WO2009125415A1 - Amorphous form of sildenafil citrate - Google Patents
Amorphous form of sildenafil citrate Download PDFInfo
- Publication number
- WO2009125415A1 WO2009125415A1 PCT/IN2008/000226 IN2008000226W WO2009125415A1 WO 2009125415 A1 WO2009125415 A1 WO 2009125415A1 IN 2008000226 W IN2008000226 W IN 2008000226W WO 2009125415 A1 WO2009125415 A1 WO 2009125415A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sildenafil citrate
- amorphous form
- amorphous
- sildenafil
- citrate
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to a novel amorphous form of sildenafil citrate, to a process for the preparation thereof and to a composition comprising thereof.
- Sildenafil citrate is known by the chemical name 1-[[3-(4,7-Dihydro-1- methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl] -4-methylpiperazine citrate.
- Sildenafil citrate is an antihypertensive agent having a treatment of male erectile dysfunction.
- Sildenafil citrate is represented by the following structure:
- Sildenafil and its citrate salt may be prepared using the procedures described in Eur. Pat. No. 00463756 and WO 2005/067936 A2.
- U.S. pat. App. No. 2004/0235857 A1 discloses crystalline forms of sildenafil citrate Anhydrous Form, Hydrated Form and Hydrated forms of sildenafil hemicitrate.
- sildenafil citrate in substantially amorphous form has higher bioavailability than when in crystalline form and that moreover the amorphous form of Sildenafil citrate has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation.
- the object of present invention is to provide a novel amorphous form of sildenafil citrate (herein after referred to as amorphous sildenafil citrate), process for preparation thereof and a pharmaceutical composition containing it.
- amorphous sildenafil citrate a novel amorphous form of sildenafil citrate
- amorphous sildenafil citrate substantially amorphous form.
- the amorphous form of sildenafil citrate present invention is characterized by powder x-ray diffraction pattern as shown in fig.1 and FTIR spectrum as shown in fig.2.
- the amorphous sildenafil citrate according to the invention is prepared by a process which constitutes a further feature of the present invention and which comprises recovering sildenafil citrate from an aqueous solution of sildenafil citrate thereof under conditions whereby a substantially amorphous product is obtained.
- Substantial amorphous sildenafil citrate refers to amorphous form having less than 5% crystallinity as measured by X-RD techniques.
- Techniques which are employed to recover amorphous sildenafil citrate from the solution thereof include those wherein water is removed from an aqueous solution of sildenafil citrate and the product deposited. Methods involving the use of these procedures include spray drying and vacuum drying.
- a pharmaceutical composition comprising amorphous sildenafil citrate and a pharmaceutically acceptable excipient.
- Preferable pharmaceutical composition of amorphous sildenafil citrate is a solid oral dosage form, comprising amorphous sildenafil citrate.
- Figure 1 is X-ray powder diffraction spectrum of amorphous sildenafil citrate.
- Figure 2 is FTIR spectrum of amorphous sildenafil citrate.
- X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-K ⁇ radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees to theta per step and a step of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
- Crystalline sildenafil citrate (5 gm) is dissolved in water (800 ml). The solution is subjected to vacuum drying at 80 0 C for 10 hours to give quantative yield of amorphous sildenafil citrate.
- Crystalline sildenafil citrate (5 gm) is dissolved in water (800 ml) and heated to 50 - 6O 0 C and the solution is subjected to spray drying at 80 0 C for 30 minutes to give quantative yield of amorphous sildenafil citrate.
- Spray dryer conditions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel amorphous form of sildenafil citrate, to a process for the preparation thereof and to a composition comprising thereof.
Description
AMORPHOUS FORM OF SILDENAFIL CITRATE
FIELD OF THE INVENTION
The invention relates to a novel amorphous form of sildenafil citrate, to a process for the preparation thereof and to a composition comprising thereof.
