment of diabetic nephropathy with an elevated serumcreatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. It may be administered with other antihypertensive agents.
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
- a single molecule like Losartan potassium, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis ( 1 TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.
- US5608075 discloses Form I of Losartan potassium characterized by an X-ray powder diffraction pattern having X-ray powder diffraction angles of: 7.24, 11.02, 14.16, 15.07, 18.46, 18.87, 26.53, 27.30 and 29.15 and Form II of Losartan potassium characterized by an X-ray powder diffraction pattern having X-ray powder diffraction angles: 2.95, 6.95, 7.91, 12.61, 14.28, 18.98, 20.01, 21.63, 29.15.
- US 7271269 discloses crystal Form X
- US2006229350 discloses crystalline Form alpha
- WO2004076442 discloses Form A & Form B
- CN1763036A discloses H-type crystalline form
- US20060241305 discloses an amorphous form of Losartan potassium.
- US20050070586 discloses process for preparation of Form I of Losartan potassium which comprise reacting Trityl Losartan with equimolar quantities of anhydrous potassium salts in a secondary/tertiary alcohol at reflux, concentrating the reaction mass to 50%, filtering triphenyl methyl methyl ether, concentrating the methanol mixture and removing residual solvents, cooling and filtering.
- US7332612B2 discloses process for preparation of Form I of Losartan potassium which comprise preparing Losartan potassium solution in a first solvent which is nonaqueous and having a boiling point of about 135 0 C or below, reducing the temperature, adding a second solvent selected from the group consisting of ethyl acetate, toluene, acetone, methylethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate, and hexane to form a mixture whereby a precipitate is formed which is isolated as Losartan potassium Form I.
- a second solvent selected from the group consisting of ethyl acetate, toluene, acetone, methylethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate, and hexane
- US5608075 discloses process for preparation of Form I of Losartan potassium which comprises adding Losartan free acid to 0.842 N KOH solution, slurry is aged at room temperature till all solid dissolves. The solution is filtered and the aqueous solution is added to refluxing azeotropic mixture of cyclohexane/isopropanol whereupon cy- clohexane/isopropanol/water distilled out and simultaneously potassium salt crystallizes. The slurry is cooled and filtered to give polymorph Form I.
- the present invention aims to provide a process for preparation of Form I of Losartan potassium.
- a primary object of the present invention to provide a process for preparation of
- Another object of the present invention is to provide a process for preparation of
- Losartan potassium Form I which is easy to operate and applicable at industrial scale.
- present invention provides a process for preparation of Losartan potassium Form I comprising steps of:
- the present invention provides a process for preparation of
- Losartan potassium Form I comprising steps of:
- FIG. 1 shows the X-ray powder diffraction pattern of Losartan potassium Form I prepared by the present invention.
- the present invention provides a process for preparation of Losartan potassium Form
- present invention provides a process for preparation of Losartan potassium Form I comprising steps of:
- Losartan potassium as taken is step (i) includes any crystalline form, amorphous form, solvate form or mixtures thereof.
- This suspension is stirred at either ambient temperature or at elevated temperature, preferably at reflux temperature for a time sufficient to form Losartan potassium Form I. Generally it takes 1 to 2 hours at reflux temperature but it may vary with the temperature. During this process solid product Losartan potassium does not dissolve.
- the suspension is cooled to about 25 0 C to about 3O 0 C during period of 1 to 2 hours.
- the suspension is further cooled to about 5° to about 1O 0 C and maintained for one hour.
- the product was filtered and solid cake was washed with chilled acetone (1O 0 C). The solid is suck dried and then dried in oven under vacuum at 60-70 0 C to give Losartan potassium Form I.
- the present invention provides a process for preparation of
- Losartan potassium Form I comprising steps of:
- step (ii) removing solvent from a solution obtained in step (i) to obtain Losartan potassium as a solid;
- FIG. 1 shows the X-ray powder diffraction pattern of Losartan potassium Form I prepared by the present invention.
- the reaction mixture was filtered hot through hyflo bed.
- the bed was washed twice with hot methanol (55 0 C) (50 ml x X). Methanol was distilled out completely from the filtrate at atmospheric pressure. High vacuum was applied till all the material gets solidified.
- Acetone (50 ml) was added and distilled out completely at atmospheric pressure. This step is repeated twice. Again acetone (300 ml) was added and refluxed for an hour. (Note: solid does not dissolve).
- the suspension was cooled to 25-3O 0 C during period of 1 to 2 hours. The suspension was further cooled to 5-1O 0 C and maintained for one hour.
