WO2014020381A1 - Novel crystalline form of azilsartan medoxomil potassium - Google Patents
Novel crystalline form of azilsartan medoxomil potassium Download PDFInfo
- Publication number
- WO2014020381A1 WO2014020381A1 PCT/IB2012/055992 IB2012055992W WO2014020381A1 WO 2014020381 A1 WO2014020381 A1 WO 2014020381A1 IB 2012055992 W IB2012055992 W IB 2012055992W WO 2014020381 A1 WO2014020381 A1 WO 2014020381A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- azilsartan medoxomil
- potassium
- medoxomil potassium
- crystalline form
- novel crystalline
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention describes novel crystalline form AL of Azilsartan medoxomil potassium (II), process for their preparation and pharmaceutical compositions containing them.
- Azilsartan medoxomil i.e. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl-2-ethoxy- 1 - ([2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH-benzimidazole-7-carboxylate (I) has the uses such as a strong and long lasting angiotensin II antagonistic activity and hypotensive action, and an insulin sensitizing activity, and which is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure, cardiac infarction and the like), nephritis, stroke and the like and metabolic diseases such as diabetes and the like (US7, 157,584).
- circulatory diseases such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure, cardiac infarction and the like),
- Azilsartan medoxomil is the prodrug of 2- ethoxy-l-([2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH-benzimidazole-7-carboxylic acid.
- azilsartan medoxomil and salt thereof such as monopotassium salt (II) are benzimidazole derivative useful as an angiotensin II receptor antagonist.
- amorphous forms of APIs generally exhibit the better solubility profile over the corresponding crystalline forms. This is because the lattice energy does not have to be overcome in order to dissolve the solid state structure as in the case for crystalline forms.
- FIG. l depicts a powder X-ray diffractogram (PXRD) of novel crystalline Form AL of azilsartan medoxomil potassium.
- the present invention provides novel crystalline form AL of Azilsartan Medoxomil potassium having X-ray powder diffraction pattern comprising peaks at about 6.2, 13.3, 14.7, 16.0, 18.7, 22.8 + 0.2 degrees 2 ⁇ .
- Another object of the present invention is to provide a process for the preparation of form AL of Azilsartan medoxomil potassium comprising the step of:
- Yet another object of the present invention is to provide a process for the preparation pharmaceutical composition comprising the said form AL of Azilsartan medoxomil potassium.
- An embodiment of present invention provides novel crystalline form AL of Azilsartan Medoxomil potassium.
- Another embodiment of present invention provides crystalline form AL of Azilsartan Medoxomil potassium, which is characterized by X-ray powder diffraction pattern as depicted in Fig 1.
- Further embodiment of the present invention is to provide novel process for the preparation of form AL of Azilsartan medoxomil potassium comprising the step of:
- Yet another embodiment of the present invention is to provide process for the preparation pharmaceutical composition comprising the said form AL of Azilsartan medoxomil potassium.
- Ester solvents as used here in above include but not limited to ethyl acetate, isopropyl acetate, butyl acetate, methyl acetate or mixture thereof.
- Facilitating crystallization used here in above includes intermolecular contacts which facilitates the assembly of the molecules in to a crystalline lattice.
- Azilsartan medoxomil (100g) was dissolved in ethyl acetate (3200 ml) at 75-80 0 C. The resulting solution was stirred over a period of 1 hr at 75-80 0 C and charcoal (2.5 g) was added to the solution at 75-80 0 C. The reaction mixture was stirred for another 1 hr at 75-80 0 C and then reaction mixture cooled and filter through hyflo bed. A solution of Potassium ethyl hexanoate (31. 4 g in 300 ml ethyl acetate) was added at 10-15 0 C to the reaction mixture and stirred for 3 hrs at 10-15°C.
Abstract
The present invention describes novel crystalline form AL of Azilsartan medoxomil potassium, process for their preparation and pharmaceutical compositions containing them.
Description
The present invention describes novel crystalline form
AL of Azilsartan medoxomil potassium (II), process for their preparation and
pharmaceutical compositions containing them.
Azilsartan medoxomil i.e.
(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl-2-ethoxy- 1 -
([2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH-benzimidazole-7-carboxylate
(I) has the uses such as a strong and long lasting angiotensin II antagonistic
activity and hypotensive action, and an insulin sensitizing activity, and which
is useful as an agent for the prophylaxis or treatment of circulatory diseases
such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure,
cardiac infarction and the like), nephritis, stroke and the like and metabolic
diseases such as diabetes and the like (US7, 157,584). Azilsartan medoxomil is
the prodrug of 2-
ethoxy-l-([2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH-benzimidazole-7-carboxylic
acid.
