WO2003099785A1 - Process for the preparation of amorphous atorvastatin calcium - Google Patents
Process for the preparation of amorphous atorvastatin calcium Download PDFInfo
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- WO2003099785A1 WO2003099785A1 PCT/IN2002/000220 IN0200220W WO03099785A1 WO 2003099785 A1 WO2003099785 A1 WO 2003099785A1 IN 0200220 W IN0200220 W IN 0200220W WO 03099785 A1 WO03099785 A1 WO 03099785A1
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- atorvastatin calcium
- acetone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to a process for the production of amorphous atorvastatin calcium.
- Atorvastatin the substance known by the chemical name [R-(R*,R*)]-2-( 4- FLUOROPHENYL)- ⁇ , ⁇ -DmYDROXY-5-(l-METHYLETHYL) PHENYL-4-
- statins [(PHENYLAMINO) CARBONYL]-lH-PYRROLE-l-HEPTA OIC ACID is a member of the class of drugs called statins.
- Statin drugs are currently the most therapeutically effective drugs available for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. Open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized.
- R-form of the ring opened acid form has surprising inhibition of the biosynthesis of cholesterol.
- Atorvastatin in its calcium salt form i.e. [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5- ( 1 -methyl ethyl)-3 -phenyl-4-[(phenylamino)carbonyl] - 1 H-pyrrole- 1 -heptanoic acid calcium salt (2: 1) having formula 1 is more suited for formulations and has been recommended as a drug.
- Atorvastatin is preferably prepared as its calcium salt, i.e.
- the amorphous forms in a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to crystalline forms (Knno T. Chem. Pharm. Bull. 1990, 38, 2003-2007).
- the bioavailability is one of the key parameters determining the form of the susbstance to be used in a pharmaceutical formulation. Since process for the crystallization and the preparation, respectively of the amorphous substance are sometimes difficult to be performed and as a result the product obtained is in a mixture of amorphous and crystalline form. There is a constant need for processes which enable the preparation of atorvastatin in an amorphous form without simultaneous formation of crystalline forms or which will enable the conversion of crystalline forms into the amorphous form.
- Atorvastatin calcium is very slightly soluble in water and it has been found that the crystalline form is less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin. It has been found that the production of amorphous atorvastatin accordingly to the previously disclosed processes was not consistently reproducible. Therefore various processes have been developed for converting the crystalline form in to amorphous form.
- WO 97/03960 describes a procedure for converting the crystalline form of atorvastatin calcium to the amorphous form.
- Process disclosed therein comprises dissolving crystalline form I atorvastatin in a non-hydroxylitic solvent like tetrahydrofuran or mixture of tetrahydrofuran and toluene.
- the process involves complete removal of the solvent under high temperature (about 90°c) and under high vacuum (about 5 mm) for 3-5 days. Exposure of the material to high temperature for several days may lead to degradation of the product. This makes the process very inconvenient to operate on a large scale. Slow removal of solvent at a manufacturing scale renders this process as less productive.
- amorphous atorvastatin described in WO 00/71116 involves dissolving crystalline form in tetrahydrofuran and reprecipitating amorphous atorvastatin by adding cyclohexane or n-hexane n-heptane.
- WO 01/28999 describes the purification of crude amorphous atorvastatin calcium by dissolving crude amorphous material in large excess of boiling ethanol or 2-propanol and filtering the hot solution and recovering the material at low temperature.
- WO 01/42209 describes the preparation of amorphous atorvastatin calcium from form I by dissolving crystalline form in about 20 - 25 times of methanol, ethanol or acetone, concentrating the solution by distillation and precipitating the product by adding diethylether.
- the process disclosed therein also is not recommended for commercial production of amorphous atorvastatin calcium due to the use of large excess of diethylether, which may not be safe on plant level.