- XRD is as shown in FIG. 1.
- XRD is substantially similar to that shown in FIG. 1.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a process for preparation of Losartan potassium Form I.
Description
Description
Title of Invention: A PROCESS FOR PREPARATION OF LOSARTAN POTASSIUM FORM I
[i]
Field of invention
[2]
[3] The present invention relates to a process for preparation of Losartan potassium
Form I. [4]
[5] The structural formula of Losartan potassium is represented by formula (I)
[6]
[8] [9]
Background of the invention
[10]
[11] The chemical name of Losartan is
2-Butyl-4-chloro- 1 - [ [2'- ( 1 H-tetrazol-5-yl) [1,1 '-biphenyl] -4-yl] methyl] - 1 H-imidazole-5 -methanol, molecular formula is C22H23C1N6O and molecular weight is 422.91. The current pharmaceutical product containing this drug is being sold as its monopotassium salt by Merck using tradename Cozaar®, in a form of oral tablets. The drug is also marketed as combination with hydrochlorothiazide using tradename Hyzaar®.
[12]
[13] Losartan is used as Antihypertensive. It is non-peptide angiotensin II receptor antagonist. It is used in the treatment of hypertension. It is also used in the treatment of diabetic nephropathy with an elevated serumcreatinine and proteinuria in patients with type 2 diabetes and a history of hypertension. It may be administered with other antihypertensive agents.
[14]
[15] Polymorphism, the occurrence of different crystal forms, is a property of some
molecules and molecular complexes. A single molecule, like Losartan potassium, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis (1TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.
[16]
[17] The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
[18]
[19] One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
[20]
[21] Many different polymorphic forms of Losartan potassium is reported in the literature.
US5608075 discloses Form I of Losartan potassium characterized by an X-ray powder diffraction pattern having X-ray powder diffraction angles of: 7.24, 11.02, 14.16, 15.07, 18.46, 18.87, 26.53, 27.30 and 29.15 and Form II of Losartan potassium characterized by an X-ray powder diffraction pattern having X-ray powder diffraction angles: 2.95, 6.95, 7.91, 12.61, 14.28, 18.98, 20.01, 21.63, 29.15.
[22]
[23] US 7271269 discloses crystal Form X, US2006229350 discloses crystalline Form alpha, WO2004076442 discloses Form A & Form B, CN1763036A discloses H-type crystalline form and US20060241305 discloses an amorphous form of Losartan potassium.
[24]
[25] US20050070586 discloses process for preparation of Form I of Losartan potassium which comprise reacting Trityl Losartan with equimolar quantities of anhydrous potassium salts in a secondary/tertiary alcohol at reflux, concentrating the reaction
mass to 50%, filtering triphenyl methyl methyl ether, concentrating the methanol mixture and removing residual solvents, cooling and filtering.
[26]
[27] US7332612B2 discloses process for preparation of Form I of Losartan potassium which comprise preparing Losartan potassium solution in a first solvent which is nonaqueous and having a boiling point of about 1350C or below, reducing the temperature, adding a second solvent selected from the group consisting of ethyl acetate, toluene, acetone, methylethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate, and hexane to form a mixture whereby a precipitate is formed which is isolated as Losartan potassium Form I.
[28]
[29] US5608075 discloses process for preparation of Form I of Losartan potassium which comprises adding Losartan free acid to 0.842 N KOH solution, slurry is aged at room temperature till all solid dissolves. The solution is filtered and the aqueous solution is added to refluxing azeotropic mixture of cyclohexane/isopropanol whereupon cy- clohexane/isopropanol/water distilled out and simultaneously potassium salt crystallizes. The slurry is cooled and filtered to give polymorph Form I.
[30]
[31] All of the above process for preparation of Form I of Losartan potassium involves mixtures of solvents which makes the process cumbersome to use at industrial scale. Moreover, the use of cyclohexane kind of solvents at industrial scale requires special care while handling it. Therefore, there is a need to find a simple process which also can be applicable at industrial scale for the preparation of Losartan potassium Form I.
[32]
[33] The present invention aims to provide a process for preparation of Form I of Losartan potassium.
[34]
Object of the invention
[35]
[36] A primary object of the present invention to provide a process for preparation of
Losartan potassium Form I.
[37]
[38] Another object of the present invention is to provide a process for preparation of
Losartan potassium Form I which is easy to operate and applicable at industrial scale.
