WO2012153312A1 - Process for the purification of pioglitazone - Google Patents
Process for the purification of pioglitazone Download PDFInfo
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- WO2012153312A1 WO2012153312A1 PCT/IB2012/052370 IB2012052370W WO2012153312A1 WO 2012153312 A1 WO2012153312 A1 WO 2012153312A1 IB 2012052370 W IB2012052370 W IB 2012052370W WO 2012153312 A1 WO2012153312 A1 WO 2012153312A1
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- WIPO (PCT)
- Prior art keywords
- pioglitazone
- dhp
- solution
- dimethylformamide
- mixture
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention provides an improved process for the preparation of pioglitazone which is substantially free of dehydropioglitazone impurity.
- Pioglitazone of Formula I chemically ( ⁇ )-5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin- dependent diabetes mellitus or "NIDDM").
- NIDDM non-insulin- dependent diabetes mellitus
- pioglitazone is its monohydrochloride salt.
- Dehydropioglitazone (hereinafter referred to as "DHP” or “DHP of Formula II") is known as an intermediate in the synthesis of pioglitazone or salts thereof.
- DHP is also present as a process impurity or degradation product in pioglitazone or salts thereof.
- reasons are attributed for the generation of DHP in pioglitazone. Some factors linked to the generation of this impurity include the incomplete reduction of DHP and the oxidation of pioglitazone during isolation or while on stability.
- U.S. Publication 2006/0252803 provides a process for the preparation of pioglitazone which involves dissolving DHP of Formula II in formic acid and hydrogenating with hydrogen in the presence of 10% Palladium on Carbon under 2 atmospheric pressures and a temperature of 80°C. This process reportedly provides pioglitazone having less than about 0.14 % of the impurity at RRT 0.64 (HPLC).
- U.S. Publication 2009/118514 provides various purification methods for pioglitazone. It provides obtaining a solution of pioglitazone with a mixture of dimethylformamide (DMF) and 4% water, DMF and 5% methanol, DMF and 10% methanol, 1 ,4-dioxane or DMF and isopropyl alcohol at a temperature of about 90°C and precipitating pioglitazone from the solution by cooling to a temperature of about 25°C.
- DMF dimethylformamide
- U.S. Publication 2007/0078170 provides a process for the preparation of pioglitazone which involves obtaining a clear solution of pioglitazone in
- dimethylformamide at 85°C and adding methanol at a temperature of 60°C and further cooling to 10°C to precipitate pioglitazone.
- API active pharmaceutical ingredient
- the purity of an API is critical for commercialization.
- the product of a chemical reaction is rarely just the target compound.
- Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product in varying amounts. Extra effort is often required to get pharmaceutically acceptable levels of purity of the target compound.
- the present invention provides a process for the preparation of pioglitazone substantially free of DHP which comprises:
- step b) treating the solution obtained in step a) with a mixture of acetone and
- pioglitazone substantially free of DHP in the context of the present invention relates to pioglitazone having DHP in an amount of 0.1% or less, preferably 0.05% or less, more preferably 0.03% or less, most preferably undetectable as determined by HPLC analysis.
- the pioglitazone may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 4,687,777; 5,585,495; 4,812,570; 5,554,758; 5,952,509 and 6, 100,403; U.S. Publication Nos. 2002/0106762 and 2002/0050563; WO 03/53367; WO 03/80056; WO 2004/07490; WO 2004/024059; WO 2004/101560 and WO 2004/101561.
- the present invention provides a process for the preparation of pioglitazone substantially free of DHP which comprises:
- step b) treating the solution obtained in step a) with a mixture of acetone and
- the solution of pioglitazone in dimethylformamide may be obtained by treating pioglitazone or a salt thereof with dimethylformamide at a suitable temperature of 20°C to reflux under stirring.
- the volume of dimethylformamide may be 3 to 10 times, preferably 4 to 7 times, to the weight of pioglitazone.
- the solution of pioglitazone obtained in step a) can be optionally clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
- the solution of pioglitazone obtained in step a) may be optionally concentrated to reduce the amount of solvent.
