Amorphous ritonavir co-precipitated

This application is a U.S. national stage of international application No. PCT/IN2012/000357, filed on May 21, 2012, the disclosure of which is incorporated herein by reference in its entirety. Priority is claimed from IN Patent Application No. 1803/CHE/2011, filed on May 27, 2011, the disclosure of which is also incorporated herein by reference in its entirety.

The present invention relates to amorphous ritonavir co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it.

Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective HIV protease inhibitor was (5S,8S,10S,11S)-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, also known as Ritonavir.

Ritonavir and its process were disclosed in U.S. Pat. No. 5,541,206.

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).

Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.

Ritonavir can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

Crystalline Form II of ritonavir was disclosed in U.S. Pat. No. 6,894,171. According to the patent also described crystalline form I of ritonavir.

U.S. Pat. No. 7,205,413 disclosed crystalline Form III, Form IV and Form V of ritonavir.

U.S. Pat. No. 7,148,359 disclosed a substantially pure amorphous ritonavir.

Process for the preparation of substantially pure amorphous ritonavir was disclosed in U.S. Pat. No. 7,183,416. According to the patent, substantially pure amorphous ritonavir can be prepared by adding a solution of ritonavir containing methanol or methylene chloride to an anti-solvent such as hexane or methyl t-butyl ether and isolating.

Process for the preparation of amorphous ritonavir was described in Journal of Pharmaceutical Sciences, Vol. 90, No. 8, P. 1015-1025 by heating the ritonavir to 135° C. in oil bath, followed by rapid cooling using liquid nitrogen or cold water.

Process for the preparation of amorphous ritonavir was described in Journal of Pharmaceutical Sciences, Vol. 91, No. 8, P. 1863-1872 by freeze-drying.

U.S. Pat. No. 5,559,158 disclosed a solid pharmaceutical composition of ritonavir having the composition is encapsulated in a hard gelatin capsule.

U.S. Pat. No. 5,948,436 disclosed pharmaceutical composition comprising a solution of ritonavir having the solution is encapsulated in a hard gelatin capsule or a soft elastic gelatin capsule.

U.S. Pat. No. 7,364,752 disclosed compositions of ritonavir prepared by solid dispersion technique.

Preparation of amorphous Form of ritonavir was described in Journal of the American association of pharmaceutical scientists, Vol. 13, No. 9, P. 7473-7476, September 1996 by spray drying of the ritonavir on polyvinylpyrillodone (PVP) and ethanol. Similarly, preparation of amorphous Form of ritonavir was described by layering of the ritonavir on microcrystalline cellulose and silicon dioxide.

It was observed that the amorphous material obtained by the process described in U.S. Pat. No. 7,181,416 was changed into molten state within about 30 minutes. Thus, the amorphous form obtained by the process of U.S. Pat. No. 7,181,416 was shown to be unstable.

We have found a novel amorphous ritonavir co-precipitated on copovidone. The amorphous ritonavir co-precipitated on copovidone is stable, reproducible and so, the amorphous ritonavir co-precipitated on copovidone is suitable for formulating ritonavir. Normally amorphous Forms are hygroscopic. Amorphous ritonavir co-precipitated on copovidone is found to be non-hygroscopic.

Thus, an object of the present invention is to provide amorphous ritonavir co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it.

In one aspect, the present invention provides amorphous ritonavir co-precipitated on copovidone.

In another aspect, the present invention provides a process for the preparation of amorphous ritonavir co-precipitated on copovidone, which comprises:

a) dissolving a mixture of ritonavir and copovidone in an alcoholic solvent; and b) removing the solvent by drying at about 50 to 80° C. to obtain amorphous ritonavir co-precipitated on copovidone.

Yet in another aspect, the present invention provides a pharmaceutical composition comprising amorphous Form of ritonavir co-precipitated on copovidone and pharmaceutically acceptable excipients.

FIG. 1 is an X-ray powder diffraction spectrum of amorphous ritonavir co-precipitated on copovidone.

X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-Kα radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.019 degrees two theta per step and a step time of 1 second. 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.

The term “room temperature” refers to temperature at about 25 to 35° C.

According to one aspect of the present invention, there is provided amorphous ritonavir co-precipitated on copovidone.

Amorphous ritonavir co-precipitated on copovidone is found to be stable.

The powdered x-ray diffractogram (PXRD) of amorphous ritonavir co-precipitated on copovidone is shown in FIG. 1 .

According to another aspect of the present invention, there is provided a process for the preparation of amorphous ritonavir co-precipitated on copovidone, which comprises:

a) dissolving a mixture of ritonavir and copovidone in an alcoholic solvent; and b) removing the solvent by drying at about 50 to 80° C. to obtain amorphous ritonavir co-precipitated on copovidone.

Ritonavir used in step (a) may be any known crystalline or amorphous Forms.

Preferably the copovidone used in step (a) may be copovidone containing with aerosil and span 20.

The alcoholic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.

The dissolution in step (a) may be performed, for example, by heating the mixture of ritonavir and copovidone in the solvent.

Drying in step (b) may preferably be carried out at about 60 to 70° C. under high vacuum.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous Form of ritonavir co-precipitated on copovidone and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The amorphous Form of ritonavir co-precipitated on copovidone may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

The invention will now be further described by the following examples, which are illustrative rather than limiting.