WO2004076443A1 - Amorphous form of losartan potassium - Google Patents
Amorphous form of losartan potassium Download PDFInfo
- Publication number
- WO2004076443A1 WO2004076443A1 PCT/IN2003/000037 IN0300037W WO2004076443A1 WO 2004076443 A1 WO2004076443 A1 WO 2004076443A1 IN 0300037 W IN0300037 W IN 0300037W WO 2004076443 A1 WO2004076443 A1 WO 2004076443A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- losartan potassium
- amorphous form
- alcohol
- ethanol
- substantially amorphous
- Prior art date
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Classifications
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
Definitions
- the invention relates to a novel amorphous form of losartan potassium, to a process for the preparation thereof and to a composition containing it.
- Losartan potassium is known by the chemical name 2-butyl-4-chloro-1- [[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-yl] methyl]-1 H-imidazole-5-methanol mono- potassium salt.
- Losartan potassium is an antihypertensive agent having a superior antagonistic activity against angiotensin II.
- Losartan and its potassium salt may be prepared using the procedures described in Eur. pat. No. 324377, 253310, 470794, 495626, WO 95/26188 and WO
- U.S. pat. No. 5,859,258 describes a crystallization process for losartan potassium to obtain the desired crystal morphology and bulk physical properties necessary for formulation.
- U.S. pat. No. 6,350,880 describes crystallization procedures of losartan potassium as a purification method for obtaining highly pure losartan potassium.
- losartan potassium occurs in two crystalline forms, Form I and Form II.
- the existence of amorphous form of losartan has now been discovered.
- losartan potassium in substantially amorphous form has higher bioavailability than when in crystalline form and that moreover the amorphous form of losartan potassium has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation.
- the object of present invention is to provide a novel amorphous form of losartan potassium (herein after referred to as amorphous losartan potassium), process for preparation thereof and a pharmaceutical composition containing it.
- Figure 1 is a powder x-ray diffractogram of amorphous losartan potassium.
- Powder x-ray diffraction pattern was measured on a Siemens D-5000 diffractometer with CuKr radiation.
- losartan potassium in substantially amorphous form.
- Any residual solvent present will desirably only be present in less than 4% mass/mass (m/m) and most preferably less than 1% m/m.
- Typical powder x-ray diffraction pattern of amorphous losartan potassium is shown in fig.1.
- the amorphous losartan potassium according to the invention is prepared by a process which constitutes a further feature of the present invention and which comprises recovering losartan potassium from a solution thereof under conditions whereby a substantially amorphous product is obtained.
- Techniques which are employed to recover amorphous losartan potassium from the solution thereof include those wherein solvent is removed from the solution and the product deposited. Methods involving the use of these procedures include spray drying and vacuum drying. Suitable solvents for dissolving losartan potassium to form solutions from which recovery is possible include alcohols; if desired mixed with others solvents. Alcohols include methanol and ethanol; and the term 'other solvents' refers to ethylacetate, chloroform and methylene dichloride. Preferred solvents are methanol or ethanol mixed with ethylacetate or chloroform.
- the alcohol to other solvent ratio is preferably between about 1 : 0.2 to about 1 : 2 and most preferably between about 1 : 1 to about 1 : 1.8.
- the concentration of losartan potassium in the solvent or the mixed solvent mixture required to form amorphous form of losartan potassium depends on the solvent or the solvent mixture used, preferred concentrations being greater than 5% mass/mass (m/m).
- the maximum concentration of the losartan potassium depends on the solvent or solvent mixture used.
- the solvents may if desired be heated as an aid for solubility and partial removal of solvent. In carrying out the spray drying technique, it is highly desirable that the boiling point of the solvent employed will lie below the coagulation point of the product of the invention under the conditions used.
- losartan potassium solution is dried under vacuum in the temperature range of 25-50°C, preferable range being 35-40°C.
- crystalline form I, and form II of losartan potassium is used for preparing amorphous losartan potassium.
- the crystalline forms (form I and form II) may be obtained by the processes described in ' US pat No. 5,608,075.