- Step b) treating the solution obtained in step a) with a mixture of antisolvent involves adding the solution of pioglitazone thereof obtained in step a) to a mixture of acetone and methanol or adding a mixture of acetone and methanol to the solution of pioglitazone obtained in step a) in optional order of succession at a temperature of about 65°C to about 75°C optionally under stirring. Preferably, it may be added at about 70°C to about 75 °C. The addition may be carried out dropwise for a time period of 15 minutes to 3 hours optionally under stirring.
- the resultant mixture may be cooled to about 20°C to about 40°C in about 15 minutes to about 3 hours optionally under stirring.
- it may to be cooled at about 30°C to about 35°C optionally under stirring.
- the mixture of acetone and methanol can be taken in any ratio, preferably in 1 : 1 ratio.
- the combined volume of the mixture of acetone and methanol may be about 5 times to about 15 times, preferably 7 to 12 times, more than the weight of pioglitazone.
- the combined volume of acetone and methanol is about 20 ml (10 ml: 10 ml) for about 2 g of pioglitazone.
- Step c) of isolating pioglitazone substantially free of DHP involves common isolation techniques such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
- the isolated pioglitazone substantially free of DHP may be further dried at about 40°C to about 60°C under vacuum.
- the pioglitazone obtained has a content of DHP in an amount of 0.05% or less.
- the obtained purified pioglitazone can then be further converted into its pharmaceutically acceptable salts, preferably the hydrochloride salt, by any of the methods known in the art.
- Dimethylformamide (10 mL) was heated to 80°C to 82°C and pioglitazone (2 g) was added to the hot solution and stirred at 80°C to get a clear solution.
- the solution was cooled to 75 °C and mixture of acetone (10 mL) and methanol (10 mL) was added to the solution in 30 to 45 minutes at 70°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with dimethylformamide/acetone/methanol mixture (6 mL).
- Dimethylformamide 200 mL was heated to 80°C to 85 °C and pioglitazone (40 g) was added to the hot solution and stirred at 80°C to get a clear solution.
- the solution was cooled to 75°C and mixture of acetone (200 mL) and methanol (200 mL) was added to this solution in 30 minutes to 45 minutes at 65°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (100 mL).
- Dimethylformamide 25 mL was heated to 80°C to 85 °C and pioglitazone (5 g) was added at 85°C.
- the solution was cooled to 55°C and a mixture of acetone (25 mL) and methanol (25 mL) was added to the solution in 30 minutes to 45 minutes at 55°C to 60°C.
- the reaction mass was cooled to 35°C to 37°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (10+lOmL).
Abstract
The present invention provides an efficient process for the purification of pioglitazone of Formula (I). It provides an improved purification for the preparation of pioglitazone substantially free of the DHP impurity of Formula (II).
Description
PROCESS FOR THE PURIFICATION OF PIOGLITAZONE
Field of the Invention
The present invention provides an improved process for the preparation of pioglitazone which is substantially free of dehydropioglitazone impurity.
Background of the Invention
Pioglitazone of Formula I, chemically (±)-5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin- dependent diabetes mellitus or "NIDDM").
The commercially available form of pioglitazone is its monohydrochloride salt.
Dehydropioglitazone (hereinafter referred to as "DHP" or "DHP of Formula II") is known as an intermediate in the synthesis of pioglitazone or salts thereof.
In addition, DHP is also present as a process impurity or degradation product in pioglitazone or salts thereof. Several reasons are attributed for the generation of DHP in pioglitazone. Some factors linked to the generation of this impurity include the
incomplete reduction of DHP and the oxidation of pioglitazone during isolation or while on stability.
Several processes are known in the literature for making pioglitazone or a salt thereof, for example, U.S. Patent Nos. 4,687,777; 5,585,495; 4,812,570; 5,554,758; 5,952,509; and 6,100,403; U.S. Publications 2002/0106762 and 2002/0050563; WO 03/53367; WO 03/80056; WO 2004/07490; WO 2004/024059; WO 2004/101560; WO 2004/101561 , WO 2005/049610; WO 2008/075380; WO 2006/1 17654; WO
2008/142706; WO 2005/058827; WO 2009/104200; and WO 2009/133576.