[39]
Summary of the invention
[40]
[41] Accordingly, present invention, provides a process for preparation of Losartan potassium Form I comprising steps of:
[42] (i) adding Losartan potassium in acetone to form a suspension;
[43] (ii) treating suspension for a time sufficient to form Losartan potassium Form I;
[44] (iii) isolating Losartan potassium Form I.
[45] [46] In another aspect, the present invention provides a process for preparation of
Losartan potassium Form I comprising steps of:
[47] (i) reacting Losartan with potassium hydroxide in methanol to form a solution;
[48] (ii) removing solvent from a solution obtained in step (i) to obtain Losartan potassium as a solid;
[49] (iii) adding acetone to the solid obtained in step (ii) to form suspension;
[50] (iv) treating suspension for a time sufficient to form Losartan potassium Form I;
[51] (v) isolating Losartan potassium Form I.
[52]
Brief description of the drawings [53] [54] FIG. 1 shows the X-ray powder diffraction pattern of Losartan potassium Form I prepared by the present invention. [55]
Detailed description of the invention [56] [57] The present invention provides a process for preparation of Losartan potassium Form
I.
[58] [59] In one embodiment, present invention, provides a process for preparation of Losartan potassium Form I comprising steps of:
[60] (i) adding Losartan potassium in acetone to form a suspension;
[61] (ii) treating suspension for a time sufficient to form Losartan potassium Form I;
[62] (iii) isolating Losartan potassium Form I.
[63] [64] Losartan potassium as taken is step (i) includes any crystalline form, amorphous form, solvate form or mixtures thereof. [65]
[66] The term 'Treating' as used herein includes processes in which, suspending, extracting, dissolving, washing, mixing and refluxing of two components either solid, liquid or in a solution form takes place.
[67]
[68] In the above process, Losartan potassium is added to acetone to form a suspension.
This suspension is stirred at either ambient temperature or at elevated temperature, preferably at reflux temperature for a time sufficient to form Losartan potassium Form I. Generally it takes 1 to 2 hours at reflux temperature but it may vary with the temperature. During this process solid product Losartan potassium does not dissolve. The suspension is cooled to about 250C to about 3O0C during period of 1 to 2 hours. The suspension is further cooled to about 5° to about 1O0C and maintained for one hour. The product was filtered and solid cake was washed with chilled acetone (1O0C). The solid is suck dried and then dried in oven under vacuum at 60-700C to give Losartan potassium Form I.
[69]
[70] In another embodiment, the present invention provides a process for preparation of
Losartan potassium Form I comprising steps of:
[71] (i) reacting Losartan with potassium hydroxide in methanol to form a solution;
[72] (ii) removing solvent from a solution obtained in step (i) to obtain Losartan potassium as a solid;
[73] (iii) adding acetone to the solid obtained in step (ii) to form suspension;
[74] (iv) treating suspension for a time sufficient to form Losartan potassium Form I;
[75] (v) isolating Losartan potassium Form I.
[76]
[77] In the above process, p otassium hydroxide flakes is added to methanol and stirred for 30 min at about 25° to about 3O0C. Losartan is added to the above prepared mixture and heated to reflux at about 650C to about 680C for an hour. The pH of the reaction mixture is checked. It should be more than 9. If pH is below 9, more solution of potassium hydroxide in methanol is added to the reaction mixture till pH more than 9 is obtained. Activated charcoal (slurry in methanol) is added to the reaction mixture and further refluxed for an hour. The reaction mixture is filtered hot through hyflo bed. The bed is washed twice with hot methanol (550C). Again activated charcoal (slurry in methanol) is added to the filtrate and refluxed for an hour. The reaction mixture was filtered hot through hyflo bed. The bed is washed twice with hot methanol (550C). The filtrate is distilled till all the solvent is evaporated to dryness at atmospheric pressure. High vacuum is applied till all the material gets solidified. Acetone is added and distilled out completely at atmospheric pressure. This step is repeated twice. Again acetone is added and refluxed for an hour. During this process solid product Losartan potassium does not dissolve. The suspension is cooled to about 250C to about 3O0C during period of 1 to 2 hours . The suspension is further cooled to about 5° to about 1O0C and maintained for one hour. The product was filtered and solid cake was washed
with chilled acetone (1O0C). The solid is suck dried and then dried in oven under vacuum at about 60° to about 7O0C to give Losartan potassium Form I.
[78]
[79] FIG. 1 shows the X-ray powder diffraction pattern of Losartan potassium Form I prepared by the present invention.
