DESC:FIELD OF INVENTION
The present invention provides a process for obtaining highly pure crystalline form of Oseltamivir free base.

BACKGROUND OF THE INVENTION
Oseltamivir, chemically Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate compound of formula I is an orally active inhibitor of influenza virus neuraminidase. Oseltamivir is represented by the following structure:

- Formula I
Various processes for preparation of oseltamivir and its pharmaceutically acceptable salts were disclosed, for example, in US 5,763,483, J. Org. Chem., Vol. 63, No. 13, 1998 (page: 4545-4550), J. Amer. Chem. Soc., Vol. 115, No. 4, 1997 (Page: 681-690), US 5,952,375,
WO 98/07685.

WO 98/07685 described in example 11 that crystalline oseltamivir free base is obtained by concentrating reaction mass containing oseltamivir free base to obtain oseltamivir free base as a foam, which is solidified on standing. It has been found that the process described in WO 98/07685 does not produce the well-defined crystalline form of oseltamivir free base in a consistently reproducible manner.

US 7,732,632 B2 discloses Oseltamivir crystalline form characterised by peaks at 2? 4.8, 5.2, 6.9, 8.7, 9.9, 10.5, 11.9, 13.0, 14.5, 17.2, 17.3, 18.4, 18.6, 19.9, 21.0, 21.3, 22.2, 22.5, 23.9 and 24.7 degrees and prepared by suspending or dissolving impure or non-crystalline oseltamivir free base in a hydrocarbon solvent and then isolating crystals to obtain oseltamivir free base in crystalline form.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
Oseltamivir free base obtained by these processes are not satisfactory from purity point of view and there is a need for a process for obtaining consistently reproducible pure crystalline oseltamivir free base.

Also the present inventors have observed that by using solvent alone, haziness is observed which is difficult in plant scale.

The present inventors have now found a process for the preparation of crystalline oseltamivir free base that can be used to obtain pharmaceutically acceptable salts of oseltamivir in high purity.
OBJECTIVES OF THE INVENTION
An objective of the present invention is to provide crystalline form of Oseltamivir free base designated as Form H.

Another objective of the present invention is to provide a process for the preparation of crystalline Oseltamivir free base Form H which is commercially viable and industrially applicable.

Another objective of the present invention is to provide crystalline Oseltamivir free base Form H which can be used to obtain pharmaceutically acceptable salts of Oseltamivir in high purity.

SUMMARY OF THE INVENTION
The present invention relates to crystalline Oseltamivir free base designated as Form H which is characterized by Powder X-Ray Diffraction, having the °2? characteristic peaks at 5.1, 10.3, 10.5 ± 0.2 degrees.

In another embodiment the present invention relates to a process for the preparation of crystalline Oseltamivir free base Form H, which comprises:
a. treating Oseltamivir free base in a solvent or mixtures thereof;
b. adding an anti-solvent
d. isolating crystalline Oseltamivir free base Form H.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows powder X-ray diffractogram pattern of crystalline Oseltamivir free base Form H.

X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- a radiation. Adequate sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 increment and scan speed of 0.2 Sec/Step. 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.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to Oseltamivir free base crystalline form designated as Form H having °2? characteristic peaks at 5.1, 10.3, 10.5 ± 0.2 degrees, further characterized by having the peaks at 8.2, 14.4 ± 0.2 degrees.

In another aspect of the present invention provides a process for the preparation of crystalline Oseltamivir free base Form H, which comprises treating Oseltamivir free base in a solvent or mixtures thereof, wherein the solvent is ester solvent; stirring the mixture of step (a) for about 15 – 30 minutes; adding an anti-solvent is selected from hydrocarbon solvent; and isolating crystalline Oseltamivir free base Form H.

In another embodiment of the present invention ester solvent is selected from the group comprising of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof.

In another embodiment of the present invention, stirring is carried out at temperature of reflux to room temperature.

In another embodiment of the present invention, hydrocarbon solvent is selected from the group comprising of n-hexane, n-heptane, cyclohexane, toluene, xylene and a mixture thereof.

In another embodiment of the present invention, isolation is carried out by conventional methods selected from filtration, concentration, precipitation.

EXAMPLES
Reference example
Oseltamivir phosphate (20 gm, HPLC purity: 97%) is stirred with water (100 ml) and methylene chloride (100 ml) for 10 minutes at 25-30° C. and then pH of the mass is adjusted to 9-10 with liquor ammonia. Separated the layers, the organic layer is subjected to carbon treatment and filtered on hiflo bed. Washed the hiflo bed with methylene chloride (20 ml) and then distilled the organic layer under vacuum at 40° C. to give 16.5 gm of oseltamivir free base as a residue.
Step-(b):
To the residue obtained in step-(a) is added n-heptane (100 ml) and stirred for 1 hour at 25-30° C. Filtered the solid and dried to give 13 gm of pure oseltamivir free base.

Example 1.
Oseltamivir was taken in ethylacetate and stirred for 15 minutes at 50°C. Cooled the reaction mass and added cyclohexane and stirred for 4 hours at 30.0 ± 5.0°C. The solid thus obtained was filtered , washed with cylcohexane and dried to yield crystalline Oseltamivir free base Form H .
,CLAIMS:We claim:

1. A process for the preparation of crystalline Oseltamivir free base Form H, which comprises:
a. treating Oseltamivir free base in a solvent or mixtures thereof;
b. adding an anti-solvent; and
d. isolating crystalline Oseltamivir free base Form H, wherein crystalline Oseltamivir free base Form H is characterized by Powder X-Ray Diffraction, having °2? characteristic peaks at 5.1, 10.3, 10.5 ± 0.2 degrees.

2. The process according to claim 1, wherein the solvent is ester solvent selected from the group comprising of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof.

3. The process according to claim 1, wherein the anti-solvent selected from hydrocarbon solvent which is selected from the group comprising of n-hexane, n-heptane, cyclohexane, toluene, xylene and a mixture thereof.