It is disclosed in US7, 157,584 that azilsartan
medoxomil and salt thereof such as monopotassium salt (II) are benzimidazole
derivative useful as an angiotensin II receptor antagonist.
Pharmaceutical Research, (2008) 25, 530, explains that
the ability to deliver the drug to the patient in a safe, efficacious and cost
effective way depends largely upon the physicochemical properties of the APIs
in the solid state and accordingly one of the challenging tasks in the
pharmaceutical industry is to design pharmaceutical materials with specific
physiochemical properties. It is known that different solid forms of the same
drug may exhibit different properties, including characteristics that have
functional implications with respect to their use as drug may have substantial
differences in such pharmaceutically important properties as dissolution rates
and bioavailability. Likewise, different polymorphs may have different
processing properties, such as hygroscopisity, flow ability and the like, which
could affect their suitability as active pharmaceuticals for commercial
production. Also, it is known in the art that the amorphous forms of APIs
generally exhibit the better solubility profile over the corresponding
crystalline forms. This is because the lattice energy does not have to be
overcome in order to dissolve the solid state structure as in the case for
crystalline forms.
Thus, there is a need to develop the novel crystalline
form of Azilsartan medoxomil Potassium, having better physicochemical
properties. Especially, for the enhancement of the solubility. Also there is a
constant need to have the cost effective and industrial friendly process for
the preparation of crystalline form of Azilsartan medoxomil Potassium.
FIG. l depicts a powder X-ray diffractogram (PXRD) of
novel crystalline Form AL of azilsartan medoxomil potassium.
Accordingly, the present invention provides novel
crystalline form AL of Azilsartan Medoxomil potassium having X-ray powder
diffraction pattern comprising peaks at about 6.2, 13.3, 14.7, 16.0, 18.7,
22.8+0.2 degrees 2θ.
Another object of the present invention is to provide
a process for the preparation of form AL of Azilsartan medoxomil potassium
comprising the step of:
(i) Dissolving azilsartan medoxomil in ester solvent
by heating;
(ii) Adding a solution of potassium ethyl hexanoate
in ester solvent to the reaction mixture;
(iii) Facilitating crystallization of azilsartan
medoxomil potassium;
(iv) Isolating crystals of form AL of azilsartan
medoxomil potassium.
Yet another object of the present invention is to
provide a process for the preparation pharmaceutical composition comprising the
said form AL of Azilsartan medoxomil potassium.
An embodiment of present invention provides novel
crystalline form AL of Azilsartan Medoxomil potassium.
Further embodiment of present invention provides
novel crystalline form AL of Azilsartan Medoxomil potassium having X-ray powder
diffraction pattern comprising peaks at about 6.2, 13.3, 14.7, 16.0, 18.7,
22.8+0.2 degrees 2θ.
Another embodiment of present invention provides
crystalline form AL of Azilsartan Medoxomil potassium, which is characterized
by X-ray powder diffraction pattern as depicted in Fig 1.
Further embodiment of the present invention is to
provide novel process for the preparation of form AL of Azilsartan medoxomil
potassium comprising the step of:
(i) Dissolving azilsartan medoxomil in ester solvent
by heating
(ii) Adding a solution of potassium ethyl hexanoate
in ester solvent to the reaction mixture
(iii) Facilitating crystallization of azilsartan
medoxomil potassium
(iv) Isolating crystals of form AL of azilsartan
medoxomil potassium
Yet another embodiment of the present invention is to
provide process for the preparation pharmaceutical composition comprising the
said form AL of Azilsartan medoxomil potassium.
Ester solvents as used here in above include but not
limited to ethyl acetate, isopropyl acetate, butyl acetate, methyl acetate or
mixture thereof.
Facilitating crystallization used here in above
includes intermolecular contacts which facilitates the assembly of the
molecules in to a crystalline lattice.
The following example illustrates the invention
further. It should be understood however, that the invention is not confined to
the specific limitations set forth in the individual example but rather to the
scope of the appended claims.
