WO2002057228A1 - Atorvastatin calcium - Google Patents
Atorvastatin calcium Download PDFInfo
- Publication number
- WO2002057228A1 WO2002057228A1 PCT/IN2001/000004 IN0100004W WO02057228A1 WO 2002057228 A1 WO2002057228 A1 WO 2002057228A1 IN 0100004 W IN0100004 W IN 0100004W WO 02057228 A1 WO02057228 A1 WO 02057228A1
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- WIPO (PCT)
- Prior art keywords
- atorvastatin calcium
- amorphous
- solvent
- atorvastatin
- calcium
- Prior art date
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- the present invention relates to a process for the production of amorphous atorvastatin calcium.
- Atorvastatin calcium a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.
- PCT application discloses novel crystalline forms of atorvastatin calcium designated as Form 1. Form II, and Form IV and method for their preparation.
- PCT application WO 97/03960 describes a procedure for converting the crystalline form of atorvastatin to the amorphous form.
- PCT application WO 00/71 1 16 claims a process for the preparation of amorphous atorvastatin calcium where the crystalline form is dissolved in a non-hydroxilic solvent is treated with a non-polar hydrocarbon anti-solvent followed by the removal of the solvent to result in the amorphous form.
- the present invention describes a process, which is ideal for large scale production of amorphous atorvastatin calcium.
- the present invention provides a process for the preparation of atorvastatin calcium in an amorphous form which comprises dissolving the heterogeneous mixture of atorvastatin in a non- hydroxylic solvent followed by the addition of a suitable non- hydroxylic solvent to precipitate the product which is then isolated.
- a suitable non- hydroxylic solvent to precipitate the product which is then isolated.
- the solution of atorvastatin in a non- hydroxylic solvent is added to a non-hydroxylic solvent to induce precipitation.
- the product can be isolated by any method known in the art such as by filtration, centrifugation or decantation. Typically, this product is isolated by filtration when any of the solvents within the scope of the process are used.
- the present invention thus provides a simple and novel process for the preparation of amorphous atorvastatin calcium and hydrates thereof.
- the starting material used in the instant invention comprises of a mixture of both amorphous and crystalline forms — henceforth referred to as heterogeneous mixture.
- the present invention comprises of:
- the non-hydroxylic solvent in step (i) is tetrahydrofuran.
- the non-hydoxylic solvent used in step (ii) is diisopropyl ether.
- the amorphous atorvastatin calcium is isolated by filtration.
- Amorphous atorvastatin calcium prepared according to the process of the present invention may be characterized by its x- ray powder diffraction pattern ( Figures 2) as shown in the accompanied drawings.
- X-ray powder diffraction patterns ( Figures 2) show no peaks which are characteristic of a heterogeneous mixmre of atorvastatin calcium ( Figure 1 of the accompanied drawings) thus demonstrating the amorphous nature of the product.
- Figure 1 is the diffractogram of heterogeneous mixture of atorvastatin calcium.
- the horizontal axis represents 2 ⁇ and the vertical axis corresponds to peak intensity.
- Figure 2 is the diffractogram of amorphous atorvastatin calcium.
- the horizontal axis represents 2 ⁇ and the vertical axis corresponds to peak intensity.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for the preparation of amorphous atorvastatin calcium and its hydrates thereof which comprises: (a) dissolving heterogeneous mixture of atorvastatin calcium in a non-hydroxylic solvent; (b) adding a non-hydroxylic solvent or adding the dissolved atorvastatin to the non-hydroxylic solvent to precipitate out atorvastatin calcium; and (c) removing the solvent by filtration to afford amorphous atorvastatin calcium.
Description
ATORVASTATIN CALCIUM
FIELD OF THE INVENTION
The present invention relates to a process for the production of amorphous atorvastatin calcium.
BACKGROUND OF THE INVENTION
The process for the production of amorphous [R-(R* R*)]-2-(4- fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid hemi calcium salt.
Atorvastatin calcium, a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.
United States Patent 5,273,995, describes that R-form of the ring opened acid form inhibits the biosynthesis of cholesterol. Atorvastatin in its calcium salt form, i.e. amorphous [R- (R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydrox>-5-(l-methylethyl)-
3ι- ?henyl-4-[(phenylamino)carbonyl]-l H-pyrrole-l -heptanoic acid hemi calcium salt (2: 1 ) is discussed in literature.
Various United States patents like, 5,003,080; 5,097,045; 5, 1 03,024; 5,124,482; 5, 149,837; 5,248.793; 5,280.126; 5,342,952, which are herein incorporated by reference, describe various processes and key intermediates for preparing atorvastatin calcium.
