The application claims priority to the Indian patent application No.997/CHE/2008 filed on April 22,2008, the contents of which are incorporated by reference in their entirety.

Field of invention:

The present invention relates to novel crystalline forms of Lopinavir designated as Lopinavir form-A, Lopinavir form-B and Lopinavir form-C. The present invention also relates to novel processes for the preparation of crystalline Lopinavir form-A, form-B, form-C, an amorphous Lopinavir and Lopinavir higher hydrate.

Back ground of the invention:

Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective and recently approved HIV protease inhibitor is (2S, 3S, 5S)-2-(-2, 6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl) amino-1,6-diphenylhexane (Lopinavir) structurally known as

Lopinavir is known to have utility for the inhibition of HIV protease and the inhibition of HIV infection. Lopinavir is particularly effective for the inhibition of HIV protease and for the inhibition of HIV infection when co-administered with Ritonavir (Keletra). Lopinavir, when combined with ritonavir, is also particularly effective for the inhibition of HIV infection when used in combination with one or more reverse transcriptase inhibitors and/or one or more other HIV protease inhibitors.

Pharmaceutical compositions comprising Lopinavir or a pharmaceutically acceptable salt and process for the preparation thereof is disclosed in US 5,914,332, wherein ethyl acetate and n-heptane is used for recrystallization to get crystalline Lopinavir. This patent also discloses processes for preparing amorphous. US '332 process gives a mixture of crystalline and amorphous. It is difficult to get the pure crystalline form of Lopinavir from prior art process.

US 6,864,369 patent describes the processes for the preparation of different polymorphic forms of Lopinavir such as crystalline hydrated and higher hydrated forms, crystalline type-II, crystalline type-Ill ethyl acetate solvate, crystalline type-Ill desolvated and crystalline type-IV non-solvated forms.

Keeping in view of the above mentioned shortcomings, there is still exists new crystalline Lopinavir and methods for obtaining new crystalline Lopinavir designated in various forms which address the short comings associated with the prior-art methods.

Object of the invention:

The main object of the present invention is to provide novel crystalline forms of Lopinavir designated as form-A, form-B and form-C.

Another object of the present invention is to provide novel processes for the preparation of crystalline forms of Lopinavir form-A, form-B, form-C, an amorphous Lopinavir and Lopinavir higher hydrate.

Summery of the invention:

The main aspect of the present invention is to provide novel crystalline forms of Lopinavir designated as form-A, form-B, form-C.

Another aspect of the present invention is to provide a novel crystalline Lopinavir form-A which is characterized by PXRD peaks at 7.09, 14.21,17.21,21.40, 21.74±0.2,20 values.

Yet another aspect of the present invention is to provide a novel crystalline Lopinavir form-B which is characterized by PXRD peaks at 9.60, 11.79, 12.39, 13.46, 15.88±O.2,20 values.

Yet another aspect of the present invention is to provide a novel crystalline Lopinavir form-C, which is characterized by PXRD peaks at 9.71, 12.39, 15.72, 16.58, 25.02±0.2, 20 values.

The main aspect of the present invention is to provide a novel process for the preparation of form-A, form-B, form-C, amorphous and higher hydrated form.

Yet another aspect of the present invention is to provide a novel process for the preparation of crystalline Lopinavir form-A comprising the steps of (a) dissolving Lopinavir in acetic acid (b) adding water and (c) isolating crystalline Lopinavir form-A.

Yet another aspect of the present invention is to provide a novel process for the preparation of crystalline Lopinavir form-B comprising the steps of (a) dissoloving Lopinavir in formic acid, (b) adding anti-solvent and (c) isolating crystalline polymorphic form-B.

Yet another aspect of the present invention is to provide a novel process for the preparation of crystalline Lopinavir form-C comprising the steps of (a) drying crystalline Lopinavir form-B at 40-50°C and (b) isolating crystalline polymorphic form-C.

Yet another aspect of the present invention is to provide a novel process for the preparation of amorphous Lopinavir comprising the steps of a) drying crystalline Lopinavir Form-B at 55-65°C and b) isolating amorphous Lopinavir.

Yet another aspect of the present invention is to provide a novel process for the preparation of Lopinavir higher hydrate comprising the steps of a) drying Lopinavir Form-A at 40-50°C and b) isolating Lopinavir higher hydrate.

Brief description of the drawings

Fig 1 is the X-ray powder diffraction pattern of Lopinavir form A

Fig 2 is the X-ray powder diffraction pattern of Lopinavir form B

Fig 3 is the Differential scanning calorimetric (DSC) curve of Lopinavir form B

Fig 4 is the TGA/DTG of crystalline Lopinavir form B

Fig 5 is the X-ray powder diffraction pattern of Lopinavir form C

Fig 6 is the X-ray powder diffraction pattern of Amorphous Lopinavir

Fig 7 is the X-ray powder diffraction pattern of Lopinavir higher hydrate

Powder X-ray Diffraction (PXRIT)

The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/0 configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out using the instrument DSC Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/minute over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/minute.

Thermogravimetric Analysis (TGA)

TGA is carried out using instrument TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/minute over a temperature range of 30°C-250°C purging with nitrogen at a flow rate of 25ml/minute.

Karl-Fisher

Water content was determined on Metrohm Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.

Detailed description of the invention:

The present invention relates to novel crystalline forms of Lopinavir designated as form-A, form-B and form-C. The invention further relates to novel processes for the preparation of crystalline Lopinavir form-A, form-B, form-C, an amorphous Lopinavir and Lopinavir higher hydrate.