- amorphous atorvastatin calcium The procedures to manufacture amorphous atorvastatin calcium disclosed in prior arts employ a large excess of solvent or a mixture of solvents, and removing the solvents at high temperature for a longer period of time. Laboratory trials conducted based on all prior arts give amorphous atorvastatin calcium accompanied with higher level of residual solvents i.e. 10,000 to 20,000 ppm, the level of residual solvents is not reduced even at higher temperature under vacuum. The prolonged heating to reduce the level of residual solvents did not result in decrease of the level of residual solvents, instead an appreciable degradation of the product was observed.
- the above object is achieved by process of the invention, which employs a single solvent of aliphatic acyclic ketone group, and the level of residual solvent in final product is less than 5000 ppm which is easily achieved by drying the product at relatively less temperature i.e. 45 to 50 °C under vacuum for 10 to 15 hours.
- the amorphous atorvastatin calcium prepared by the process disclosed herein does not show any degradation of the product.
- amorphous atorvastatin calcium is produced by dissolving form - I or a mixture of crystalline and amorphous atorvastatin calcium in aliphatic acyclic ketones filtering the solution and removing the solvent at 45 to 50 °C under vacuum till desired level of residual solvent below 5000 ppm is achieved providing pure amorphous atorvastatin calcium as revealed by X-ray powder difractogram.
- the solvent is selected from acetone, 2-butanone, 3-pentanone, 2- pentanone or 2-hexanone.
- Acetone is the most preferred solvent due to its lowest boiling point i.e. 56 °C as compared to other aliphatic acyclic ketones.
- Employing acetone as a solvent gives desired level of residual solvent in final product at relatively low temperature i.e. 45 to 50°C under vacuum for 10 to 15 hours, while other aliphatic acyclic ketones gives higher level of residual solvents even at higher temperature under vacuum for prolonged heating.
- Atorvastatin calcium form - 1 can easily be dissolved in 10 - 15 volumes of acetone at 45 - 50 °C while a mixture of crystalline and amorphous atorvastatin calcium requires 30 - 50 volumes of acetone depending on the composition of crystalline and amorphous atorvastatin calcium in a particular mixture.
- the invention disclosed herein gives pure amorphous atorvastatin calcium by using atorvastatin calcium form - I or any mixture of crystalline and amorphous atorvastatin calcium demonstrating the wide scope and capability of the process disclosed herein. Detailed description of the invention
- form - I of atorvastatin calcium is dissolved in 15 volumes of acetone at 40 - 45 °C and the solution is filtered to remove suspended and extraneous material.
- the filtered solution is concentrated at 45 - 50 °C under vacuum leaving behind approximately 2.5 - 3 volumes of acetone.
- the concentrated solution of atorvastatin calcium in acetone is placed on glass tray, which is put in vacuum dryer.
- the remaining acetone is removed at 45 - 50 °C under vacuum for 2 - 3 hours resulting in the white flakes of amorphous atorvastatin calcium which is uniformly powdered.
- the powdered amorphous atorvastatin calcium is dried at 45 - 50 °C under vacuum for 15 hours to get acetone content in final product less than 5000 ppm.
- X-ray powder difractogram reveals the material to be completely amorphous (figure - 2)
- a mixture of crystalline and amorphous atorvastatin calcium is dissolved at 50 - 55 °C in 30 - 50 volumes of acetone depending on the composition of crystalline and amorphous atorvastatin calcium in the mixture.
- the solution is filtered to remove suspended particles and extraneous material.
- the filtered solution is concentrated at 45 - 50 °C under vacuum leaving behind approximately 2.5 - 3 volumes of acetone.
- the concentrated solution of atorvastatin calcium in acetone is placed on glass tray, which is put in vacuum dryer. The remaining acetone is removed at 45 - 50 °C under vacuum for 2 - 3 hours resulting in the white flakes of amorphous atorvastatin calcium, which is uniformly powdered.
- the powdered amorphous atorvastatin calcium is dried at 45 - 50 °C under vacuum for 15 hours to get acetone content in final product less than 5000 ppm.