Azilsartan medoxomil (100g) was dissolved in ethyl
acetate (3200 ml) at 75-800C. The resulting solution was stirred
over a period of 1 hr at 75-800C and charcoal (2.5 g) was added to
the solution at 75-800C. The reaction mixture was stirred for
another 1 hr at 75-800C and then reaction mixture cooled and filter
through hyflo bed. A solution of Potassium ethyl hexanoate (31. 4 g in 300 ml
ethyl acetate) was added at 10-15 0C to the reaction mixture and
stirred for 3 hrs at 10-15°C. Raised the temperature up to75-80oC
and stirred the reaction mixture for another 1 hr and then cooled to
25-30oC. The crystalline solid thus obtained was filtered in
dehumidified area and dried under vacuum to obtained 85 g of crystalline form
AL of azilsartan medoxomil potassium. XRD as provided in Fig. 1.
Claims (4)
- Novel crystalline form AL of Azilsartan Medoxomil potassium having X-ray powder diffraction pattern comprising peaks at about 6.2, 13.3, 14.7, 16.0, 18.7, 22.8+0.2 degrees 2θ.
- A novel process for the preparation of form AL of Azilsartan medoxomil potassium comprising steps of:(i) Dissolving azilsartan medoxomil in ester solvent by heating(ii) Adding a solution of potassium ethyl hexanoate in ester solvent to the reaction mixture(iii) Facilitating crystallization of azilsartan medoxomil potassium(iv) Isolating crystals of form AL of azilsartan medoxomil potassium.
- The process according to claim 2 where in ester is selected from the group comprising ethyl acetate, isopropyl acetate, butyl acetate, methyl acetate or mixture thereof.
- The process according to claim 3 where in ester is ethyl acetate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2216/MUM/2012 | 2012-08-01 | ||
| IN2216MU2012 | 2012-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014020381A1 true WO2014020381A1 (en) | 2014-02-06 |
Family
ID=50027332
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2012/055992 WO2014020381A1 (en) | 2012-08-01 | 2012-10-30 | Novel crystalline form of azilsartan medoxomil potassium |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140364464A1 (en) * | 2012-01-14 | 2014-12-11 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
| CN105753854A (en) * | 2014-12-16 | 2016-07-13 | 重庆朗天制药有限公司 | New preparation method of azilsartan kamedoxomil |
| WO2017131218A1 (en) * | 2016-01-28 | 2017-08-03 | 株式会社トクヤマ | Azilsartan and method for producing same |
| JP2018087178A (en) * | 2016-11-30 | 2018-06-07 | 株式会社トクヤマ | Method for producing azilsartan |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157584B2 (en) * | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| CN102351853A (en) * | 2011-08-29 | 2012-02-15 | 石药集团欧意药业有限公司 | Azilsartan medoxomil compound, preparation method and medicinal composition thereof |
| WO2012090043A1 (en) * | 2010-12-29 | 2012-07-05 | Jubilant Life Sciences Limited | Novel solid state forms of azilsartan medoxomil and preparation thereof |
| WO2012107814A1 (en) * | 2011-02-08 | 2012-08-16 | Jubilant Life Sciences Limited | An improved process for the preparation of azilsartan medoxomil |
| WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
-
2012
- 2012-10-30 WO PCT/IB2012/055992 patent/WO2014020381A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157584B2 (en) * | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| WO2012090043A1 (en) * | 2010-12-29 | 2012-07-05 | Jubilant Life Sciences Limited | Novel solid state forms of azilsartan medoxomil and preparation thereof |
| WO2012107814A1 (en) * | 2011-02-08 | 2012-08-16 | Jubilant Life Sciences Limited | An improved process for the preparation of azilsartan medoxomil |
| CN102351853A (en) * | 2011-08-29 | 2012-02-15 | 石药集团欧意药业有限公司 | Azilsartan medoxomil compound, preparation method and medicinal composition thereof |
| WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140364464A1 (en) * | 2012-01-14 | 2014-12-11 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
| US9403811B2 (en) * | 2012-01-14 | 2016-08-02 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
| CN105753854A (en) * | 2014-12-16 | 2016-07-13 | 重庆朗天制药有限公司 | New preparation method of azilsartan kamedoxomil |
| WO2017131218A1 (en) * | 2016-01-28 | 2017-08-03 | 株式会社トクヤマ | Azilsartan and method for producing same |
| CN109071519A (en) * | 2016-01-28 | 2018-12-21 | 株式会社德山 | Azilsartan and its manufacturing method |
| JP2018087178A (en) * | 2016-11-30 | 2018-06-07 | 株式会社トクヤマ | Method for producing azilsartan |
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