The present invention relates to stable Form I of ritonavir and a process for preparation of Form I of Ritonavir.
Ritonavir of Formula I is chemically, [5S-(5R*,8R*,10R*,11R*)]-10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-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 Removed)
US patent No. 5,541,206 (the '206 patent) and its equivalent PCT Patent Application WO 94/14436 and US Patent No 5,567,823 (the '823 patent) discloses process for 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. The disclosure further suggests that the Form I of ritonavir obtained as per the '206 and the '823 patent have more than 5 or 10% of Form II in it. Further it also provides a process for the preparation of Form I of Ritonavir from Form II of Ritonavir where in the process involves the use of seed crystals of Form I of Ritonavir.
US Patent Application US 2004/0024031 provide Form III, Form IV and Form V of Ritonavir and provide process for their preparation. It also provides process for the preparation of Form I and Form II of Ritonavir.
Organic Process Research & Development 2000, 4, 413-417 provides process for the preparation of Form I of Ritonavir with less than 3% Form II of Ritonavir contamination wherein the process involves the use of seed crystals of Form I of Ritonavir. It also provides a process for the preparation of Form II of Ritonavir.
The present inventors have found a simple process for the preparation of Form I of Ritonavir, wherein the process is characterized by the fact that, 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 II of ritonavir when detected by X-Ray Powder Diffraction (XRPD).
A first aspect of the invention provides a process for the preparation of Form I of Ritonavir, which comprises of:
a) dissolving ritonavir in an organic solvent,
b) concentrating the solution to get residue
c) adding an anti-solvent to the residue obtained in step b),
d) isolating Form I of Ritonavir from the reaction mixture thereof,
wherein the process is characterized by the fact that, no seed crystals are used.
Ritonavir can be prepared by process known to a skilled artisan. The so obtained Ritonavir is suspended in an organic solvent selected from a group comprising of esters, lower alkanols, ethers, ketones, polar aprotic solvents, halogenated hydrocarbons or mixtures thereof. To the mixture so obtained an anti-solvent selected from a group comprising of C5-7 straight or branched chain alkanes, C5-7 cycloalkanes,
C4-12 ethers, petroleum ether or mixtures thereof is added. The reaction mass is stirred, filtered and dried to get Form I of Ritonavir.
A second aspect of the invention provides a stable Form I of ritonavir having no detectable quantity of Form II of ritonavir.
It has been observed that upon storage the Form I of ritonavir has a tendency to get converted to Form II of ritonavir. There is a significant difference in the solubility of Form I and Form II in water or dissolution media. A slow conversion of Form I to Form II causes lot of problem to the formulation chemist. The quantities of excipients required for dissolving the bulk powder for preparation of formulation vary significantly. It is therefore advisable to either have a stable form I of ritonavir or Form II of ritonavir as starting material for preparation of dosage form. Due to less solubility Form II is not desirable. Stable form I of ritonavir has no detectable quantity of Form II and is also stable under normal storage conditions.
Figure 1 depicts XRD of Form I of Ritonavir.
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 are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF FORM I OF RITONAVIR
Ritonavir (5.0 g) was suspended in ethyl acetate (37.5 ml). The mixture was stirred and heated at 60°C till the entire solid dissolved. The solution was filtered to remove any undissolved suspended particles. The filtrate was concentrated under vacuum at 60°C completely to give an oily residue, which was cooled at 30°C and N-heptane (50 ml) was charged. The contents were stirred for 16-17 hours at 30°C. N-heptane (50 ml) was
added to the thick slurry and stirred for another 4 hours at 30°C. The solid was filtered and dried under vacuum at 60°C for 24 hours. Yield: 4.5 g

WE CLAIM:
1. A process for the preparation of Form I of Ritonavir, which comprises of:
a) dissolving ritonavir in an organic solvent,
b) concentrating the solution to get residue
c) adding an anti-solvent to the residue obtained in step b),
d) isolating Form I of Ritonavir from the reaction mixture thereof,
wherein the process is characterized by the fact that, no seed crystals are used.
2. A process according to claim 1, wherein ritonavir is dissolved in organic solvent selected from a group comprising of esters, lower alkanols, ethers, ketones, polar aprotic solvents, halogenated hydrocarbons or mixtures thereof.
3. A process according to claim 1, wherein anti-solvent is selected from selected from a group comprising of C5-7 straight or branched chain alkane, C5-7 cycloalkane, C4-12 ethers, petroleum ether or mixtures thereof.
4. A stable Form I of ritonavir having no detectable quantity of Form II of ritonavir.

5. A pharmaceutical composition comprising stable Form I of Ritonavir having no detectable quantity of Form II of ritonavir.
6. A method of treating HIV-infection comprising administering to a mammal in need thereof a therapeutically effective amount of stable Form I of Ritonavir having no detectable quantity of Form II of ritonavir either alone or in combination with other anti-retroviral agents.