WO2005009955A1 - Ezetimibe polymorphs - Google Patents

Ezetimibe polymorphs Download PDF

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Publication number
WO2005009955A1
WO2005009955A1 PCT/IN2003/000258 IN0300258W WO2005009955A1 WO 2005009955 A1 WO2005009955 A1 WO 2005009955A1 IN 0300258 W IN0300258 W IN 0300258W WO 2005009955 A1 WO2005009955 A1 WO 2005009955A1
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Prior art keywords
ezetimibe
solvent
process according
ketone
methyl
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PCT/IN2003/000258
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
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Hetero Drugs Limited
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Priority to AU2003259547A priority Critical patent/AU2003259547A1/en
Priority to PCT/IN2003/000258 priority patent/WO2005009955A1/en
Publication of WO2005009955A1 publication Critical patent/WO2005009955A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

  • the present invention relates to novel polymorphs of ezetimibe, to processes for their preparation and to pharmaceutical compositions containing them.
  • ezetimibe can be prepared in two well- defined, stable and consistently reproducible crystalline forms and a sufficiently stable amorphous form for pharmaceutical preparations.
  • the object of the present invention is to provide stable novel polymorphs of ezetimibe, processes for preparing these forms and pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION
  • ezetimibe form H1 a novel crystalline form of ezetimibe, designated as ezetimibe form H1 and typical form
  • H1 x-ray powder diffraction spectrum of ezetimibe form H1 is shown in figure 1.
  • Ezetimibe form H1 is characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 8.3, 13J, 13.9, 16.5,
  • ezetimibe form H1 is prepared by dissolving ezetimibe in a suitable solvent and then precipitating ezetimibe form H1 from the solution.
  • the 'suitable solvent' is selected from ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; chlorinated solvents such as methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methanol, ethanol; and a mixture thereof.
  • ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone
  • esters such as ethyl acetate, methyl acetate,
  • Preferable solvents are acetone, ethylacetate, tetrahydrofuran, chloroform, methyl tert-butyl ether and methanol. Precipitation can be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti-solvent or a combination thereof.
  • Preferable anti-solvents are n-heptane, cyclohexane, diisopropyl ether, petroleum ether and n-hexane, n-heptane being more preferable.
  • Ezetimibe obtained by a known process; or form H2 or amorphous ezetimibe obtained by the process described below may be used in this process.
  • ezetimibe form H2 and typical form
  • H2 x-ray powder diffraction spectrum of ezetimibe form H2 is shown in figure 2.
  • Ezetimibe form H2 is characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 16.4, 18.6, 19.0, 19.4, 20.2, 22.4, 22.9, 23.6, 23.9, 25.6, 27.9 and 29J degrees.
  • a process is provided for preparation of ezetimibe form H2.
  • Ezetimibe form H2 is prepared by dissolving ezetimibe in dioxane, acetonitrile or dimethylformamide and then precipitating ezetimibe form H2 from the solution.
  • Precipitation can be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti-solvent or a combination thereof.
  • Preferable anti-solvent is water.
  • Ezetimibe obtained by a known process; or form H1 or amorphous ezetimibe may be used in the process.
  • a novel amorphous ezetimibe there is provided a novel amorphous ezetimibe.
  • the amorphous ezetimibe is characterized by having broad x-ray diffraction spectrum as in figure 3.
  • a process is provided for preparation of amorphous ezetimibe.
  • Amorphous ezetimibe is prepared by dissolving ezetimibe in an alcohol, ketone or ester solvent; or a mixture thereof and removing the solvent.
  • the solvent may be removed from the solution by vacuum drying, freeze drying, lyophilization or spray drying.
  • the preferable alcohol is methanol, ethanol, isopropyl alcohol, tert-butyl alcohol or n-butyl alcohol;
  • preferable ketone is acetone diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone or methyl propyl ketone;
  • preferable ester solvent is ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate or methyl formate.
  • More preferable solvent is methanol, ethanol, acetone or ethyl acetate. Ezetimibe obtained by a known process, form H1 or form H2 may be used in the process.
  • a pharmaceutical composition comprising ezetimibe form H1 and a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition comprising ezetimibe form H2 and a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition comprising amorphous ezetimibe and a pharmaceutically acceptable carrier or diluent.
  • Figure 3 is a x-ray powder diffraction spectrum of amorphous ezetimibe. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Kr radiation.
  • Example 1 Ezetimibe (3 gm) is dissolved in acetone (25 ml) at about 30°C and stirred for 3 hours at the same temperature. Then the solution is cooled to 0°C, stirred for 1 hour at 0°C to 5°C and filtered to give 2.9 gm of ezetimibe form H1.
  • Example 2 Ezetimibe (10 gm) is mixed with ethyl acetate (125 ml), heated to reflux temperature and maintained for 2 hours 30 minutes at the same temperature.
  • Example 3 Ezetimibe (10 gm) is mixed with dioxane (25 ml) and stirred for 4 hours. Then water (250 ml) is added to isolate 9.8 gm of ezetimibe form H2.
  • Example 4 Ezetimibe (2 gm) is dissolved in acetonitrile (25 ml) at 40°C and maintained for 3 hours at the same temperature. The solution is cooled to about 25°C, maintained for 2 hours at this temperature and filtered to give 1.8 gm of ezetimibe form H2.
  • Example 5 Example 1 is repeated using ezetimibe form H2 instead of ezetimibe to give 2.8 gm of ezetimibe form H1.
  • Example 6 Ezetimibe (10 gm) is dissolved in methanol (50 ml). The solution is subjected to vacuum drying at about 40°C for 10 hours to give 9.8 gm of amorphous ezetimibe.
  • Example 7 Example 6 is repeated by subjecting the solution to spray drying instead of vacuum drying to give amorphous ezetimibe.
  • Example 8 Example 1 is repeated using amorphous ezetimibe instead of ezetimibe to give 2.8 gm of ezetimibe form H1.

