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 di ₀ : 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 di ₀ : 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.