[80]
[81] The following example illustrates the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
[82]
[83] Example-1
[84] Preparation of Losartan potassium Form I
[85]
[86] Potassium hydroxide flakes (15.2 g) was added to methanol (200 ml) and stirred for
30 min at 25-3O0C. Losartan (100 g) was added to the above prepared mixture and heated to reflux (65-680C) for an hour. The pH of the reaction mixture was checked. It should be more than 9. (If not then added solution of potassium hydroxide in methanol till pH more than 9 is obtained). Activated charcoal (5 g slurry in 25 ml methanol) was added to the reaction mixture and further refluxed for an hour. The reaction mixture was filtered hot through hyflo bed. The bed was washed twice with hot methanol (550C) (50 ml x 2). Again activated charcoal (5 g slurry in 25ml methanol) was added to the filtrate and refluxed for an hour. The reaction mixture was filtered hot through hyflo bed. The bed was washed twice with hot methanol (550C) (50 ml x X). Methanol was distilled out completely from the filtrate at atmospheric pressure. High vacuum was applied till all the material gets solidified. Acetone (50 ml) was added and distilled out completely at atmospheric pressure. This step is repeated twice. Again acetone (300 ml) was added and refluxed for an hour. (Note: solid does not dissolve). The suspension was cooled to 25-3O0C during period of 1 to 2 hours. The suspension was further cooled to 5-1O0C and maintained for one hour. The product was filtered; the solid cake was washed with chilled acetone (1O0C) (50 ml x 2) and suck dried. The product was dried in oven under vacuum at 60-700C to give Losartan potassium Form I (90-94 g)
[87] XRD is as shown in FIG. 1.
[88]
[89] Example-2
[90] Preparation of Losartan potassium Form I
[91]
[92] Losartan potassium amorphous form was added to acetone. The suspension was
refluxed for an hour. (Note: solid does not dissolve). The suspension was cooled to 25-3O0C during period of 1 to 2 hours. The suspension was further cooled to 5-1O0C and maintained for one hour. The product was filtered; the solid cake was washed with chilled acetone (1O0C) and suck dried. The product was dried in oven under vacuum at 60-700C to give Losartan potassium Form I.
[93] XRD is substantially similar to that shown in FIG. 1.
[94]
Claims
[Claim 1] 1. A process for preparation of Losartan potassium Form I comprising steps of:
(i) adding Losartan potassium in acetone to form a suspension;
(ii) treating suspension for a time sufficient to form Losartan potassium
Form I;
(iii) isolating Losartan potassium Form I. [Claim 2] 2. A process for preparation of Losartan potassium Form I comprising steps of:
(i) reacting Losartan with potassium hydroxide in methanol to form a solution;
(ii) removing solvent from a solution obtained in step (i) to obtain
Losartan potassium as a solid;
(iii) adding acetone to the solid obtained in step (ii) to form suspension;
(iv) treating suspension for a time sufficient to form Losartan potassium Form I; isolating Losartan potassium Form I.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP5705381B2 (en) * | 2013-02-28 | 2015-04-22 | 三井金属鉱業株式会社 | Blackened surface-treated copper foil, method for producing blackened surface-treated copper foil, copper-clad laminate and flexible printed wiring board |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002094816A1 (en) * | 2001-05-18 | 2002-11-28 | Aurobindo Pharma Limited | Process for the crystallization of losartan potassium |
WO2005021535A2 (en) * | 2003-08-27 | 2005-03-10 | Zentiva, A.S. | A method of removing the triphenylmethane protecting group |
WO2007020654A1 (en) * | 2005-08-16 | 2007-02-22 | Suven Life Sciences | An improved process for the preparation of losartan |
-
2009
- 2009-10-13 WO PCT/IB2009/054485 patent/WO2010046804A2/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002094816A1 (en) * | 2001-05-18 | 2002-11-28 | Aurobindo Pharma Limited | Process for the crystallization of losartan potassium |
WO2005021535A2 (en) * | 2003-08-27 | 2005-03-10 | Zentiva, A.S. | A method of removing the triphenylmethane protecting group |
WO2007020654A1 (en) * | 2005-08-16 | 2007-02-22 | Suven Life Sciences | An improved process for the preparation of losartan |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5705381B2 (en) * | 2013-02-28 | 2015-04-22 | 三井金属鉱業株式会社 | Blackened surface-treated copper foil, method for producing blackened surface-treated copper foil, copper-clad laminate and flexible printed wiring board |
JPWO2014133164A1 (en) * | 2013-02-28 | 2017-02-09 | 三井金属鉱業株式会社 | Blackened surface-treated copper foil, method for producing blackened surface-treated copper foil, copper-clad laminate and flexible printed wiring board |
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