Abstract

The present invention relates to novel polymorphs of ezetimibe, to processes for their preparation and to pharmaceutical compositions containing them.

Description

EZETIMIBE POLYMORPHS
FILELD OF THE INVENTION
The present invention relates to novel polymorphs of ezetimibe, to processes for their preparation and to pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION
Ezetimibe of formula (1):
Figure imgf000002_0001
Or (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] -4-(4-hydroxyphenyl)-2-azetidinone is Cholesterol absorption inhibitor and their therapeutic uses were disclosed in US 5,767,115. Various processes for preparation of ezetimibe were described in US 5,767,115, WO 97/16424, WO
97/45406, US 5,886,171, WO 00/34240. Polymorphs of ezetimibe were not reported in the literature. Processes described in the prior art do not produce consistently reproducible crystalline forms. So, there is a need for stable, well-defined and reproducible crystalline forms. It has now been discovered that ezetimibe can be prepared in two well- defined, stable and consistently reproducible crystalline forms and a sufficiently stable amorphous form for pharmaceutical preparations. The object of the present invention is to provide stable novel polymorphs of ezetimibe, processes for preparing these forms and pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a novel crystalline form of ezetimibe, designated as ezetimibe form H1 and typical form
H1 x-ray powder diffraction spectrum of ezetimibe form H1 is shown in figure 1. Ezetimibe form H1 is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 8.3, 13J, 13.9, 16.5,
18.7, 19.1 , 20.2, 22.5, 23.1, 23.7, 23.9, 25.7, 28.1 and 29.8 degrees. In accordance with the present invention, a process is provided for preparation of ezetimibe form H Ezetimibe form H1 is prepared by dissolving ezetimibe in a suitable solvent and then precipitating ezetimibe form H1 from the solution. The 'suitable solvent' is selected from ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; esters such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; chlorinated solvents such as methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methanol, ethanol; and a mixture thereof. Preferable solvents are acetone, ethylacetate, tetrahydrofuran, chloroform, methyl tert-butyl ether and methanol. Precipitation can be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti-solvent or a combination thereof. Preferable anti-solvents are n-heptane, cyclohexane, diisopropyl ether, petroleum ether and n-hexane, n-heptane being more preferable. Ezetimibe obtained by a known process; or form H2 or amorphous ezetimibe obtained by the process described below may be used in this process. In accordance with the present invention, there is provided a novel crystalline form of ezetimibe, designated as ezetimibe form H2 and typical form
H2 x-ray powder diffraction spectrum of ezetimibe form H2 is shown in figure 2. Ezetimibe form H2 is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 16.4, 18.6, 19.0, 19.4, 20.2, 22.4, 22.9, 23.6, 23.9, 25.6, 27.9 and 29J degrees. In accordance with the present invention, a process is provided for preparation of ezetimibe form H2. Ezetimibe form H2 is prepared by dissolving ezetimibe in dioxane, acetonitrile or dimethylformamide and then precipitating ezetimibe form H2 from the solution. Precipitation can be effected by conventional means such as partial removal of solvent, lowering the