Field of Invention:
The present invention relates to an alternate process for the preparation of Stavudine polymorphic form-I from a mixture containing one or more polymorphic forms.
Background of the Invention:
Stavudine chemically is 2\3'-didehydro-3'-deoxythymidine has the formula given below

and also known as d4T which is approved by U.S. Food & Drug Administration for the therapeutic treatment of patients infected with retroviruses.
U.S. patent No.4,904,770 discloses the existence of three polymorphic forms namely Form-I, Form-II & Form-Ill in Stavudine. U.S. patent 4,904,770 also discloses Form-I & Form-II are anhydrous forms, where as Form-Ill is hydrated form and Form-I is kinetically most stable and cannot be converted to Form-II & HI.
U.S. patent No.4,978,655 discloses a synthetic route for the preparation of Stavudine in which oxetane is reacted with potassium tert butoxide using DMSO as a solvent. In this patent inventors did not discussed about the polymorphic form of the final product.
U.S. Patent No.5,608,048 discloses a process for obtaining Stavudine Form-I from a mixture containing one or more of polymorphic Forms I, II and III by crystallizing in a single anhydrous solvent such as methanol, ethanol, n-propanol, isopropanol, acetonitrile and ethyl acetate with a controlled rate of cooling i.e. rate of cooling not exceeding 20 C per hour.

U.S. Patent No.6,635,753 discloses the novel stavudine solvates of N,N-dimethylacetamide, N,N-dimethylacrylamide, N,N-dimethylpropionamide etc.
U.S. 2003/0225279 discloses a process for obtaining stavudine Form-I from a mixture of polymorphic Form-I and at least one of the polymorphic Form-II and III using Solution-Enhanced Dispersion by Supercritical fluids (SEDS) technique.
There is a long felt need of the industry to provide an alternate process for the preparation of Stavudine Form-I by using mixture of solvents with improved polymorphic purity.
Summary of the invention:
The main object of the present invention is to provide a consistent process for the preparation of Stavudine polymorphic Form-I
Another object of the present invention is to provide an alternate process for the preparation of stable crystalline Stavudine polymorphic Form-I.
Yet another object of the present invention is to provide a process for the preparation of Stavudine polymorphic Form-I with improved polymorphic purity.
Accordingly in the present invention, mixture containing one or more polymorphic forms of stavudine is dissolved in a mixture of solvents at elevated temperatures followed by cooling at a controlled rate and isolation yields pure polymorphic Form-I.
Detailed description of the invention:
Thus in accordance with the present invention preparation of Stavudine polymorphic Form-I comprises the following steps.
- Suspending stavudine in a mixture of solvents selected from the group consisting of alkanols, organic esters and organic acids
- Raising the temperature to elevated temperature

- Checking for the clear solution
- Maintaining for some time at the same temperature
- Cooling the reaction mass slowly to around 48°C
- Seeding the reaction mass with pure form-I
- Allowing the reaction mass to cool to 25°C over period of time

- Maintaining for lhr at 25°C
- Slowly cooling the mass to 10°C at a rate of 5° per 10 min
- Maintaining for lhr at 10°C
- Isolating and drying the product to get Stavudine form-I.
The invention will be more clearly understood with reference to the following Examples.
Example-1: Preparation of Stavudine form-I
To a clean flask charged 160 ml mixture of methyl acetate (91%) + methanol (2.5%) + acetic acid (6.5%). Charged Stavudine (lOg) under stirring. Heated the mixture to 54-55°C with slow stirring for clear solution. Maintained the reaction mass for one hour and stopped heating. Allowed the mixture to cool. At 48°C seeded the mixture with pure form-I and allowed it to cool from 55 to 25°C in 4 hrs. Then maintained for one hour at 25°C and cooled to 10°C at a rate 10°C per 20 min. Maintained for one hour at 10°C, filtered the product and dried. Yield: 6.1 g.
Few more experiments are carried out in similar process using the solvents in different ratios as described in Table-1.

We claim:
1. A process for the preparation of Stavudine form-I comprises the following steps.
- Suspending Stavudine in a mixture of solvents selected from the group consisting of alkanols, organic esters and organic acids
- Raising the temperature to elevated temperature
- Checking for the clear solution
- Maintaining for some time at the same temperature
- Cooling the reaction mass slowly to around 48°C
- Seeding the reaction mass with pure form-I
- Allowing the reaction mass to cool to 25°C over period of time
- Maintaining for lhr at 25°C
- Slowly cooling the mass to 10°C at a rate of 5° per 10 min
- Maintaining for lhr at 25°C
- Isolating and drying to get Stavudine form-I
2. The process as claimed in claim 1, wherein the organic solvent is a mixture of methyl
acetate, methanol and acetic acid
3. The process as claimed in claim 1, wherein the ratio of methyl acetate, methanol and
acetic acid is according to Table-1
Dated: 6th December 2004