- X-ray powder difractogram reveals the material to be completely amorphous (figure - 4)
- Figure 1 depicts X-ray Powder difractogram of atorvastatin calcium form - I.
- the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
- Figures 2 depicts X-ray powder difractogram of amorphous atorvastatin calcium.
- the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
- Figures 3 depicts X-ray powder difractogram of mixture of crystalline and amorphous atorvastatin calcium.
- the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
- Figures 4 depicts X-ray powder difractogram of amorphous atorvastatin calcium. The horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
- Example 2 10 g of a mixture of crystalline and amorphous Atorvastatin calcium was dissolved in 500 ml of acetone at 50 to 55 °C. The solution was filtered and acetone was removed by vacuum distillation at 45 to 50 °C leaving behind approximately 30 ml of acetone. The concentrated solution of atorvastatin calcium in acetone was further dried in vacuum oven at 45 to 50 °C for 3 hours providing white flakes of amorphous atorvastatin calcium which was uniformly powdered. The powdered amorphous atorvastatin calcium was dried at 45 - 50 °C under vacuum for 15 hours to give 8.5 g white solid material with acetone content in final product less than 5000 ppm. X-ray powder difractogram reveals the material to be completely amorphous (figure - 4).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The present invention relates to a process for the preparation of amorphous atorvastatin calcium. In essence, the process comprises dissolving form - I or a mixture of crystalline and amorphous atorvastatin calcium in a solvent consisting of an aliphatic acyclic ketone, filtering the solution and removing the solvent at 40 to 50 °C under vacuum.
Description
PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
Field of invention
The present invention relates to a process for the production of amorphous atorvastatin calcium.
Background of the invention
Atorvastatin, the substance known by the chemical name [R-(R*,R*)]-2-( 4- FLUOROPHENYL)-β,δ-DmYDROXY-5-(l-METHYLETHYL) PHENYL-4-
[(PHENYLAMINO) CARBONYL]-lH-PYRROLE-l-HEPTA OIC ACID is a member of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. Open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized.
According to the disclosure contained in the U.S. Patent No. 5273995, R-form of the ring opened acid form has surprising inhibition of the biosynthesis of cholesterol. Atorvastatin in its calcium salt form, i.e. [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5- ( 1 -methyl ethyl)-3 -phenyl-4-[(phenylamino)carbonyl] - 1 H-pyrrole- 1 -heptanoic acid calcium salt (2: 1) having formula 1 is more suited for formulations and has been recommended as a drug.
United states patents 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,385,929; 5,397,792; European Patent 409,281; and PCT publication No. 8,907,598 describe various processes and key intermediates for preparing atorvastatin.
Atorvastatin is preferably prepared as its calcium salt, i.e. [R-(R*,R*)]-2-(4- fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-1 -heptanoic acid calcium salt (2 : 1) since the calcium salt is desirable and it enables easy formulation of atorvastatin for example, tablets, capsules, lozenges, powder and the like for oral administration. Different polymorphic forms of atorvastatin calcium such as Form I, Form II, Form III, Form IV, Form V and amorphous form have been reported in WO 97/03958, WO 97/03959, WO 97/03960 and WO 01/36384.
It is known that the amorphous forms in a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to crystalline forms (Knno T. Chem. Pharm. Bull. 1990, 38, 2003-2007). In some therapeutical indications the bioavailability is one of the key parameters determining the form of the susbstance to be used in a pharmaceutical formulation. Since process for the crystallization and the preparation, respectively of the amorphous substance are sometimes difficult to be performed and as a result the product obtained is in a mixture of amorphous and crystalline form. There is a constant need for processes which enable the preparation of atorvastatin in an amorphous form without simultaneous formation of crystalline forms or which will enable the conversion of crystalline forms into the amorphous form.
Atorvastatin calcium is very slightly soluble in water and it has been found that the crystalline form is less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin. It has been found that the production of amorphous atorvastatin accordingly to the previously disclosed processes was not consistently reproducible. Therefore various processes have been developed for converting the crystalline form in to amorphous form.