temperature or by adding anti-solvent or a combination thereof. Preferable anti-solvent is water. Ezetimibe obtained by a known process; or form H1 or amorphous ezetimibe may be used in the process. In accordance with the present invention, there is provided a novel amorphous ezetimibe. The amorphous ezetimibe is characterized by having broad x-ray diffraction spectrum as in figure 3. In accordance with the present invention, a process is provided for preparation of amorphous ezetimibe. Amorphous ezetimibe is prepared by dissolving ezetimibe in an alcohol, ketone or ester solvent; or a mixture thereof and removing the solvent. The solvent may be removed from the solution by vacuum drying, freeze drying, lyophilization or spray drying. The preferable alcohol is methanol, ethanol, isopropyl alcohol, tert-butyl alcohol or n-butyl alcohol; preferable ketone is acetone diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone or methyl propyl ketone; preferable ester solvent is ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate or methyl formate. More preferable solvent is methanol, ethanol, acetone or ethyl acetate. Ezetimibe obtained by a known process, form H1 or form H2 may be used in the process. In accordance with the present invention, there is provided a pharmaceutical composition comprising ezetimibe form H1 and a pharmaceutically acceptable carrier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising ezetimibe form H2 and a pharmaceutically acceptable carrier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising amorphous ezetimibe and a pharmaceutically acceptable carrier or diluent. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of ezetimibe form H1. Figure 2 is a x-ray powder diffraction spectrum of ezetimibe form H2. Figure 3 is a x-ray powder diffraction spectrum of amorphous ezetimibe. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-Kr radiation.
The invention will now be further described by the following non-limiting examples. Example 1 Ezetimibe (3 gm) is dissolved in acetone (25 ml) at about 30°C and stirred for 3 hours at the same temperature. Then the solution is cooled to 0°C, stirred for 1 hour at 0°C to 5°C and filtered to give 2.9 gm of ezetimibe form H1. Example 2 Ezetimibe (10 gm) is mixed with ethyl acetate (125 ml), heated to reflux temperature and maintained for 2 hours 30 minutes at the same temperature. The solution is cooled to about 25°C, maintained for 5 hours at this temperature and then n-heptane (300 ml) is added to give 9.3 gm of ezetimibe form H1. Example 3 Ezetimibe (10 gm) is mixed with dioxane (25 ml) and stirred for 4 hours. Then water (250 ml) is added to isolate 9.8 gm of ezetimibe form H2. Example 4 Ezetimibe (2 gm) is dissolved in acetonitrile (25 ml) at 40°C and maintained for 3 hours at the same temperature. The solution is cooled to about 25°C, maintained for 2 hours at this temperature and filtered to give 1.8 gm of ezetimibe form H2. Example 5 Example 1 is repeated using ezetimibe form H2 instead of ezetimibe to give 2.8 gm of ezetimibe form H1. - Example 6 Ezetimibe (10 gm) is dissolved in methanol (50 ml). The solution is subjected to vacuum drying at about 40°C for 10 hours to give 9.8 gm of amorphous ezetimibe. Example 7 Example 6 is repeated by subjecting the solution to spray drying instead of vacuum drying to give amorphous ezetimibe. Example 8 Example 1 is repeated using amorphous ezetimibe instead of ezetimibe to give 2.8 gm of ezetimibe form H1.

