WO2015056219A1 - Process for simultaneous drying and micronization of valsartan - Google Patents
Process for simultaneous drying and micronization of valsartan Download PDFInfo
- Publication number
- WO2015056219A1 WO2015056219A1 PCT/IB2014/065383 IB2014065383W WO2015056219A1 WO 2015056219 A1 WO2015056219 A1 WO 2015056219A1 IB 2014065383 W IB2014065383 W IB 2014065383W WO 2015056219 A1 WO2015056219 A1 WO 2015056219A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- valsartan
- micronization
- less
- drying
- microns
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Definitions
- the present invention provides a process for the preparation of micronized valsartan, wherein the process involves simultaneous drying and micronization steps.
- the invention also provides micronized valsartan substantially free of ethyl acetate.
- Valsartan an angiotensin receptor blocker, is chemically described as N-(l- oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [l,l'-biphenyl]-4-yl]methyl]-L-valine. Its chemical structure is depicted in Formula I.
- Valsartan is indicated for the treatment of hypertension, treatment of heart failure, and reduction in cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
- the present invention provides a process for the preparation of micronized valsartan, wherein the process involves simultaneous drying and micronization steps.
- the process of the present invention requires a shorter time for the simultaneous drying and micronization steps.
- the present invention also provides micronized valsartan substantially free of ethyl acetate.
- a first aspect of the present invention provides a process for the preparation of micronized valsartan, wherein the process comprises subjecting valsartan to drying and micronization simultaneously.
- a second aspect of the present invention provides valsartan, having a dgo particle size distribution of less than 60 microns, a dso of less than 30 microns, and a dio of less than 10 microns, prepared by a process which comprises subjecting valsartan to drying and
- the valsartan obtained has a dgo particle size distribution of less than 40 microns, a dso of less than 20 microns, and a dio of less than 5 microns.
- a third aspect of the present invention provides valsartan substantially free of ethyl acetate.
- the valsartan used for preparing micronized valsartan may be prepared by any of the methods described in U.S. Patent No. 5,399,578 or PCT Publication Nos. WO 2005/049588 and WO 2005/049587.
- the valsartan used as a starting material may be crude valsartan.
- the crude valsartan, as used herein, refers to valsartan having an ethyl acetate content of 20,000 ppm or more.
- the simultaneous drying and micronization of valsartan is carried out using an instrument such as a turbo dryer. Any instrument that can simultaneously perform the drying and micronization can be used.
- the turbo dryer used in the present invention may be selected from any of the commercially available turbo dryers.
- the simultaneous drying and micronization of valsartan is carried out for about 25 hours to about 55 hours, for example, for 35 hours to 50 hours, in a turbo dryer.
- the drying and micronization steps are carried out at a temperature or temperature range of about 40°C to about 70°C, for example, at 50°C to 60°C, in a turbo dryer.
- the crude valsartan is subjected to a turbo dryer.
- the simultaneous drying and micronization is carried out in a turbo dryer at about 40°C to about 70°C for about 25 hours to about 55 hours.
- the dried and micronized valsartan is obtained.
- valsartan substantially free of ethyl acetate refers to a valsartan having an ethyl acetate content of less than 600 ppm.
- the valsartan substantially free of ethyl acetate contains less than 500 ppm of ethyl acetate.
- valsartan having an ethyl acetate content of less than 600 ppm and a ds>o particle size distribution of less than 60 microns, a dso of less than 30 microns, and a dio of less than 10 microns, is provided.
- VTD Vacuum Tray Dryer
- RVD Rotary Vacuum Dryer
- VTD Vacuum Tray Dryer
- RVD Rotary Vacuum Dryer
- Vacuum 600 mm to 700 mm of Hg in a vacuum tray dryer and 640 mm to 700 mm of
- Jacket hot water temperature 50°C to 55°C
- Jacket hot water temperature 50°C to 55°C
- the process of simultaneous drying and micronizing reduced the processing time from 140 hours (reference example) to 43 hours.
- the simultaneous processing also produced a valsartan product having a significantly lower final ethyl acetate content (1293 ppm vs 440 ppm).