WO 97/03960 describes a procedure for converting the crystalline form of atorvastatin calcium to the amorphous form. Process disclosed therein comprises dissolving crystalline form I atorvastatin in a non-hydroxylitic solvent like tetrahydrofuran or mixture of tetrahydrofuran and toluene. The process involves complete removal of the solvent under high temperature (about 90°c) and under high vacuum (about 5 mm) for 3-5 days. Exposure of the material to high temperature for several days may lead to degradation of the product. This makes the process very inconvenient to operate on a large scale. Slow removal of solvent at a manufacturing scale renders this process as less productive.
The process for the preparation of amorphous atorvastatin described in WO 00/71116 involves dissolving crystalline form in tetrahydrofuran and reprecipitating amorphous atorvastatin by adding cyclohexane or n-hexane n-heptane.
WO 01/28999 describes the purification of crude amorphous atorvastatin calcium by dissolving crude amorphous material in large excess of boiling ethanol or 2-propanol and filtering the hot solution and recovering the material at low temperature.
WO 01/42209 describes the preparation of amorphous atorvastatin calcium from form I by dissolving crystalline form in about 20 - 25 times of methanol, ethanol or acetone, concentrating the solution by distillation and precipitating the product by adding diethylether. The process disclosed therein also is not recommended for commercial production of amorphous atorvastatin calcium due to the use of large excess of diethylether, which may not be safe on plant level. Summary of the invention
It is the object of the invention to eliminate the drawbacks of the known procedures and to provide a simple reproducible and economically feasible process for the preparation of high purity and uniformly amorphous atorvastatin calcium.
The procedures to manufacture amorphous atorvastatin calcium disclosed in prior arts employ a large excess of solvent or a mixture of solvents, and removing the solvents at high temperature for a longer period of time. Laboratory trials conducted based on all prior arts give amorphous atorvastatin calcium accompanied with higher level of residual solvents i.e. 10,000 to 20,000 ppm, the level of residual solvents is not reduced even at higher temperature under vacuum. The prolonged heating to reduce the level of residual solvents did not result in decrease of the level of residual solvents, instead an appreciable degradation of the product was observed.
The above object is achieved by process of the invention, which employs a single solvent of aliphatic acyclic ketone group, and the level of residual solvent in final product is less than 5000 ppm which is easily achieved by drying the product at relatively less temperature i.e. 45 to 50 °C under vacuum for 10 to 15 hours. The amorphous atorvastatin calcium prepared by the process disclosed herein does not show any degradation of the product.
According to the present invention, amorphous atorvastatin calcium is produced by dissolving form - I or a mixture of crystalline and amorphous atorvastatin calcium in aliphatic acyclic ketones filtering the solution and removing the solvent at 45 to 50 °C under vacuum till desired level of residual solvent below 5000 ppm is achieved providing pure amorphous atorvastatin calcium as revealed by X-ray powder difractogram.
Preferably, the solvent is selected from acetone, 2-butanone, 3-pentanone, 2- pentanone or 2-hexanone. Acetone is the most preferred solvent due to its lowest boiling
point i.e. 56 °C as compared to other aliphatic acyclic ketones. Employing acetone as a solvent gives desired level of residual solvent in final product at relatively low temperature i.e. 45 to 50°C under vacuum for 10 to 15 hours, while other aliphatic acyclic ketones gives higher level of residual solvents even at higher temperature under vacuum for prolonged heating.