Claims

We claim:
I. A crystalline ezetimibe form H1, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 8.3, 13J, 13.9, 16.5, 18J, 19.1 , 20.2, 22.5, 23.1, 23.7, 23.9, 25.7, 28.1 and 29.8 degrees. 2. A crystalline ezetimibe form H1 as defined in claim 1, further characterized by an x-ray powder diffraction spectrum as in figure 1.
3. A process for preparation of ezetimibe form H1 as defined in claim 1 , which comprises the steps of: a) dissolving ezetimibe in a suitable solvent; and b) precipitating ezetimibe form H1 from the solution; wherein the suitable solvent is selected from ketones, esters, chlorinated solvents, tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methanol, ethanol; and a mixture thereof.
4. A process according to claim 3, wherein the ketones are selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; the esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; the chlorinated solvents are selected from methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride. 5. A process according to claim 4, wherein the ketone is acetone, the ester is ethyl acetate and the chlorinated solvent is chloroform.
6. A process according to claim 3, wherein the solvent is tetrahydrofuran or methyl tert-butyl ether.
7. A process according to claim 3, wherein the precipitation is effected by removal of the solvent, lowering the temperature or adding anti-solvent or a combination thereof.
8. A process according to claim 7, wherein the anti-solvent is selected from n- heptane, cyclohexane, diisopropyl ether, petroleum ether and n-hexane.
9. A process according to claim 8, wherein the anti-solvent is n-heptane. 10. A crystalline ezetimibe form H2, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 16.4, 18.6, 19.0, 19.4, 20.2, 22.4, 22.9, 23.6, 23.9, 25.6, 27.9 and 29.7 degrees.
II. A crystalline ezetimibe form H2 as defined in claim 10, further characterized by an x-ray powder diffraction spectrum as in figure 2.
12. A process for preparation of ezetimibe form H2 as defined in claim 10, which comprises the steps of: a) dissolving ezetimibe in dioxane, acetonitrile or dimethylformamide; and b) precipitating ezetimibe form H2 from the solution. 13. A process according to claim 12, wherein the precipitation is effected by removal of the solvent, lowering the temperature or adding anti-solvent or a combination thereof.
14. A process according to claim 13, wherein the anti-solvent is water.
15. Amorphous ezetimibe characterized by an x-ray powder diffraction spectrum as in figure 3.
16. A process for preparation of amorphous ezetimibe as defined in claim 15, which comprises the steps of: a) dissolving ezetimibe in an alcohol, ketone or ester solvent; and b) removing the solvents from the solution formed in step (a) by vacuum drying, freeze drying, lyophilization or spray drying.
17. A process according to claim 16, wherein the alcohol is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol; the ketone is selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; and the ester solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate.
18. A process according to claim 17, wherein the alcohol is methanol, the ketone is acetone and the ester solvent is ethyl acetate.
19. A process according to claim 16, wherein the solvent is removed by vacuum drying.
20. A process according to claim 16, wherein the solvent is removed by spray drying.
21. A pharmaceutical composition comprising ezetimibe form H1 of claim 1 and a pharmaceutically acceptable carrier or diluent. 22. A pharmaceutical composition comprising ezetimibe form H2 of claim 10 and a pharmaceutically acceptable carrier or diluent. 23. A pharmaceutical composition comprising amorphous ezetimibe of claim 15 and a pharmaceutically acceptable carrier or diluent.
PCT/IN2003/000258 2003-07-31 2003-07-31 Ezetimibe polymorphs WO2005009955A1 (en)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060808A1 (en) * 2004-12-03 2006-06-08 Teva Pharmaceutical Industries Ltd. Ezetimibe polymorphs
WO2008032338A2 (en) * 2006-09-11 2008-03-20 Manne Satyanarayana Reddy Improved process for the preparation of ezetimibe and its intermediates
WO2008074723A1 (en) * 2006-12-21 2008-06-26 Lek Pharmaceuticals D.D. Inclusion complex of ezetimibe and a cyclodextrin and processes in the preparation thereof
WO2008089984A2 (en) 2007-01-24 2008-07-31 Krka Process for the preparation of ezetimibe and derivatives thereof
EP1953140A1 (en) * 2007-01-24 2008-08-06 Krka Process for the preparation of ezetimibe and derivatives thereof
US7635705B2 (en) 2005-06-20 2009-12-22 Schering Corporation Heteroatom-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists
EP2204170A1 (en) 2008-12-01 2010-07-07 LEK Pharmaceuticals D.D. Pharmaceutical composition comprising ezetimibe and simvastatin
EP2368543A1 (en) 2010-03-25 2011-09-28 KRKA, tovarna zdravil, d.d., Novo mesto Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe
WO2011158052A1 (en) 2010-06-18 2011-12-22 Nanoform Cardiovascular Therapeutics Ltd. Nanostructured ezetimibe compositions, process for the preparation thereof and pharmaceutical compositions containing them
AU2007248793B2 (en) * 2006-05-03 2013-06-20 Cook Medical Technologies Llc Endoscope rotational and positioning apparatus and method
US8921352B2 (en) 2005-07-06 2014-12-30 Krka Pharmaceutical composition comprising simvastatin and ezetimibe
CN104940153A (en) * 2015-07-23 2015-09-30 青岛蓝盛洋医药生物科技有限责任公司 Ezetimibe composition tablet as medicine for treating hyperlipidemia
CN104983713A (en) * 2015-07-23 2015-10-21 青岛蓝盛洋医药生物科技有限责任公司 Ezetimibe composition capsule for treating cardio-cerebral vascular system diseases
CN105017119A (en) * 2015-07-23 2015-11-04 青岛蓝盛洋医药生物科技有限责任公司 Lipid-lowering drug ezetimibe compound
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
CN106892851A (en) * 2017-03-09 2017-06-27 上海华源医药科技发展有限公司 A kind of new method for preparing Ezetimibe crystal formation I
US10905736B2 (en) * 2016-09-28 2021-02-02 The Regents Of The University Of California Ezetimibe-associated ApoA-I mimetic peptides showing enhanced synergism