- Another feature of the present invention is to provide a pharmaceutical composition comprising amorphous losartan potassium.
- compositions containing amorphous losartan potassium may be in a form suitable for oral dosage as a tablet, capsule, suspension. Any conventional technique may be used for the preparation of pharmaceutical formulation according to the invention.
- suitable diluents are lactose, micro crystalline cellulose, starch, mannitol.
- binders are polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl hydroxy propyl cellulose.
- suitable disintigrants are sodium starch glycollate, crospovidone, croscarmellose sodium.
- Example-1 Losartan potassium crystals (50 gm) are added to the mixture containing methanol (100 ml) and ethylacetate (150 ml) and stirred for 1 hour to dissolve. The solution is dried under vacuum at 35-40°C for 18 hours to give 42 gm of amorphous losartan potassium.
- Example-2 is repeated using 50 gm of losartan potassium Form-I.
- Example-3 Losartan potassium crystals (30 gm) are dissolved in the mixture containing ethanol (100 ml) and chloroform (120 ml). The solution obtained is spray dried to obtain 22.5 gm of amorphous losartan potassium.
- Example-4 Losartan potassium crystals (30 gm) are dissolved in the mixture containing ethanol (100 ml) and chloroform (120 ml). The solution obtained is spray dried to obtain 22.5 gm of amorphous losartan potassium.
- Example-4 Losartan potassium crystals (30 gm) are dissolved in the mixture containing ethanol (100 ml) and chloroform (120 ml). The solution obtained is spray dried to obtain 22.5 gm of amorphous losartan potassium.
- Example-4 Losartan potassium crystals (30 gm) are dissolved in the mixture containing ethanol (100 ml) and chloroform (120 ml). The solution obtained is spray dried to obtain 22.5 gm of amorphous losartan potassium.
- Emample-3 is repeated using losartan potassium Form-ll.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (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)
Abstract
The invention relates to a novel amorphous form of losartan potassium, to a process for the preparation thereof, and to a composition containing it.
Description
AMORPHOUS FORM OF LOSARTAN POTASSIUM
F1LELD OF THE INVENTION
The invention relates to a novel amorphous form of losartan potassium, to a process for the preparation thereof and to a composition containing it.
BACKGROUND OF THE INVENTION
Losartan potassium is known by the chemical name 2-butyl-4-chloro-1- [[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-yl] methyl]-1 H-imidazole-5-methanol mono- potassium salt.
Losartan potassium is an antihypertensive agent having a superior antagonistic activity against angiotensin II.
Losartan and its potassium salt may be prepared using the procedures described in Eur. pat. No. 324377, 253310, 470794, 495626, WO 95/26188 and WO
02/094816.
U.S. pat. No. 5,859,258 describes a crystallization process for losartan potassium to obtain the desired crystal morphology and bulk physical properties necessary for formulation. U.S. pat. No. 6,350,880 describes crystallization procedures of losartan potassium as a purification method for obtaining highly pure losartan potassium.
U.S. pat. No. 5,608,075 discloses two crystalline forms of losartan potassium,
Form I and Form II and processes for preparation thereof.
Thus, losartan potassium occurs in two crystalline forms, Form I and Form II. The existence of amorphous form of losartan has now been discovered. We have also found that losartan potassium in substantially amorphous form has higher bioavailability than when in crystalline form and that moreover the amorphous form of losartan potassium has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation. Thus, the object of present invention is to provide a novel amorphous form of losartan potassium (herein after referred to as amorphous losartan potassium), process for preparation thereof and a pharmaceutical composition containing it.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a powder x-ray diffractogram of amorphous losartan potassium.
Powder x-ray diffraction pattern was measured on a Siemens D-5000 diffractometer with CuKr radiation.
DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided losartan potassium in substantially amorphous form.
Any residual solvent present will desirably only be present in less than 4% mass/mass (m/m) and most preferably less than 1% m/m. Typical powder x-ray diffraction pattern of amorphous losartan potassium is shown in fig.1.