The process mentioned in the above patents does not produce atorvastatin calcium in its amorphous form consistently. Often a mixture of crystalline and amorphous form is obtained which is not suitable for filtration and drying and therefore not a desirable process for large-scale production.
PCT application, WO 97/03959, discloses novel crystalline forms of atorvastatin calcium designated as Form 1. Form II, and Form IV and method for their preparation. PCT application WO 97/03960 describes a procedure for converting the crystalline form of atorvastatin to the amorphous form.
The process described in the above mentioned patent involves dissolving the crystalline atorvastatin (form-I) in a non hydroxylic solvent like tetrahydrofuran or mixtures of tetrahydrofuran and toluene, followed by removal of the
s xolvents under high temperature (about 90°C) and high vacuum
(about 5mm). This process may not suitable on a large scale as the conditions used for drying may lead to degradation of the product.
PCT application WO 00/71 1 16 claims a process for the preparation of amorphous atorvastatin calcium where the crystalline form is dissolved in a non-hydroxilic solvent is treated with a non-polar hydrocarbon anti-solvent followed by the removal of the solvent to result in the amorphous form.
SUMMARY OF THE INVENTION
It is desirable to have a process, which provides amorphous atorvastatin using a procedure, which can be readily scaled up to a commercial scale. The present invention describes a process, which is ideal for large scale production of amorphous atorvastatin calcium.
The present invention provides a process for the preparation of atorvastatin calcium in an amorphous form which comprises dissolving the heterogeneous mixture of atorvastatin in a non- hydroxylic solvent followed by the addition of a suitable non- hydroxylic solvent to precipitate the product which is then isolated. Alternatively, the solution of atorvastatin in a non-
hydroxylic solvent is added to a non-hydroxylic solvent to induce precipitation.
The product can be isolated by any method known in the art such as by filtration, centrifugation or decantation. Typically, this product is isolated by filtration when any of the solvents within the scope of the process are used.
Major advantages of the present invention compared to the prior art processes are: i. Produces amorphous atorvastatin consistently. ii. Avoids the necessity to remove solvents. iii. Simpler and faster filtration. iv. Easy to operate on large-scale. v. Avoids the use of hydrocarbons.
The present invention thus provides a simple and novel process for the preparation of amorphous atorvastatin calcium and hydrates thereof. The starting material used in the instant invention comprises of a mixture of both amorphous and crystalline forms — henceforth referred to as heterogeneous mixture. The present invention comprises of:
(i) Dissolving the heterogeneous mixture of atorvastatin calcium in a non-hydroxylic solvent;
'(ii) Adding, a non-hydroxylic solvent to precipitate the material: and
(iii) Removing the solvent by filtration to afford amorphous atorvastatin calcium.
The non-hydroxylic solvent in step (i) is tetrahydrofuran.
The non-hydoxylic solvent used in step (ii) is diisopropyl ether.
The amorphous atorvastatin calcium is isolated by filtration.
Amorphous atorvastatin calcium prepared according to the process of the present invention may be characterized by its x- ray powder diffraction pattern (Figures 2) as shown in the accompanied drawings. X-ray powder diffraction patterns (Figures 2) show no peaks which are characteristic of a heterogeneous mixmre of atorvastatin calcium (Figure 1 of the accompanied drawings) thus demonstrating the amorphous nature of the product.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is the diffractogram of heterogeneous mixture of atorvastatin calcium. The horizontal axis represents 2Θ and the vertical axis corresponds to peak intensity.
Figure 2 is the diffractogram of amorphous atorvastatin calcium. The horizontal axis represents 2Θ and the vertical axis corresponds to peak intensity.
The present invention is illustrated by the following examples, which an intended to limit the effective scope of the claims.
DETAILED DESCRIPTION OF THE INVENTION
Example 1
[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l- methyIethyI)-3-phenyI-4-|(phenyIamino)carbonyI]-lH- pyrrole-1-heptanoic acid hemi calcium salt (Amorphous Atorvasatin calcium).
A heterogeneous mixture of Atorvastatin calcium (10 g) was dissolved in tetrahydrofuran (200 ml) at 55°C and filtered over hyflo supercell. The filtrate was evaporated to 40 ml stage under vacuum and precipitated using diisopropyl ether (200 ml) at room temperature. The mixture was stirred for 30 min. at room temperature and filtered. The product was washed with diisopropyl ether (15 ml). The product was dried in vacuum tray drier (650 mm/Hg) at 55°C for 24 hrs to yield 9 g.
) -ray powder diffraction pattern (Figure 2 as shown in the accompanied drawings) demonstrates the amorphous nature of the product as against the heterogeneous nature of the starting material (Figure 1 as shown in the accompanied drawings)
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.