BACKGROUND OF THE INVENTION
Sildenafil citrate is known by the chemical name 1-[[3-(4,7-Dihydro-1- methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl] -4-methylpiperazine citrate. Sildenafil citrate is an antihypertensive agent having a treatment of male erectile dysfunction. Sildenafil citrate is represented by the following structure:
Sildenafil and its citrate salt may be prepared using the procedures described in Eur. Pat. No. 00463756 and WO 2005/067936 A2.
U.S. pat. App. No. 2004/0235857 A1 discloses crystalline forms of sildenafil citrate Anhydrous Form, Hydrated Form and Hydrated forms of sildenafil hemicitrate.
Analytical profiles of drug substances and excipients Vol. 27, 395 disclose three crystalline forms of sildenafil citrate, Form I, Form Il and Form III.
The existence of amorphous form of sildenafil has now been discovered. We have also found that sildenafil citrate in substantially amorphous form has higher bioavailability than when in crystalline form and that moreover the amorphous form of Sildenafil citrate has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation.
Thus, the object of present invention is to provide a novel amorphous form of sildenafil citrate (herein after referred to as amorphous sildenafil citrate), process for preparation thereof and a pharmaceutical composition containing it.
DETAILED DESCRIPTION OF THE INVENTION According to one aspect of the present invention, there is provided sildenafil citrate substantially amorphous form.
The amorphous form of sildenafil citrate present invention is characterized by powder x-ray diffraction pattern as shown in fig.1 and FTIR spectrum as shown in fig.2.
The amorphous sildenafil citrate according to the invention is prepared by a process which constitutes a further feature of the present invention and which comprises recovering sildenafil citrate from an aqueous solution of sildenafil citrate thereof under conditions whereby a substantially amorphous product is obtained.
Substantial amorphous sildenafil citrate refers to amorphous form having less than 5% crystallinity as measured by X-RD techniques.
Techniques which are employed to recover amorphous sildenafil citrate from the solution thereof include those wherein water is removed from an aqueous solution of sildenafil citrate and the product deposited. Methods involving the use of these procedures include spray drying and vacuum drying.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous sildenafil citrate and a pharmaceutically acceptable excipient.
Preferable pharmaceutical composition of amorphous sildenafil citrate is a solid oral dosage form, comprising amorphous sildenafil citrate.
BRIEF DESCRIPTION OF THE DRAWING Figure 1 is X-ray powder diffraction spectrum of amorphous sildenafil citrate. Figure 2 is FTIR spectrum of amorphous sildenafil citrate.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-Kα radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees to theta per step and a step of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Example 1
Crystalline sildenafil citrate (5 gm) is dissolved in water (800 ml). The solution is subjected to vacuum drying at 800C for 10 hours to give quantative yield of amorphous sildenafil citrate.
Example 2
Crystalline sildenafil citrate (5 gm) is dissolved in water (800 ml) and heated to 50 - 6O0C and the solution is subjected to spray drying at 800C for 30 minutes to give quantative yield of amorphous sildenafil citrate. Spray dryer conditions
Aspiration: 100 %
Inlet temperature: 1400C Pumping: 20 - 22 %
Outlet temperature: 60-650C
Claims
1. Sildenafil citrate in substantially amorphous form.
2. Sildenafil citrate in amorphous form characterized by a powder x-ray diffraction pattern of Fig.1.
3. A process for preparing sildenafil citrate in substantially amorphous form comprising the steps of: a) dissolving sildenafil citrate crystals in water, or a mixture of water and water soluble solvents b) vacuum drying or spray drying the solution obtained in step (a).