- This result is unexpected and surprising because the valsartan in the two examples was subjected to very similar processing conditions. As such, one of skill in the art would expect the final ethyl acetate content to be similar. In fact, because the valsartan was subjected to elevated temperatures and vacuum for almost 100 additional hours, one of skill in the art would expect those processing conditions to result in a lower ethyl acetate content.
- the process according to the invention also is believed to reduce the costs associated with producing the micronized and dried valsartan active ingredient compared to known techniques. Such costs include energy costs for both operating the equipment and heating the valsartan as well as the manpower costs to operate the equipment. These reduced costs provide significant financial advantages to a company producing the valsartan according to this method.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a process for the preparation of micronized valsartan, wherein the process involves simultaneous drying and micronization steps. The invention also provides micronized valsartan substantially free of ethyl acetate.
Description
PROCESS FOR SIMULTANEOUS DRYING AND MICRONIZATION OF
VALSARTAN
Field of the Invention
The present invention provides a process for the preparation of micronized valsartan, wherein the process involves simultaneous drying and micronization steps. The invention also provides micronized valsartan substantially free of ethyl acetate.
Background of the Invention
Valsartan, an angiotensin receptor blocker, is chemically described as N-(l- oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [l,l'-biphenyl]-4-yl]methyl]-L-valine. Its chemical structure is depicted in Formula I.
FORMULA I
Valsartan is indicated for the treatment of hypertension, treatment of heart failure, and reduction in cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Processes for the preparation of valsartan are described in U.S. Patent No.
5,399,578 and PCT Publication Nos. WO 2005/049588, WO 2005/049587, and WO 2005/051929, which are incorporated herein by reference. According to these processes, the drying of valsartan, such as vacuum tray drying, rotary vacuum drying, spray drying, or freeze drying, takes a very long time for completion and requires a separate step for micronization.
Summary of the Invention
The present invention provides a process for the preparation of micronized valsartan, wherein the process involves simultaneous drying and micronization steps. The process of the present invention requires a shorter time for the simultaneous drying and micronization steps. The present invention also provides micronized valsartan substantially free of ethyl acetate.
Detailed Description of the Invention
The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
A first aspect of the present invention provides a process for the preparation of micronized valsartan, wherein the process comprises subjecting valsartan to drying and micronization simultaneously.
A second aspect of the present invention provides valsartan, having a dgo particle size distribution of less than 60 microns, a dso of less than 30 microns, and a dio of less than 10 microns, prepared by a process which comprises subjecting valsartan to drying and
micronization simultaneously. Preferably, the valsartan obtained has a dgo particle size distribution of less than 40 microns, a dso of less than 20 microns, and a dio of less than 5 microns.
A third aspect of the present invention provides valsartan substantially free of ethyl acetate.
The valsartan used for preparing micronized valsartan may be prepared by any of the methods described in U.S. Patent No. 5,399,578 or PCT Publication Nos. WO 2005/049588 and WO 2005/049587. The valsartan used as a starting material may be crude valsartan. The crude valsartan, as used herein, refers to valsartan having an ethyl acetate content of 20,000 ppm or more.
The simultaneous drying and micronization of valsartan is carried out using an instrument such as a turbo dryer. Any instrument that can simultaneously perform the drying and micronization can be used. The turbo dryer used in the present invention may be selected from any of the commercially available turbo dryers.
The simultaneous drying and micronization of valsartan is carried out for about 25 hours to about 55 hours, for example, for 35 hours to 50 hours, in a turbo dryer. The drying and
micronization steps are carried out at a temperature or temperature range of about 40°C to about 70°C, for example, at 50°C to 60°C, in a turbo dryer.
Accordingly, the crude valsartan is subjected to a turbo dryer. The simultaneous drying and micronization is carried out in a turbo dryer at about 40°C to about 70°C for about 25 hours to about 55 hours. The dried and micronized valsartan is obtained.
In the context of present invention, "valsartan substantially free of ethyl acetate" refers to a valsartan having an ethyl acetate content of less than 600 ppm. Preferably, the valsartan substantially free of ethyl acetate contains less than 500 ppm of ethyl acetate.