Claims
1 . A process for the preparation of amorphous atorvastatin calcium and hydrates thereof which comprises:
(i) dissolving heterogeneous mixture of atorvastatin calcium in a non-hydroxylic solvent; (ii ) adding a non-hydroxylic solvent or adding the dissolved atorvastatin to the non-hydroxylic solvent to precipitate out atorvastatin calcium; and (iii) removing the solvent by filtration followed by drying to afford amorphous atorvastatin calcium.
2. The process as claimed in claim 1, wherein the non- hydroxylic solvent in step (i) is tetrahydrofuran.
3. The process as claimed in claim 1, wherein the non-hydoxylic solvent used in step (ii) is diisopropyl ether.
4. The process as claimed in claim 1, wherein said amorphous atorvastatin calcium is isolated by filtration.
5. The process as claimed in claim 1 wherein said heterogenous mixture of atorvastatin calcium comprises a mixture of both amorphous and crystalline forms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2001/000004 WO2002057228A1 (en) | 2001-01-17 | 2001-01-17 | Atorvastatin calcium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2001/000004 WO2002057228A1 (en) | 2001-01-17 | 2001-01-17 | Atorvastatin calcium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002057228A1 true WO2002057228A1 (en) | 2002-07-25 |
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ID=11076296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2001/000004 WO2002057228A1 (en) | 2001-01-17 | 2001-01-17 | Atorvastatin calcium |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2002057228A1 (en) |
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004089895A1 (en) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| US6867306B2 (en) | 2001-01-19 | 2005-03-15 | Biocon Limited | Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
| WO2005100313A1 (en) * | 2004-04-16 | 2005-10-27 | Pfizer Products Inc. | Process for forming amorphous atorvastatin calcium |
| US6992194B2 (en) | 2000-11-30 | 2006-01-31 | Teva Pharmaceutical Industries, Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| WO2006026531A1 (en) * | 2004-08-27 | 2006-03-09 | Cordis Corporation | Solvent free amorphous rapamycin |
| US7144915B2 (en) | 2001-06-29 | 2006-12-05 | Warner-Lambert Company, Llc | Crystalline forms of [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) |
| US7208608B2 (en) * | 2002-02-01 | 2007-04-24 | Zentiva A. S. | Method of manufacturing an amorphous form of the hemi-calcium salt of (3R,5R) 7-3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yll-3, 5-dihydroxyheptanoic acid (actorvastatin) |
| WO2007057755A1 (en) | 2005-11-21 | 2007-05-24 | Warner-Lambert Company Llc | Novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept anoic acid magnesium |
| EP1810667A1 (en) | 2006-01-20 | 2007-07-25 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising amorphous atorvastatin |
| WO2008053312A2 (en) * | 2006-11-02 | 2008-05-08 | Cadila Pharmaceuticals Limited | Process for preparing amorphous atorvastatin hemi calcium salt and its intermediate |
| US7411075B1 (en) | 2000-11-16 | 2008-08-12 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
| EP1977738A1 (en) | 2003-06-12 | 2008-10-08 | Warner-Lambert Company LLC | Pharmaceutical compositions comprising atorvastatin manufactured without granulation |
| US7501450B2 (en) * | 2000-11-30 | 2009-03-10 | Teva Pharaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7538136B2 (en) | 2000-12-27 | 2009-05-26 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of atorvastatin |
| US7655692B2 (en) | 2003-06-12 | 2010-02-02 | Pfizer Inc. | Process for forming amorphous atorvastatin |
| US7790197B2 (en) | 2003-06-09 | 2010-09-07 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
| US7939675B2 (en) | 2004-10-28 | 2011-05-10 | Pfizer, Inc. | Process for forming amorphous atorvastatin |
| WO2011088806A2 (en) | 2010-01-19 | 2011-07-28 | Zentiva, K.S. | A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form |
| US7994343B2 (en) | 2004-03-17 | 2011-08-09 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium in amorphous form |
| US8026376B2 (en) | 2004-07-20 | 2011-09-27 | Pfizer, Inc. | Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) |
| EP2540704A2 (en) | 2004-05-05 | 2013-01-02 | Pfizer Products Inc. | Benethamine salt forms of atorvastatin |
| US9034913B2 (en) | 2005-09-21 | 2015-05-19 | Pfizer Inc. | Process for annealing amorphous atorvastatin |
| CN106432033A (en) * | 2016-10-21 | 2017-02-22 | 江苏阿尔法药业有限公司 | Preparation method of amorphous atorvastatin calcium |
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2001
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Cited By (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7732623B2 (en) | 1999-11-17 | 2010-06-08 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