4. A pharmaceutical composition comprising sildenafil citrate in substantially amorphous form and a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2008/000226 WO2009125415A1 (en) | 2008-04-07 | 2008-04-07 | Amorphous form of sildenafil citrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2008/000226 WO2009125415A1 (en) | 2008-04-07 | 2008-04-07 | Amorphous form of sildenafil citrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009125415A1 true WO2009125415A1 (en) | 2009-10-15 |
Family
ID=41161591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2008/000226 WO2009125415A1 (en) | 2008-04-07 | 2008-04-07 | Amorphous form of sildenafil citrate |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2009125415A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722019A (en) * | 2015-07-23 | 2018-02-23 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound for treating male erectile dysfunction |
| US9968609B2 (en) | 2014-03-19 | 2018-05-15 | Vigorous Solutions Ltd. | Sildenafil solutions and methods of making and using same |
| CN109867677A (en) * | 2017-12-04 | 2019-06-11 | 广州白云山医药集团股份有限公司白云山化学制药厂 | A kind of method that recycling prepares silaenafil |
| CN112618508A (en) * | 2021-01-15 | 2021-04-09 | 遂成药业股份有限公司 | Stable amorphous sildenafil citrate tablet and production process thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040235857A1 (en) * | 2003-02-11 | 2004-11-25 | Pfizer Inc | Crystalline therapeutic agent |
| WO2005067936A2 (en) * | 2004-01-05 | 2005-07-28 | Teva Pharmaceutical Industries Ltd. | Methods for the production of sildenafil base and citrate salt |
| WO2005115330A2 (en) * | 2004-05-28 | 2005-12-08 | Pfizer Products Inc. | Pharmaceutical compositions with enhanced performance |
| EP1779852A2 (en) * | 2004-01-05 | 2007-05-02 | Teva Pharmaceutical Industries Ltd. | Methods for the production of sildenafil base and citrate salt |
-
2008
- 2008-04-07 WO PCT/IN2008/000226 patent/WO2009125415A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040235857A1 (en) * | 2003-02-11 | 2004-11-25 | Pfizer Inc | Crystalline therapeutic agent |
| WO2005067936A2 (en) * | 2004-01-05 | 2005-07-28 | Teva Pharmaceutical Industries Ltd. | Methods for the production of sildenafil base and citrate salt |
| EP1779852A2 (en) * | 2004-01-05 | 2007-05-02 | Teva Pharmaceutical Industries Ltd. | Methods for the production of sildenafil base and citrate salt |
| WO2005115330A2 (en) * | 2004-05-28 | 2005-12-08 | Pfizer Products Inc. | Pharmaceutical compositions with enhanced performance |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9968609B2 (en) | 2014-03-19 | 2018-05-15 | Vigorous Solutions Ltd. | Sildenafil solutions and methods of making and using same |
| US10211534B2 (en) | 2014-03-19 | 2019-02-19 | Vigorous Solutions Ltd. | Sildenafil solutions and methods of making and using same |
| CN107722019A (en) * | 2015-07-23 | 2018-02-23 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound for treating male erectile dysfunction |
| CN107722018A (en) * | 2015-07-23 | 2018-02-23 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound for treating male erectile dysfunction |
| CN107722020A (en) * | 2015-07-23 | 2018-02-23 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound for treating male erectile dysfunction |
| CN107827895A (en) * | 2015-07-23 | 2018-03-23 | 青岛华之草医药科技有限公司 | A kind of method for the sildenafil citrate compound for preparing treatment male erectile dysfunction |
| CN107880047A (en) * | 2015-07-23 | 2018-04-06 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound |
| CN107880048A (en) * | 2015-07-23 | 2018-04-06 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound |
| CN107903270A (en) * | 2015-07-23 | 2018-04-13 | 青岛华之草医药科技有限公司 | A kind of sildenafil citrate compound for treating male erectile dysfunction |
| CN109867677A (en) * | 2017-12-04 | 2019-06-11 | 广州白云山医药集团股份有限公司白云山化学制药厂 | A kind of method that recycling prepares silaenafil |
| CN112618508A (en) * | 2021-01-15 | 2021-04-09 | 遂成药业股份有限公司 | Stable amorphous sildenafil citrate tablet and production process thereof |
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