The amorphous losartan potassium according to the invention is prepared by a process which constitutes a further feature of the present invention and which comprises recovering losartan potassium from a solution thereof under conditions whereby a substantially amorphous product is obtained.
Techniques which are employed to recover amorphous losartan potassium from the solution thereof include those wherein solvent is removed from the solution and the product deposited. Methods involving the use of these procedures include spray drying and vacuum drying. Suitable solvents for dissolving losartan potassium to form solutions from which recovery is possible include alcohols; if desired mixed with others solvents. Alcohols include methanol and ethanol; and the term 'other solvents' refers to ethylacetate, chloroform and methylene dichloride. Preferred solvents are methanol or ethanol mixed with ethylacetate or chloroform. In the case where alcohol is mixed with other solvents like ethylacetate or chloroform, the alcohol to other solvent ratio (vol./vol.) is preferably between about 1 : 0.2 to about 1 : 2 and most preferably between about 1 : 1 to about 1 : 1.8.
The concentration of losartan potassium in the solvent or the mixed solvent mixture required to form amorphous form of losartan potassium depends on the solvent or the solvent mixture used, preferred concentrations being greater than 5% mass/mass (m/m). The maximum concentration of the losartan potassium depends on the solvent or solvent mixture used. The solvents may if desired be heated as an aid for solubility and partial removal of solvent.
In carrying out the spray drying technique, it is highly desirable that the boiling point of the solvent employed will lie below the coagulation point of the product of the invention under the conditions used.
In carrying out the vacuum drying technique, losartan potassium solution is dried under vacuum in the temperature range of 25-50°C, preferable range being 35-40°C.
According to another aspect of the present invention, crystalline form I, and form II of losartan potassium is used for preparing amorphous losartan potassium. The crystalline forms (form I and form II) may be obtained by the processes described in'US pat No. 5,608,075.
Another feature of the present invention is to provide a pharmaceutical composition comprising amorphous losartan potassium.
The compositions containing amorphous losartan potassium may be in a form suitable for oral dosage as a tablet, capsule, suspension. Any conventional technique may be used for the preparation of pharmaceutical formulation according to the invention. Examples of suitable diluents are lactose, micro crystalline cellulose, starch, mannitol. Examples of binders are polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl hydroxy propyl cellulose. Examples of suitable disintigrants are sodium starch glycollate, crospovidone, croscarmellose sodium.
The following non-limiting examples illustrate the invention.
EXAMPLES Example-1 Losartan potassium crystals (50 gm) are added to the mixture containing methanol (100 ml) and ethylacetate (150 ml) and stirred for 1 hour to dissolve. The solution is dried under vacuum at 35-40°C for 18 hours to give 42 gm of amorphous losartan potassium.
Example-2 Example-1 is repeated using 50 gm of losartan potassium Form-I.
Example-3 Losartan potassium crystals (30 gm) are dissolved in the mixture containing ethanol (100 ml) and chloroform (120 ml). The solution obtained is spray dried to obtain 22.5 gm of amorphous losartan potassium. Example-4
Emample-3 is repeated using losartan potassium Form-ll.
Claims
We claim
1) Losartan potassium in substantially amorphous form.
2) Losartan potassium in amorphous form characterized by a powder x-ray diffraction pattern of Fig.1.
3) A process for preparing losartan potassium in substantially amorphous form comprising the steps of: a) dissolving losartan potassium crystals in methanol or ethanol, or mixture thereof; and b) vacuum drying the solution obtained in step (a).
4) A process for preparing losartan potassium in substantially amorphous form comprising the steps of: a) dissolving losartan potassium crystals in methanol or ethanol, or mixture thereof, and b) spray drying the solution obtained in step (a).
5) A process for preparing losartan potassium in substantially amorphous form comprising the steps of: a) dissolving losartan potassium crystals in a mixture comprising alcohol and either ethylacetate or chloroform; and b) vacuum drying the solution obtained in step (a); wherein alcohol includes methanol and ethanol.
6) A process according to claim 5 wherein alcohol is methanol.