Atorvastatin calcium form - 1 can easily be dissolved in 10 - 15 volumes of acetone at 45 - 50 °C while a mixture of crystalline and amorphous atorvastatin calcium requires 30 - 50 volumes of acetone depending on the composition of crystalline and amorphous atorvastatin calcium in a particular mixture. The invention disclosed herein gives pure amorphous atorvastatin calcium by using atorvastatin calcium form - I or any mixture of crystalline and amorphous atorvastatin calcium demonstrating the wide scope and capability of the process disclosed herein. Detailed description of the invention
According to the process of present invention form - I of atorvastatin calcium is dissolved in 15 volumes of acetone at 40 - 45 °C and the solution is filtered to remove suspended and extraneous material. The filtered solution is concentrated at 45 - 50 °C under vacuum leaving behind approximately 2.5 - 3 volumes of acetone. The concentrated solution of atorvastatin calcium in acetone is placed on glass tray, which is put in vacuum dryer. The remaining acetone is removed at 45 - 50 °C under vacuum for 2 - 3 hours resulting in the white flakes of amorphous atorvastatin calcium which is uniformly powdered. The powdered amorphous atorvastatin calcium is dried at 45 - 50 °C under vacuum for 15 hours to get acetone content in final product less than 5000 ppm. X-ray powder difractogram reveals the material to be completely amorphous (figure - 2)
According to the present invention a mixture of crystalline and amorphous atorvastatin calcium is dissolved at 50 - 55 °C in 30 - 50 volumes of acetone depending on the composition of crystalline and amorphous atorvastatin calcium in the mixture. The solution is filtered to remove suspended particles and extraneous material. The filtered solution is concentrated at 45 - 50 °C under vacuum leaving behind approximately 2.5 - 3 volumes of acetone. The concentrated solution of atorvastatin calcium in acetone is placed on glass tray, which is put in vacuum dryer. The remaining acetone is removed at 45 - 50 °C under vacuum for 2 - 3 hours resulting in the white flakes of amorphous atorvastatin calcium, which is uniformly powdered. The powdered amorphous atorvastatin calcium is dried at 45 - 50 °C under vacuum for 15 hours to get acetone content in final product less
than 5000 ppm. X-ray powder difractogram reveals the material to be completely amorphous (figure - 4)
The present invention will now be described with reference to the following non- limiting Examples and the accompanying drawings in which: Figure 1 depicts X-ray Powder difractogram of atorvastatin calcium form - I. The horizontal axis presents 2θ and the vertical axis corresponds to peak intensity.
Figures 2 depicts X-ray powder difractogram of amorphous atorvastatin calcium. The horizontal axis presents 2θ and the vertical axis corresponds to peak intensity.
Figures 3 depicts X-ray powder difractogram of mixture of crystalline and amorphous atorvastatin calcium. The horizontal axis presents 2θ and the vertical axis corresponds to peak intensity.
Figures 4 depicts X-ray powder difractogram of amorphous atorvastatin calcium. The horizontal axis presents 2Θ and the vertical axis corresponds to peak intensity. Example : 1 10 g of Atorvastatin calcium form - 1 was dissolved in 150 ml of acetone at 40 to 45
°C. The solution was filtered and acetone was removed by vacuum distillation at 45 to 50 C leaving behind approximately 30 ml of acetone. The concentrated solution of atorvastatin calcium in acetone was further dried in vacuum oven at 45 to 50 °C for 3 hours providing white flakes of amorphous atorvastatin calcium which was uniformly powdered. The powdered amorphous atorvastatin calcium was dried at 45 - 50 °C under vacuum for 15 hours to give 8.5 g white solid material with acetone content in final product being less than 5000 ppm. X-ray powder difractogram revealed the material to be completely amorphous (figure - 2). Example 2 : 10 g of a mixture of crystalline and amorphous Atorvastatin calcium was dissolved in 500 ml of acetone at 50 to 55 °C. The solution was filtered and acetone was removed by vacuum distillation at 45 to 50 °C leaving behind approximately 30 ml of acetone. The concentrated solution of atorvastatin calcium in acetone was further dried in vacuum oven at 45 to 50 °C for 3 hours providing white flakes of amorphous atorvastatin calcium which was uniformly powdered. The powdered amorphous atorvastatin calcium was dried at 45 - 50 °C under vacuum for 15 hours to give 8.5 g white solid material with acetone content in final product less than 5000 ppm. X-ray powder difractogram reveals the material to be completely amorphous (figure - 4).