In an embodiment of this invention, valsartan having an ethyl acetate content of less than 600 ppm and a ds>o particle size distribution of less than 60 microns, a dso of less than 30 microns, and a dio of less than 10 microns, is provided.
Instrument Details
Turbo Dryer: Turbo Dryer, Volume - 5 Liters
Vacuum Tray Dryer (VTD): 2 VTDs run parallel to each other (SS, 48 trays and SS, 36 trays)
Rotary Vacuum Dryer (RVD): 2 RVDs run parallel to each other (2.5 Kl and 2.2 Kl)
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.
Reference Example: Process for the Preparation of Valsartan
Crude valsartan (350 Kg) was added to a vacuum tray dryer for 12 hours. The material obtained was subjected to milling for 24 hours and then dried in a rotary vacuum dryer for 104 hours. The following parameters were controlled in the drying process:
Dryer: Vacuum Tray Dryer (VTD) and Rotary Vacuum Dryer (RVD)
Temperature range: 50°C to 54°C
Vacuum: 600 mm to 700 mm of Hg in a vacuum tray dryer and 640 mm to 700 mm of
Hg in a rotary vacuum dryer.
Jacket hot water temperature : 50°C to 55°C
Yield: 208.2 kg
Total time for drying and micronization: 140 hours
Final ethyl acetate content: 1293 ppm
Final Particle Size by Malvern (in μ): dgo- 42μ; d$o'. 1 1 μ; and di0: 3 μ.
Example: Process for the Preparation of Valsartan
Crude valsartan (1.5 kg; ethyl acetate content: 7889 ppm) was added to a turbo dryer for
40 hours to 48 hours. The following parameters were controlled during the drying and micronization steps:
Dryer: Turbo dryer
Temperature: 54°C to 55°C
Vacuum: 680 mm of Hg
Jacket hot water temperature : 50°C to 55°C
Rotations per minute (RPM): 200 rpm
Yield: 1.0 kg.
Total time for drying and micronization: 43 hours
Initial ethyl acetate content: 7889 ppm
Final ethyl acetate content: 440 ppm
Final Particle Size by Malvern (in μ): dgo- 38.86 μ; d$o'. 12.35 μ; and di0: 2.59 μ.
As should be evident from the above examples, the process of simultaneous drying and micronizing reduced the processing time from 140 hours (reference example) to 43 hours. In reducing the processing time, the simultaneous processing also produced a valsartan product having a significantly lower final ethyl acetate content (1293 ppm vs 440 ppm). This result is unexpected and surprising because the valsartan in the two examples was subjected to very similar processing conditions. As such, one of skill in the art would expect the final ethyl acetate content to be similar. In fact, because the valsartan was subjected to elevated temperatures and vacuum for almost 100 additional hours, one of skill in the art would expect those processing conditions to result in a lower ethyl acetate content.
The process according to the invention also is believed to reduce the costs associated with producing the micronized and dried valsartan active ingredient compared to known techniques. Such costs include energy costs for both operating the equipment and heating the
valsartan as well as the manpower costs to operate the equipment. These reduced costs provide significant financial advantages to a company producing the valsartan according to this method.
Claims
1. A process for the preparation of micronized valsartan, wherein the process comprises subjecting valsartan to drying and micronization simultaneously.
2. Valsartan having a dgo particle size distribution of less than 60 microns, a dso of less than 30 microns, and a dio of less than 10 microns, prepared by a process which comprises subjecting valsartan to drying and micronization simultaneously.
3. Valsartan substantially free of ethyl acetate.
4. The process according to claim 1 or claim 2, wherein the simultaneous drying and micronization of valsartan is carried out using a turbo dryer.
5. The process according to claim 1 or claim 2, wherein the simultaneous drying and micronization of valsartan is carried out at a temperature of about 40°C to about 70°C.
6. The process according to claim 1 or claim 2, wherein the simultaneous drying and micronization of valsartan is carried out for about 25 hours to about 55 hours.
7. The process according to claim 1, wherein the micronized valsartan obtained has a ds>o particle size distribution of less than 60 microns, a dso of less than 30 microns, and a dio of less than 10 microns.
