Form 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULE 2006COMPLETE SPECIFICATION [See section 10 and rule 13]

1. TITLE OF THE INVENTION
"A process for preparation of Valsartan"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies ACT 1956 vvu
(c) ADDRESS: B.S.D. Marg, Govandi,Mumbai 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and the manner in which it is to be performed.


A process for preparation of Valsartan Technical field
The present invention relates to a process to prepare micronised Valsartan.

Formula I
BACKGROUND & PRIOR ART
Valsartan also known as N-(l-Oxopentyl)-N-[[2'-(lH-tetrazoI-5-yl)[l,l'-biphenyl]-4-yl]methyl]-L-valine [Formula 1] is an antihypertensive agent. Synthesis of Valsartan is disclosed in U.S.Patents 5,399,578, 6271,375, 5,260,325, WO 02/006253, WO 99/67231, Moenius et. al., Int. J. Labeled compounds and radio pharmaceuticals., 43(13), 1245-1252, 2000 and Peter et al, Bioorganic & Med. Chem. Lett., 4(1), 29-34, 1994.
Valsartan is an active angiotensin II antagonist specifically acting on the ATI receptor sub type. U. S. Patent 5,399,578 discloses use of Valsartan as

antihypertensive agent. U.S.Patents 6,465,502 disclose use of valsartan in the treatment of Lung cancer.
U.S. Patent 5,399,578 discloses crystallization of Valsartan from ethyl acetate having melting point in the range of 105-115°C. The patent also reports crystallization of Valsartan from diisopropyl ether with melting point in the range of 116-117°C.
Int. J. Labeled compounds and radio pharmaceuticals, 43(13), 1245-1252, 2000 reports crystallization of Valsartan from 1:1 mixture of ethyl acetate: hexane.
WO04083192 discloses process to prepare highly pure amorphous Valsartan along with eleven crystalline polymorphic forms. Further WO 03089417 describes two crystalline polymorphic forms of Valsartan.
WO4087681 discloses a process for preparation of novel amorphous form of valsartan, by spray drying an alcoholic solution of valsartan. The patent discloses a process for preparation of amorphous form but does not disclose any particle size. Particle size is a critical physical parameter and plays a crucial role in bioavailability.
It has been observed that particle size of Valsartan is d10 = 5.039m, d50 = 77.29m. and d90 = 383.55m, when crystallized by using solvent ethyl acetate as disclosed in prior art after passing through 30 mesh sieve. On micronization the particle size of Valsartan reduces to < l0m.. Valsartan is listed in USP Forum where, an absorption test is mentioned. The micronised Valsartan as obtained by known methods changes its physical appearance as well as fails an absorbance test.
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Rate of dissolution is an important solid state physical property of a drug substance. The rate of dissolution of drug in the aqueous stomach fluid has a therapeutic consequence as it imposes an upper limit on the rate at which the orally administrated drug can reach the blood stream of the patient.
The rate of dissolution can be substantially improved especially for water insoluble drug substance and a stable dissolution profile can be obtained by varying the particle size. Valsartan being insoluble in water, micronisation can improve the dissolution profile and hence bioavailability. Valsartan is heat sensitive, hygroscopic, and very abrasive in nature.
The conventional method of micronization of solid involves jet or fluid energy mills and ball mills. The basic principal in all these techniques involve application of force on the particle in the form of collision which will act at the imperfection in crystal surface, initiating crack propagation through the particle. As the size of the particle decrease, the number of imperfection decreases thereby the task of reducing the particle size becomes more difficult.
Another drawback of micronization like jet milling is that there is a friction amongst particle and between particles and the mill surface. It can be of concern if the material to be milled is abrasive thus causing considerable damage to the mill surface and contaminating the API. The method involves the collision of the solid particle, which will generate heat, and may results in thermal decomposition. Hence the technique is not suitable for heat sensitive compounds. The heat generated during micronization can also lead to change in the physical appearance, polymorphic form.
The present invention relates to the improvement of solid state characteristic properties, especially particle size of Valsartan without affecting its chemical activity as well as physical appearance.
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OBJECTIVES
A primary objective of the present invention is to provide micronised Valsartan.
Another objective is to provide micronized Valsartan without any physical deformity.
Another object of the present invention is to provide micronized Valsartan having improved bioavailability.
Another object of the present invention is to provide pharmaceutical composition comprising Valsartan with a particle size d9o < 10m.
Detailed Description
The present invention describes a process to prepare a Valsartan having particle size d9o< l0m.
The advantage of the process is that it directly gives Valsartan with particle size d9o< l0m without milling and hence does not affect the physical appearance of the end product.
The process described herein involves spray drying the solution of Valsartan in organic solvents. The spray drying process is economical, less energy consuming, can be run continuously leading to higher production, requires less maintenance and is industrially viable.
The micronized Valsartan is characterized by X-ray powder diffraction and is amorphous in nature but not purely amorphous (Fig 1).
The micronized Valsartan exhibits small endotherm at 66-69°C in DSC with melting enthalpy 10-16 J/g(figure 2).
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Concentration of Valsartan used for spray drying is preferably in the range of from 8-12 % weight/volume.
Spray drying is carried out in the inlet temperature range of 40-180° C and outlet temperature range 25-65°C.
As used herein, a solvent is any liquid substance, which has capacity to dissolve the organic compound Valsartan, either at room temperature or higher.
The present invention also provides micronized Valsartan as pharmaceutical compositions that are particularly useful for its angiotensin II antagonist activity. Such compositions comprise micronized Valsartan with pharmaceutically acceptable carriers and/or excipients known to one of skilled in the art. Suitable forms for oral administration, include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions. In general micronized Valsartan of the present invention may be administered at a daily dosage of about 50 mg to about 500 mg per day, and preferably about 50 mg to about 350 mg per day.
X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panaiytical, diffractometer equipped with accelerator detector using Copper Ka (y = 1.5406 Å radiation with scanning range between 4-50 9 at scanning speed of 27min.
Differential Scanning Calorimeter was performed on Mettler DSC 20 instrument. Samples of 2 mg to 3 mg weighed in aluminum crucibles with holes were scanned at a heating rate of 10°C per minute under nitrogen atmosphere at rate of 35 ml/min.
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Example 1
Preparation of Micronized Valsartan
Valsartan is prepared by known process and is dissolved in acetone at a temperature range of 30-40 °C. Concentration of Valsartan used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C. (d10=1.906, d50 = 4.134, d90 = 7.554)
Example 2
Preparation of Micronized Valsartan
Valsartan is prepared by known process and is dissolved in acetone containing 10% water at a temperature range of 30-40 °C. Concentration of Valsartan used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C. (d10=l -686, d50 = 4.420, d90 = 8.684)
Example 3
Preparation of Micronized Valsartan
Valsartan is prepared by known process and is dissolved in Ethyl acetate at a temperature range of 30-40 C. Concentration of Valsartan used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C. (d10= 1.542, d50 = 3.850, d90 = 7.869)
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Example 4
Preparation of Micronized Valsartan
Valsartan is prepared by known process and is dissolved in MDC at a temperature range of 30-40 °C. Concentration of Valsartan used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120 C and outlet temperature 65°C. (d10=2.011, d50 = 4.636, d90 = 8.611)
Dated this the 23ra day of June, 2006
Dr K G Rajendran
Head-Knowledge Cell
UJSV Limited
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Abstract
The invention relates to a stable process to prepare micronised Valsartan and pharmaceutical compositions thereof. Valsartan is prepared by known process and then dissolved in an organic solvent and further spray dried to obtain Micronized Valsartan.
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