PROCESS FOR THE PREPARATION OF FORM I AND FORIVl II OF

Field of The Invention The present invention relates to processes for the preparation of Form I and Form

II of Ritonavir.

Background of The Invention

Ritonavir of Formula I is chemically, [5S-(5R*,8R* _J 10R* ₅ l lR*)]-10^Hydroxy-2- mettiyl-5-(l-methylethyl)-l-[2-a-methyleihyl)-4-ihiazolyl]-3 _> 6-dioxo-8,ll - bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester and is indicated in combination with other anti-retroviral agents for the treatment of HIV- infection.

Formula I U.S. Patent No. 5,541 ,206 (the '206 patent) and its equivalent PCT Patent

Application WO 94/14436, and U.S. Patent No 5,567,823 (the '823 patent) discloses a process for the preparation of Ritonavir,

PCT Patent Application WO 00/04016 (the '016 application) provides processes for preparation of crystalline Form II and amorphous Ritonavir. The disclosure of the '016 application suggests that the product obtained as per the processes of the '206 patent and the "823 patent is Form I of ritonavir, That disclosure provides a process for the preparation of Form T of Ritonavir from Form ϊI of Ritonavir wherein seed crystals of Form i of Ritonavir are used. That disclosure also provides a process for the

preparation of Form U of Ritonavir from Form I of Ritonavir or a mixture of Form I and

Form II of Ritonavir wherein the process involves the use of seed crystals of (2S)-N-((LS)- l-Beπzyl-2-((4S,5S)~4-ben2yl-2~oxo-l-3-oxazolidin-5-yl)ethy l)-2-((((2-isopropy[-l,3- ιhiazol~4-yl)methyl)amino)carbofiyl)amino)-3-methylbutaiiam ide or Form II of Ritonavir. U.S. Patent Application US 2004/0024031 describes Form III, Form IV and Form

V of Ritonavir, and provides processes for their preparation. It also provides a process for the preparation of Form 1 of Ritonavir.

Org, Proc. Res. & Dew, (2000), 4, 413-417 provides a process for the preparation of Form I of Ritonavir contaminated with less than 3% Form II of Ritonavir, wherein seed crystals of Form I of Ritonavir are used. It also provides a process for the preparation of Form II of Ritonavir wherein seed crystals of Form II of Ritonavir are used.

Summary of the Invention

The present inventors have found a simple process for the preparation of Form I and Form II of Ritonavir, wherein no seed crystals are used. As part of the present invention the term "Form I of Ritonavir" refers to Form I of ritonavir having less than 5% of Form ϊl of ritonavir as determined by X -Ray Powder Diffraction (XRPD).

A first aspect provides a process for the preparation of Form I of Ritonavir, comprising of: a) dissolving ritonavir in an organic solvent; b) contacting the solution obtained in step a) with an anti-solvent; and c) isolating Form I of Ritonavir from the reaction mixture thereof, wherein no seed crystals are used. Ritonavir can be prepared by processes known to skilled artisan. The so-obtained

Ritonavir is dissolved in an organic solvent, such as esters, lower alkanols, ethers, ketones, polar aprotic solvents, halogenated hydrocarbons or mixtures thereof. Sn some embodiments the organic solvent can be an ester, for example, ethyl acetate. The mixture so obtained is contacted with an anti-solvent wherein the anti-solvent can be Cs-? straight or branched chain alkanes, C ₆ - ₇ cycloalkanes, Cn _-I2 ethers,

petroleum ether or mixtures thereof is added. In some embodiments the anti-solvent can be ^¬ an alkane, for example, n -heptane. The addition can be completed in, for example, about 1-5 minutes, while maintaining the temperature at, for example, about 0-30°C. The reaction mass can be stirred, filtered and dried to get Form I of Ritonavir. A second aspect provides a process for the preparation of Form II of Ritonavir, comprising: a) dissolving ritonavir in an organic solvent; b) contacting an anti -solvent with the solution obtained in step a); and c) isolating Form I S of Ritonavir from the reaction mixture thereof, wherein no seed crystals are used.

Ritonavir can be prepared by processes known to skilled artisans. The so-obtained Ritonavir is dissolved in an organic solvent such as esters, lower alkanols, ethers, ketones, polar aprotic solvents, halogenated hydrocarbons or mixtures thereof. In some embodiments, the organic solvent can be an ester, for example, ethyl acetate. An anti- solvent such as C ₅ . ₇ straight or branched chain alkanes, C5.7 cycloalkanεs, C ₄ -U ethers, petroleum ether or mixtures thereof, is contacted with the solution so obtained. In some embodiments, the anti-solvent can be an alkane, such as n-heptane. The addition can be completed in for example, about 30-40 minutes, while maintaining the temperature at for example, about 40-50°C. The such as reaction mass is stirred, filtered and dried to get Form II of Ritonavir.

Figure 1 is an XRD (X- Ray powder Diffraction) spectrum of Form I of Ritonavir.

Figure Ia is a table listing the positions and intensities of spectral features found in Figure 1.

Figure 2 is an XRD (X-Ray powder Diffraction) spectrum of Form II of Ritonavir. Figure 2a is a table listing the positions and intensities of spectral features found in Figure 2.

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 arc intended to be included within the scope of the present invention.

Example 1: Preparation of Form I of Ritonavir

Ritonavir (100 g) was suspended in ethyl acetate (400 ml). The mixture was heated at 7O ⁰ C and stirred to get a clear solution. The solution was cooled to 5O ⁰ C. Activated charcoal (5 g) was added to the solution, stirred for 15 minutes at 55-5O ⁰ C and filtered through hyflobed. The hyflobed was washed with ethyl acetate (50 ml) and the filtrate was collected. The filtrate was charged into n-Heptane (1000 ml) at 20-25 ⁰ C in 2-3 minutes, maintaining the temperature at 20-25 ⁰ C and stirred for 4 hours at 2G-25°C. The solid obtained was filtered at 20-25 ⁰ C and washed with n-heptane (100 nil) by making slurry at 20-25 ⁰ C and dried to obtain the title compound, in a yield of 95g.

Example 2: Preparation of Form II of Ritonavir

Ritonavir (100 g) was suspended in ethyl acetate (400 ml), The mixture was heated at 7O ⁰ C and stirred to get a clear solution. The solution was cooled to 5O ⁰ C. Activated charcoal (5 g) was added to the solution, stirred for 15 minutes at 55-5O ⁰ C and filtered through hyflobed. The hyflobed was washed with ethyl acetate (50 ml) and the filtrate was collected. n-Heptane (1000 ml) was charged into the filtrate at.4()-50°C in 30-40 minutes, stirred at the same temperature for 1 hour, cooled to 20-25 ⁰ C and stirred for 4 hours at 20- 25 ⁰ C. The solid obtained was filtered at 20-25 ⁰ C and washed with n-heptane (100 m!) by making slurry at 20-25 ⁰ C and dried to obtain the title compound, in yield 95g.