7) A process for preparing losartan potassium in substantially amorphous form comprising the steps of: a) dissolving losartan potassium crystals in a mixture comprising alcohol and either ethylacetate or chloroform; and b) spray drying the solution obtained in step (a); wherein alcohol includes methanol and ethanol.
8) A process according to claim 7 wherein alcohol is ethanol. 9) A pharmaceutical composition comprising losartan potassium in substantially amorphous form and a pharmaceutically acceptable carrier.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000037 WO2004076443A1 (en) | 2003-02-25 | 2003-02-25 | Amorphous form of losartan potassium |
| AU2003209669A AU2003209669A1 (en) | 2003-02-25 | 2003-02-25 | Amorphous form of losartan potassium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2003/000037 WO2004076443A1 (en) | 2003-02-25 | 2003-02-25 | Amorphous form of losartan potassium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004076443A1 true WO2004076443A1 (en) | 2004-09-10 |
Family
ID=32922922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2003/000037 WO2004076443A1 (en) | 2003-02-25 | 2003-02-25 | Amorphous form of losartan potassium |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003209669A1 (en) |
| WO (1) | WO2004076443A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006076097A2 (en) * | 2004-12-07 | 2006-07-20 | Nektar Therapeutics | Stable non-crystalline formulation comprising losartan |
| US8530488B2 (en) | 2007-10-24 | 2013-09-10 | Generics [Uk] Limited | Crystalline forms of bosentan |
| US8664390B2 (en) | 2007-06-29 | 2014-03-04 | Generics (Uk) Limited | Process for the introduction of hydroxyethoxy side chain in bosentan |
| US8785461B2 (en) | 2008-02-08 | 2014-07-22 | Generics [Uk] Limited | Process for preparing bosentan |
| US8975402B2 (en) | 2008-11-03 | 2015-03-10 | Generics [Uk] Limited | HPLC method for the analysis of bosetan and related substances and use of these substances as reference standards and markers |
| JP2016535767A (en) * | 2013-11-01 | 2016-11-17 | 深▲せん▼信立泰藥業股▲ふん▼有限公司 | Arisartan isoproxil amorphous form, preparation method thereof and pharmaceutical composition containing the amorphous form |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5140037A (en) * | 1990-03-20 | 1992-08-18 | E. I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with imidazole angiotensin-ii receptor antagonists |
| WO2003048135A1 (en) * | 2001-11-14 | 2003-06-12 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of losartan potassium and process for their preparation |
-
2003
- 2003-02-25 WO PCT/IN2003/000037 patent/WO2004076443A1/en not_active Application Discontinuation
- 2003-02-25 AU AU2003209669A patent/AU2003209669A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5140037A (en) * | 1990-03-20 | 1992-08-18 | E. I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with imidazole angiotensin-ii receptor antagonists |
| WO2003048135A1 (en) * | 2001-11-14 | 2003-06-12 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of losartan potassium and process for their preparation |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006076097A2 (en) * | 2004-12-07 | 2006-07-20 | Nektar Therapeutics | Stable non-crystalline formulation comprising losartan |
| WO2006076097A3 (en) * | 2004-12-07 | 2006-09-14 | Nektar Therapeutics | Stable non-crystalline formulation comprising losartan |
| US8664390B2 (en) | 2007-06-29 | 2014-03-04 | Generics (Uk) Limited | Process for the introduction of hydroxyethoxy side chain in bosentan |
| US8530488B2 (en) | 2007-10-24 | 2013-09-10 | Generics [Uk] Limited | Crystalline forms of bosentan |
| US8785461B2 (en) | 2008-02-08 | 2014-07-22 | Generics [Uk] Limited | Process for preparing bosentan |
| US8975402B2 (en) | 2008-11-03 | 2015-03-10 | Generics [Uk] Limited | HPLC method for the analysis of bosetan and related substances and use of these substances as reference standards and markers |
| JP2016535767A (en) * | 2013-11-01 | 2016-11-17 | 深▲せん▼信立泰藥業股▲ふん▼有限公司 | Arisartan isoproxil amorphous form, preparation method thereof and pharmaceutical composition containing the amorphous form |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003209669A1 (en) | 2004-09-17 |
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