This application claims priority to Indian patent application No. 2549/CHE/2009 filed on Oct 22, 2009.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of stable Lamivudine Form I.
BACKGROUND OF THE INVENTION
Lamivudine of Formula I is an antiviral drug presently marketed by GlaxoSmithkline and is available as "EPIVIR", indicated for the treatment against retroviruses such as Human immuno deficiency virus (HIV), Hepatitis B virus (HBV) and Human T-Lymphotrophic virus (HTLV).
US 5047407 patent describes the preparation of (+)-(2R, cw)-4-amino-l-(2-hydroxymethyl-1, 3-oxathiolan-5-yl)-(l#)-pyrimidin-2-one (Lamivudine, 3TC), its antiviral activity and its use in pharmaceutical product.
US 5905082 patent provides a process for the preparation of Lamivudine by enzymatic separation. This patent also discloses the existence of two polymorphic forms of Lamivudine viz., needle-shaped crystals (Form-I) and bipyramidal crystals (Form-II). It also discloses the processes for the preparation of Form-I and Form-II.
WO 2007119248A1 application provides novel monoclinic crystals of Lamivudine and its process for the preparation.

WO 2008114279A2 application discloses the Form-Ill, Form-IV, Form-V and amorphous Lamivudine. It also discloses the processes for the preparation of Form-I and Form-II.
WO2009037538A2 application discloses a process for the preparation of Lamivudine of Form-I by dissolving Lamivudine in aqueous ethanol at 45-55°C then removing ethanol under reduced pressure below 42°C to obtain product as a solid residue, followed by addition of ethyl acetate / methyl isobutyl ketone to get Lamivudine Form-I.
Though several processes for the preparation of Lamivudine Form I have been reported, it has also been reported that Form I is unsuitable for formulation due to handling and stability reasons. Because of this reason, Lamivudine Form I had to be converted to Form II before being formulated. The process according to the present invention overcomes the prior art problems by using mixture of solvents which can be dried easily as well obtain a stable Lamivudine Form I.
SUMMARY OF THE INVENTION
In the main aspect, the present invention provides a process for the preparation of Lamivudine Form I comprising the steps of: a) dissolving Lamivudine in a mixture of solvents at elevated temperature; b) cooling the solution, and c) isolating stable Lamivudine Form I.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a representative X-ray diffraction pattern of stable Lamivudine Form I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for the preparation of stable Lamivudine Form I by dissolving Lamivudine in mixture of solvents at elevated temperature,

cooling the solution to ambient temperature and isolated the stable Lamivudine Form I.
In the embodiment, the present invention provides a process for the preparation of stable Lamivudine Form I comprising the steps of:
a) dissolving Lamivudine in a mixture of solvents at elevated temperature,
b) cooling the solution, and
c) isolating stable Lamivudine Form I.
According to the present invention, Lamivudine is suspended in a mixture of solvents and heated to elevated temperature (reflux) to get a clear solution, followed by cooled to ambient temperature and isolated stable Lamivudine Form I. The mixture of solvents is combination of water and acetone.
According to the present invention, Lamivudine Form I is having enhanced stability to heat and humidity. The obtained Lamivudine Form I is subjected to long-term (25°C and 60% relative humidity) and accelerated (at 40°C and 75% relative humidity) stability. The Lamivudine Form I is found to be chemically and physically very stable. There is no substantial increase in moisture content, PXRD pattern remains same as initial and no degradation observed in HPLC.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.
EXPERIMENTAL SECTION Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker D8 Discover powder diffractometer equipped with goniometer of 0/0

configuration and LynxEye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 26 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Example
Lamivudine (100 g) was dissolved in a mixture of acetone (1 L) and water (150 mL) at reflux temperature and maintained for 30 min. The reaction mass cooled to 25-35°C in a period of 30 min. and maintained for another 30 min. The separated solid was filtered, washed with chilled acetone (100 mL) and dried under reduced pressure at 40-45°C for 2-3h to yield stable Lamivudine Form-I (70 g) with HPLC purity - 99.96 %.
Solid State Stability
The solid state stability of Lamivudine Form I was determined by storing approximately 30 g of the sample at Long-term (25°C and 60% relative humidity) and accelerated (at 40°C and 75% relative humidity) stress conditions for 6 months. The samples were tested by PXRD, Karl-Fisher titrator and HPLC for final purity and degradation products. The results are given in the following Table 1. The Lamivudine Form I was found to be chemically and physically very stable. No substantial increase in moisture content was observed. The PXRD pattern remains same as initial and there is no degradation observed in HPLC.

Physical Stability
The physical stability of the Lamivudine Form I was determined by storing approximately 5.0 g of the sample a) at 50°C, b) at 70°C, c) at 90% Relative Humidity (RH) and d) by slurring in different solvents at 25-30°C. The samples are tested by PXRD and Karl-Fisher titrator. No discernible form conversion was observed in Form I under slurry, drying and humid conditions. The results are shown in the following Table 2.
The above mentioned observations indicate that Lamivudine Form I is quite stable unlike the prior art literature and can be used as an alternative to thermodynamically most stable Lamivudine Form II.

Claims
1 A process for the preparation of stable Lamivudine Form I comprising the steps
of:
a) dissolving Lamivudine in a mixture of solvent at elevated temperature,
b) cooling the solution, and
c) isolating stable Lamivudine Form I.

2 The process according to claim 1, wherein said solvent mixture is combination of water and acetone.
3 The process according to claim 1, wherein said elevated temperature is reflux temperature.
4 The process according to claim 1, wherein the solution is cooled to room temperature.
5 The process according to claim 1, wherein the said Lamivudine Form I is stable and is isolated by filtration.
6 The process according to claim 1, wherein the said Lamivudine Form I has long-term stability at 25°C and 60% relative humidity.
7 The process according to claim 1, wherein the said Lamivudine Form I has accelerated stability at 40°C and 75% relative humidity.