Claims
1. A process for the preparation of amorphous atorvastatin calcium which comprises dissolving form - 1 or a mixture of crystalline and amorphous atorvastatin calcium in a solvent consisting of an aliphatic acyclic ketone, filtering the solution and removing the solvent at 40 to 50 °C under vacuum .
2. A process as claimed in claim 1 wherein after dissolving said form - 1 or a mixture of crystalline and amorphous atorvastatin calcium in -said solvent, the resultant solution is filtered to remove suspended and extraneous material, subjecting resultant solution to partial concentration to leave behind behind approximately 2.5
- 3 volumes of solvent, further removing said solvent in vacuum dryer, grinding white flakes so produced to uniform powder and further drying said uniform powder in vacuum dryer to obtain atorvastatin calcium in amorphous form.
3. A process as claimed in claim 1 or 2 wherein said solvent is selected from acetone, 2-butanone, 3-pentanone, 2-pentanone or 2-hexanone.
4. A process as claimed in claim 3 wherein the amount of said solvent is 10 - 20 volumes for atorvastatin calcium form - I and 30 - 70 volumes for a mixture of crystalline and amorphous atorvastatin calcium.
5. A process as claimed in claim 4 wherein the amount of said solvent is 15 volumes of acetone for atorvastatin calcium form - 1 and 50 volumes of acetone for a mixture of crystalline and amorphous atorvastatin calcium.
6. A process as claimed in any preceding claim wherein acetone is removed under vacuum at 45 - 50 C leaving behind 2 - 5 volumes of acetone.
7. A process as claimed in claim 6 wherein acetone is removed under vacuum at 45 - 50 °C leaving behind 2.5 - 3 volumes of acetone.
8. A process as claimed in claim 7 wherein acetone is further removed in vacuum dryer at 30 - 50 °C.
9. A process as claimed in claim 8 wherein acetone is further removed in vacuum dryer at 45 - 50 °C. ■ 10. A process as claimed in any preceding claim wherein uniform powder is dried in vacuum dryer at 30 - 50 °C for 5 - 25 hours. 11. A process as claimed in claim 10 wherein uniform powder is dried in vacuum dryer at 45 - 50 °C for 10 - 15 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002356423A AU2002356423A1 (en) | 2002-05-28 | 2002-11-15 | Process for the preparation of amorphous atorvastatin calcium |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN472/MUM/2002 | 2002-05-28 | ||
| IN472MU2002 | 2002-05-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003099785A1 true WO2003099785A1 (en) | 2003-12-04 |
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ID=29560492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2002/000220 Ceased WO2003099785A1 (en) | 2002-05-28 | 2002-11-15 | Process for the preparation of amorphous atorvastatin calcium |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2002356423A1 (en) |
| PL (1) | PL357490A1 (en) |
| WO (1) | WO2003099785A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006021969A1 (en) * | 2004-08-27 | 2006-03-02 | Biocon Limited | Process for atorvastatin calcium amorphous |
| WO2006045018A1 (en) | 2004-10-18 | 2006-04-27 | Teva Pharmaceutical Industries Ltd. | Process for preparing amorphous atorvastatin hemi-calcium by dissolving the salt in an organic solvent which is a mixture of an alcohol and a ketone and/or an ester and removing the solvent |
| WO2006012499A3 (en) * | 2004-07-22 | 2006-07-20 | Teva Pharma | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation |
| US7151183B2 (en) * | 2000-11-30 | 2006-12-19 | Teva Pharmaceutical Industries Ltd. | Processes for preparing amorphous atorvastatin hemi-calcium |
| EP2075246A1 (en) | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | A process for preparation of amorphous form of atorvastatin hemi-calcium salt |