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JP2007526251A (en) * 2004-12-03 2007-09-13 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 Ezetimibe polymorph
WO2006060808A1 (en) * 2004-12-03 2006-06-08 Teva Pharmaceutical Industries Ltd. Ezetimibe polymorphs
US7846946B2 (en) 2005-06-20 2010-12-07 Schering Plough Corporation Heteroatom-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists
US7635705B2 (en) 2005-06-20 2009-12-22 Schering Corporation Heteroatom-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists
US8921352B2 (en) 2005-07-06 2014-12-30 Krka Pharmaceutical composition comprising simvastatin and ezetimibe
AU2007248793B2 (en) * 2006-05-03 2013-06-20 Cook Medical Technologies Llc Endoscope rotational and positioning apparatus and method
WO2008032338A3 (en) * 2006-09-11 2009-10-15 Manne Satyanarayana Reddy Improved process for the preparation of ezetimibe and its intermediates
WO2008032338A2 (en) * 2006-09-11 2008-03-20 Manne Satyanarayana Reddy Improved process for the preparation of ezetimibe and its intermediates
EP1939174A1 (en) * 2006-12-21 2008-07-02 LEK Pharmaceuticals D.D. Inclusion complex of ezetimibe and a cyclodextrin and processes in the preparation thereof
WO2008074723A1 (en) * 2006-12-21 2008-06-26 Lek Pharmaceuticals D.D. Inclusion complex of ezetimibe and a cyclodextrin and processes in the preparation thereof
WO2008089984A3 (en) * 2007-01-24 2008-09-18 Krka Process for the preparation of ezetimibe and derivatives thereof
EP1953140A1 (en) * 2007-01-24 2008-08-06 Krka Process for the preparation of ezetimibe and derivatives thereof
WO2008089984A2 (en) 2007-01-24 2008-07-31 Krka Process for the preparation of ezetimibe and derivatives thereof
EA017349B1 (en) * 2007-01-24 2012-11-30 Крка Process for the preparation of ezetimibe and derivatives thereof
EP2204170A1 (en) 2008-12-01 2010-07-07 LEK Pharmaceuticals D.D. Pharmaceutical composition comprising ezetimibe and simvastatin
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
EP2368543A1 (en) 2010-03-25 2011-09-28 KRKA, tovarna zdravil, d.d., Novo mesto Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe
WO2011116973A1 (en) 2010-03-25 2011-09-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe
WO2011158052A1 (en) 2010-06-18 2011-12-22 Nanoform Cardiovascular Therapeutics Ltd. Nanostructured ezetimibe compositions, process for the preparation thereof and pharmaceutical compositions containing them
CN104940153A (en) * 2015-07-23 2015-09-30 青岛蓝盛洋医药生物科技有限责任公司 Ezetimibe composition tablet as medicine for treating hyperlipidemia
CN104983713A (en) * 2015-07-23 2015-10-21 青岛蓝盛洋医药生物科技有限责任公司 Ezetimibe composition capsule for treating cardio-cerebral vascular system diseases
CN105017119A (en) * 2015-07-23 2015-11-04 青岛蓝盛洋医药生物科技有限责任公司 Lipid-lowering drug ezetimibe compound
US10905736B2 (en) * 2016-09-28 2021-02-02 The Regents Of The University Of California Ezetimibe-associated ApoA-I mimetic peptides showing enhanced synergism
CN106892851A (en) * 2017-03-09 2017-06-27 上海华源医药科技发展有限公司 A kind of new method for preparing Ezetimibe crystal formation I

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