| US7411075B1 (en) | 2000-11-16 | 2008-08-12 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
| US7488750B2 (en) | 2000-11-30 | 2009-02-10 | Teva Pharmaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7342120B2 (en) | 2000-11-30 | 2008-03-11 | Teva Pharmaceutical Industries, Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7144916B2 (en) | 2000-11-30 | 2006-12-05 | Teva Pharmaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7456297B2 (en) | 2000-11-30 | 2008-11-25 | Teva Pharmaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7151183B2 (en) | 2000-11-30 | 2006-12-19 | Teva Pharmaceutical Industries Ltd. | Processes for preparing amorphous atorvastatin hemi-calcium |
| US7161012B2 (en) | 2000-11-30 | 2007-01-09 | Teva Pharmaceutical Industries Ltd. | Processes for preparing amorphous atorvastatin hemi-calcium |
| US7189861B2 (en) | 2000-11-30 | 2007-03-13 | Teva Pharmaceutical Industries, Ltd. | Processes for preparing amorphous atorvastatin hemi-calcium |
| US7468444B2 (en) | 2000-11-30 | 2008-12-23 | Teva Pharmaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7501450B2 (en) * | 2000-11-30 | 2009-03-10 | Teva Pharaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US6992194B2 (en) | 2000-11-30 | 2006-01-31 | Teva Pharmaceutical Industries, Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7256212B2 (en) | 2000-11-30 | 2007-08-14 | Teva Pharmaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| US7538136B2 (en) | 2000-12-27 | 2009-05-26 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of atorvastatin |
| US6867306B2 (en) | 2001-01-19 | 2005-03-15 | Biocon Limited | Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds |
| US7144915B2 (en) | 2001-06-29 | 2006-12-05 | Warner-Lambert Company, Llc | Crystalline forms of [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) |
| US7208608B2 (en) * | 2002-02-01 | 2007-04-24 | Zentiva A. S. | Method of manufacturing an amorphous form of the hemi-calcium salt of (3R,5R) 7-3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yll-3, 5-dihydroxyheptanoic acid (actorvastatin) |
| EA013500B1 (en) * | 2003-04-11 | 2010-06-30 | Лек Фармасьютиклз Д.Д. | Process for the preparation of amorphous calcium salt of atorvastatin |
| US8697741B2 (en) | 2003-04-11 | 2014-04-15 | Lek Pharmaceutical D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| US8367848B2 (en) | 2003-04-11 | 2013-02-05 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| WO2004089895A1 (en) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| US7790197B2 (en) | 2003-06-09 | 2010-09-07 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
| EP1977738A1 (en) | 2003-06-12 | 2008-10-08 | Warner-Lambert Company LLC | Pharmaceutical compositions comprising atorvastatin manufactured without granulation |
| US7655692B2 (en) | 2003-06-12 | 2010-02-02 | Pfizer Inc. | Process for forming amorphous atorvastatin |
| US7994343B2 (en) | 2004-03-17 | 2011-08-09 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium in amorphous form |
| WO2005100313A1 (en) * | 2004-04-16 | 2005-10-27 | Pfizer Products Inc. | Process for forming amorphous atorvastatin calcium |
| EP3581564A1 (en) | 2004-05-05 | 2019-12-18 | Pfizer Products Inc. | Diethylamine salt forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid |
| EP2540704A2 (en) | 2004-05-05 | 2013-01-02 | Pfizer Products Inc. | Benethamine salt forms of atorvastatin |
| US8895758B2 (en) | 2004-07-20 | 2014-11-25 | Warner-Lambert Company Llc | Forms of [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) |
| US8563750B2 (en) | 2004-07-20 | 2013-10-22 | Warner-Lambert Company Llc | Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylmino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) |
| US8026376B2 (en) | 2004-07-20 | 2011-09-27 | Pfizer, Inc. | Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) |
| US9790177B2 (en) | 2004-07-20 | 2017-10-17 | Warner-Lambert Company Llc | Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-beta, gamma-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) |
| US9481647B2 (en) | 2004-07-20 | 2016-11-01 | Warner-Lambert Company Llc | Forms of [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) |
| US9199932B2 (en) | 2004-07-20 | 2015-12-01 | Warner-Lambert Company Llc | Forms of [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) |
| US7393952B2 (en) | 2004-08-27 | 2008-07-01 | Cordis Corporation | Solvent free amorphous rapamycin |
| WO2006026531A1 (en) * | 2004-08-27 | 2006-03-09 | Cordis Corporation | Solvent free amorphous rapamycin |
| US9056831B2 (en) | 2004-10-28 | 2015-06-16 | Pfizer Inc. | Process for forming amorphous atorvastatin |
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