| US7994343B2 (en) | 2004-03-17 | 2011-08-09 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium in amorphous form |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003960A1 (en) * | 1995-07-17 | 1997-02-06 | Warner-Lambert Company | NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS [R-(R*,R*)]-2-(4-FLUOROPHENYL)-β,δ-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID CALCIUM SALT (2:1) |
| WO2000071116A1 (en) * | 1999-05-25 | 2000-11-30 | Ranbaxy Laboratories Limited | Process for the production of amorphous atorvastatin calcium |
| WO2001028999A1 (en) * | 1999-10-18 | 2001-04-26 | EGIS Gyógyszergyár Rt. | Process for the preparation of amorphous atorvastatin calcium |
| WO2001042209A1 (en) * | 1999-12-10 | 2001-06-14 | Lek Pharmaceutical And Chemical Company D.D. | Process for the preparation of amorphous atorvastatin |
| WO2002043732A1 (en) * | 2000-11-30 | 2002-06-06 | Teva Pharmaceutical Industries Ltd. | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
-
2002
- 2002-11-15 AU AU2002356423A patent/AU2002356423A1/en not_active Abandoned
- 2002-11-15 WO PCT/IN2002/000220 patent/WO2003099785A1/en not_active Ceased
- 2002-12-02 PL PL02357490A patent/PL357490A1/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003960A1 (en) * | 1995-07-17 | 1997-02-06 | Warner-Lambert Company | NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS [R-(R*,R*)]-2-(4-FLUOROPHENYL)-β,δ-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID CALCIUM SALT (2:1) |
| WO2000071116A1 (en) * | 1999-05-25 | 2000-11-30 | Ranbaxy Laboratories Limited | Process for the production of amorphous atorvastatin calcium |
| WO2001028999A1 (en) * | 1999-10-18 | 2001-04-26 | EGIS Gyógyszergyár Rt. | Process for the preparation of amorphous atorvastatin calcium |
| WO2001042209A1 (en) * | 1999-12-10 | 2001-06-14 | Lek Pharmaceutical And Chemical Company D.D. | Process for the preparation of amorphous atorvastatin |
| WO2002043732A1 (en) * | 2000-11-30 | 2002-06-06 | Teva Pharmaceutical Industries Ltd. | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7151183B2 (en) * | 2000-11-30 | 2006-12-19 | Teva Pharmaceutical Industries Ltd. | Processes for preparing amorphous atorvastatin hemi-calcium |
| US7994343B2 (en) | 2004-03-17 | 2011-08-09 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium in amorphous form |
| WO2006012499A3 (en) * | 2004-07-22 | 2006-07-20 | Teva Pharma | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation |
| WO2006021969A1 (en) * | 2004-08-27 | 2006-03-02 | Biocon Limited | Process for atorvastatin calcium amorphous |
| US7645888B2 (en) | 2004-08-27 | 2010-01-12 | Biocon Limited | Process for the production of amorphous atorvastatin calcium |
| WO2006045018A1 (en) | 2004-10-18 | 2006-04-27 | Teva Pharmaceutical Industries Ltd. | Process for preparing amorphous atorvastatin hemi-calcium by dissolving the salt in an organic solvent which is a mixture of an alcohol and a ketone and/or an ester and removing the solvent |
| US20060106230A1 (en) * | 2004-10-18 | 2006-05-18 | Michael Pinchasov | Processes for preparing amorphous atorvastatin hemi-calcium |
| JP2007515430A (en) * | 2004-10-18 | 2007-06-14 | テバ ファーマシューティカル インダストリーズ リミティド | Method for preparing amorphous atorvastatin hemi-calcium by dissolving a salt in an organic solvent which is a mixture of alcohol and ketone and / or ester and removing the solvent |
| EP2075246A1 (en) | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | A process for preparation of amorphous form of atorvastatin hemi-calcium salt |
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| Publication number | Publication date |
|---|---|
| AU2002356423A1 (en) | 2003-12-12 |
| PL357490A1 (en) | 2003-12-01 |
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