U.S. Publication 2006/0252803 provides a process for the preparation of pioglitazone which involves dissolving DHP of Formula II in formic acid and hydrogenating with hydrogen in the presence of 10% Palladium on Carbon under 2 atmospheric pressures and a temperature of 80°C. This process reportedly provides pioglitazone having less than about 0.14 % of the impurity at RRT 0.64 (HPLC).
It also provides a process for the preparation of pioglitazone which involves combining DHP of Formula II with dimethylformamide and hydrogenating with hydrogen in the presence of Palladium on Carbon under 3 atmospheric pressures and a temperature of 50°C. It is reported that -68.5% of DHP was converted to pioglitazone, containing about 3.5 % impurities (HPLC).
U.S. Publication 2009/118514 provides various purification methods for pioglitazone. It provides obtaining a solution of pioglitazone with a mixture of dimethylformamide (DMF) and 4% water, DMF and 5% methanol, DMF and 10% methanol, 1 ,4-dioxane or DMF and isopropyl alcohol at a temperature of about 90°C and precipitating pioglitazone from the solution by cooling to a temperature of about 25°C.
U.S. Publication 2007/0078170 provides a process for the preparation of pioglitazone which involves obtaining a clear solution of pioglitazone in
dimethylformamide at 85°C and adding methanol at a temperature of 60°C and further cooling to 10°C to precipitate pioglitazone.
Impurities in pioglitazone or its hydrochloride salt, or any active pharmaceutical ingredient ("API"), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The purity of an API is critical for commercialization. The product of a chemical reaction is rarely just the target compound. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product in varying amounts. Extra effort is often required to get pharmaceutically acceptable levels of purity of the target compound.
As known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways and by identifying the parameters that influence the amount of impurities in the final product.
Extensive experimentation has been carried out by the present inventors to reduce the level of DHP in pioglitazone. As a result, the present inventors found an improved method for the preparation of pioglitazone substantially free of DHP by controlling the parameters such as solvents, time and temperature. The pioglitazone substantially free of DHP made by the process of the present invention is amenable for commercial scale.
Summary of the Invention
The present invention provides a process for the preparation of pioglitazone substantially free of DHP which comprises:
a) obtaining a solution of pioglitazone in dimethylformamide;
b) treating the solution obtained in step a) with a mixture of acetone and
methanol at a temperature of about 65°C to about 75°C; and
c) isolating pioglitazone substantially free of DHP.
Detailed Description of the Invention
The term "pioglitazone substantially free of DHP" in the context of the present invention relates to pioglitazone having DHP in an amount of 0.1% or less, preferably 0.05% or less, more preferably 0.03% or less, most preferably undetectable as determined by HPLC analysis.
The pioglitazone may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 4,687,777; 5,585,495; 4,812,570; 5,554,758; 5,952,509 and 6, 100,403; U.S. Publication Nos. 2002/0106762 and 2002/0050563; WO
03/53367; WO 03/80056; WO 2004/07490; WO 2004/024059; WO 2004/101560 and WO 2004/101561.
The present invention provides a process for the preparation of pioglitazone substantially free of DHP which comprises:
a) obtaining a solution of pioglitazone in dimethylformamide;
b) treating the solution obtained in step a) with a mixture of acetone and
methanol at a temperature of about 65°C to about 75°C; and
c) isolating pioglitazone substantially free of DHP.
The solution of pioglitazone in dimethylformamide may be obtained by treating pioglitazone or a salt thereof with dimethylformamide at a suitable temperature of 20°C to reflux under stirring.
The volume of dimethylformamide may be 3 to 10 times, preferably 4 to 7 times, to the weight of pioglitazone.
The solution of pioglitazone obtained in step a) can be optionally clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities. The solution of pioglitazone obtained in step a) may be optionally concentrated to reduce the amount of solvent.
Step b), treating the solution obtained in step a) with a mixture of antisolvent involves adding the solution of pioglitazone thereof obtained in step a) to a mixture of acetone and methanol or adding a mixture of acetone and methanol to the solution of pioglitazone obtained in step a) in optional order of succession at a temperature of about 65°C to about 75°C optionally under stirring. Preferably, it may be added at about 70°C to about 75 °C. The addition may be carried out dropwise for a time period of 15 minutes to 3 hours optionally under stirring.