8. The process according to claim 7, wherein the micronized valsartan obtained has an ethyl acetate content of less than 600 ppm.
9. The valsartan of claim 3, wherein the content of ethyl acetate is less than 600 ppm.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3114DE2013 | 2013-10-18 | ||
| IN3114/DEL/2013 | 2013-10-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2015056219A1 true WO2015056219A1 (en) | 2015-04-23 |
Family
ID=51844805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2014/065383 Ceased WO2015056219A1 (en) | 2013-10-18 | 2014-10-16 | Process for simultaneous drying and micronization of valsartan |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2015056219A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399578A (en) | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
| WO2005049587A1 (en) | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for preparation of biphenyl tetrazole |
| WO2005049588A1 (en) | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for isolation of valsartan |
| WO2005051929A1 (en) | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Conversion of aromatic nitriles into tetrazoles |
| WO2010091169A2 (en) * | 2009-02-04 | 2010-08-12 | Dr. Reddy's Laboratories Ltd. | Preparation of valsartan |
-
2014
- 2014-10-16 WO PCT/IB2014/065383 patent/WO2015056219A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399578A (en) | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
| WO2005049587A1 (en) | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for preparation of biphenyl tetrazole |
| WO2005049588A1 (en) | 2003-11-21 | 2005-06-02 | Ranbaxy Laboratories Limited | Process for isolation of valsartan |
| WO2005051929A1 (en) | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Conversion of aromatic nitriles into tetrazoles |
| WO2010091169A2 (en) * | 2009-02-04 | 2010-08-12 | Dr. Reddy's Laboratories Ltd. | Preparation of valsartan |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102827153B (en) | Crystal formation of Azilsartan and preparation method thereof | |
| CN106916177B (en) | A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes | |
| JP2016505071A5 (en) | ||
| CN103974949A (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
| DE2726618A1 (en) | ALLYL CARBONIC ACID ESTER, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
| EP4119546A1 (en) | Bifunctional compound, preparation method therefor, and use thereof | |
| MX2011011756A (en) | Salts of 3-pentylphenylacetic acid and pharmaceutical uses thereof. | |
| JP2017537092A (en) | Formulation containing chlorogenic acid crystal form and use thereof | |
| CN102367254A (en) | More stable doxofylline compound and pharmaceutical composite thereof | |
| JP2014530204A5 (en) | ||
| WO2015056219A1 (en) | Process for simultaneous drying and micronization of valsartan | |
| CN105218479B (en) | The new derivatives, preparation method and application of 2- [3- cyano-4-isobutoxy phenyl] -4- methylthiazol-5-formic acid | |
| CN106470981B (en) | Novel derivatives of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid, their preparation method and application | |
| RU2485102C2 (en) | Cyclic indole-3-carboxamide, production and use thereof as therapeutic preparations | |
| EP2601180A1 (en) | Highly crystalline valsartan | |
| WO2010045582A3 (en) | Compositions and methods for treating or preventing hypoxic or ischemic injury | |
| CN104211693B (en) | Rivaroxaban crystalline form, preparation method and application | |
| JP5990089B2 (en) | Composition comprising salted fermented ginseng extract | |
| CN105198865A (en) | Puerarin Dihydrate | |
| WO2014030082A1 (en) | Novel method to obtain olmesartan medoxomil with reduced particle size | |
| KR20150042275A (en) | Pharmaceutical formulations containing 3-(4-cinnamyl-l-piperazinyl) amino derivatives of 3-formylrifamycin sv and 3-formylrifamycin s and a process of their preparation | |
| Khalili et al. | The effects of aqueous extract of vaccinium arctostaphylos leaves on blood pressure in renal hypertensive rats | |
| JP7282350B2 (en) | METHOD FOR PRODUCING PROTEIN GLYCATION INHIBITOR | |
| CN104402801B (en) | Method for separating DNJ and preparing DNJ nanosuspension | |
| CN103408626B (en) | Halometasone polycrystalline type and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14792607 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 14792607 Country of ref document: EP Kind code of ref document: A1 |