After the completion of addition, the resultant mixture may be cooled to about 20°C to about 40°C in about 15 minutes to about 3 hours optionally under stirring.
Preferably, it may to be cooled at about 30°C to about 35°C optionally under stirring.
The mixture of acetone and methanol can be taken in any ratio, preferably in 1 : 1 ratio. The combined volume of the mixture of acetone and methanol may be about 5 times
to about 15 times, preferably 7 to 12 times, more than the weight of pioglitazone. For example, the combined volume of acetone and methanol is about 20 ml (10 ml: 10 ml) for about 2 g of pioglitazone.
Step c) of isolating pioglitazone substantially free of DHP involves common isolation techniques such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The isolated pioglitazone substantially free of DHP may be further dried at about 40°C to about 60°C under vacuum. The pioglitazone obtained has a content of DHP in an amount of 0.05% or less.
The obtained purified pioglitazone can then be further converted into its pharmaceutically acceptable salts, preferably the hydrochloride salt, by any of the methods known in the art.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1 : Purification of Pioglitazone
Dimethylformamide (10 mL) was heated to 80°C to 82°C and pioglitazone (2 g) was added to the hot solution and stirred at 80°C to get a clear solution. The solution was cooled to 75 °C and mixture of acetone (10 mL) and methanol (10 mL) was added to the solution in 30 to 45 minutes at 70°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with dimethylformamide/acetone/methanol mixture (6 mL).
DHP impurity content after purification: 0.05%
DHP impurity content before purification: 0.16%
Yield: 90%
Example 2: Purification of Pioglitazone
Dimethylformamide (200 mL) was heated to 80°C to 85 °C and pioglitazone (40 g) was added to the hot solution and stirred at 80°C to get a clear solution. The solution was cooled to 75°C and mixture of acetone (200 mL) and methanol (200 mL) was added to this solution in 30 minutes to 45 minutes at 65°C to 75°C. After complete addition, the reaction mass was cooled to 30°C to 35°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (100 mL).
DHP impurity content after purification: 0.04%
DHP impurity content before purification: 0.15%
Yield: 92%
Example 3: Purification of Pioglitazone (Control)
Dimethylformamide (25 mL) was heated to 80°C to 85 °C and pioglitazone (5 g) was added at 85°C. The solution was cooled to 55°C and a mixture of acetone (25 mL) and methanol (25 mL) was added to the solution in 30 minutes to 45 minutes at 55°C to 60°C. After complete addition, the reaction mass was cooled to 35°C to 37°C slowly in about 2 hours and was filtered. The solid was washed with acetone/methanol mixture (10+lOmL).
DHP impurity content after purification: 0.11%
DHP impurity content before purification: 0.12%
Yield: 92%
Claims
We claim:
1) A process for preparing pioglitazone substantially free of DHP comprising the steps of:
a) obtaining a solution of pioglitazone in dimethylformamide; and
b) treating the solution obtained in step a) with a mixture of acetone and methanol at a temperature of about 65°C to about 75°C;
2) The process of claim 1, wherein the solution in step a) is obtained by treating pioglitazone or a salt thereof with dimethylformamide at a temperature of 20°C to reflux under stirring.
3) The process of claim 1, wherein the volume of dimethylformamide used for
preparing the solution in step a) is 3 to 10 times with respect to the weight of pioglitazone used.
4) The process of claim 3, wherein the volume of dimethylformamide is 4 to 7 times with respect to the weight of pioglitazone used.
5) The process of claim 1, wherein the acetone-methanol mixture is a 1 : 1 mixture. 6) The process of claim 1, wherein pioglitazone obtained contains 0.05% or less of DHP content as measured by HPLC.
7) The process of claim 1, further comprising the step of converting pioglitazone substantially free of DHP into its pharmaceutically acceptable salts.
8) The process of claim 7, wherein the pharmaceutically acceptable salt is the
hydrochloride salt.
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