In one embodiment of the present invention provides a crystalline Lopinavir form-A, characterized by powder X-ray diffraction pattern with peaks at 7.09±0.2, 10.82±0.2, 14.21±0.2, 16.28±0.2, 16.67±0.2, 17.21±0.2, 18.48±0.2, 21.40±0.2, 21.74±0.2, 22.56±0.2, 23.12±0.2, 23.44±0.2,23.92±0.2,24.13±0.2,28.48±0.2,26 values.

Yet another embodiment of the present invention provides crystalline Lopinavir form-A, as shown in figure 1.

Another embodiment of the present invention provides a novel process for the preparation of crystalline Lopinavir form A comprising the steps of:

a. dissolving Lopinavir in acetic acid
b. adding water and
c. isolating crystalline Lopinavir form-A

According to the present invention, there is provided a novel process for the preparation of crystalline Lopinavir form-A, wherein Lopinavir is suspended in acetic acid at 20-3 5°C, the resulting slurry is heated to about 80°C, preferably between 60-70°C to get a clear solution. The resulting solution is then cooled to 25-30°C followed by water addition over a period of 30-60 minutes at 25-30°C under stirring. The obtained solid is filtered to get crystalline Lopinavir form-A.

Yet another embodiment of the present invention is to provide a crystalline Lopinavir form-B, characterized by powder X-ray diffraction pattern with peaks at 9.60±0.2, 11.79±0.2, 12.39±0.2, 13.46±0.2, 15.52±0.2, 15.85±0.2, 16.25±0.2, 16.87±0.2, 17.27±0.2, 18.26±0.2, 18.67±0.2, 19.15±0.2, 19.86±0.2, 22.74±0.2, 23.30±0.2, 23.56±0.2, 23.93±0.2, 24.95±0.2,26 values.

Yet another embodiment of the present invention is to provide crystalline Lopinavir form-B, as shown in figure 2.

Yet another embodiment of the present invention is to provide crystalline Lopinavir form-B is further characterized by the DSC as shown in figure 3 with a broad melting endotherm between 80 to 110°C with peak maxima at about 83.18°, attributed to desolvation followed by melting of the product.

Yet another embodiment of the present invention, crystalline Lopinavir form-B is a Formic acid solvate having formic acid content of 5-7% which is analyzed by TGA as shown in figure 4 and moisture content typically ranging from 3-4% by weight supported by KF method.

Yet another embodiment of the present invention is to provide a novel process for the preparation of crystalline Lopinavir form-B comprising the steps of:

a) dissolving Lopinavir in formic acid
b) additing anti-solvent and

c) isolating crystalline Lopinavir form-B

According to the present invention, there is provided a novel process for the preparation of crystalline Lopinavir form-B, wherein Lopinavir is suspended in formic acid at 20-35 °C, the resulting slurry is heated to about 80°C preferably between 60-70°C to get the clear solution. The resulting solution is cooled to 25-30 °C, anti-solvent is added over a period of 30-60 minutes at 25-30 °C under stirring. The anti solvent is selected from water, ether solvent or mixtures thereof; ether solvent is selected from isopropyl ether. The obtained solid is filtered to get crystalline Lopinavir form-B.

Yet another embodiment of the present invention is to provide a novel crystalline Lopinavir form-C, characterized by powder X-ray diffraction pattern with peaks at 9.71±0.2, 10.09±0.2, 12.39±0.2, 13.54±0.2, 15.44±0.2, 15.72±0.2, 16.18±0.2, 16.58±0.2, 18.88±0.2, 19.55±0.2, 20.24±0.2, 20.78±0.2, 22.41±0.2, 23.13±0.2, 23.68±0.2, 24.39±0.2, 25.02±0.2, 26.11±0.2, 26 values.

Yet another embodiment of the present invention is to provide crystalline Lopinavir form-C, as shown in figure 5.

According to the present invention crystalline Lopinavir form-C is an anhydrous form having moisture content less than 0.5% by weight supported by KF method.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Lopinavir form-C comprising the steps of:

a) drying crystalline Lopinavir form-B at 40-50°C and
b) isolating crystalline Lopinavir form-C

Yet another embodiment of the present invention is to provide novel process for the preparation of amorphous Lopinavir, as shown in figure 6.

According to the present invention, there is provided a novel process for the preparation of Lopinavir form- C, whereas crystalline Lopinavir form-B is subjected to drying in a static dryer temperature between 40-50°C for several days under vacuum and isolating crystalline Lopinavir form-C.

A further embodiment of the present invention is to provide a process for the preparation of amorphous Lopinavir comprising the steps of

a) drying crystalline Lopinavir Form-B at 55-65°C and
b) isolating amorphous Lopinavir.

According to the present invention, there is provided a novel process for the preparation of amorphous Lopinavir, wherein crystalline Lopinavir form-B is subjected to drying in a static dryer temperature between 55-65°C for 3-5hrs under vacuum and isolating amorphous Lopinavir.

Yet another embodiment of the present invention is to provide Lopinavir higher hydrate as shown in figure 7.

Yet another embodiment, the present invention is to provide a novel process for the preparation of Lopinavir higher hydrate comprising the steps of,

a) drying crystalline Lopinavir form-A at 40-50°C and
b) isolating the Lopinavir higher hydrate .

According to the present invention, there is provided a novel process for the preparation of Lopinavir higher hydrate (type-1), wherein crystalline Lopinavir form-A is subjected to drying in a static dryer temperature between 40-50°C for 24 hrs under vacuum and isolating Lopinavir higher hydrate.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

EXAMPLES

Example 1: Preparation of Lopinavir form A

Lopinavir (l0g) is suspended in acetic acid (5ml) and stirred at 25-30°C for 10 min. The slurry is then heated at 60-65°C to get the clear solution. The resulting solution is then slowly cooled to 25-30°C and water (200ml) is added in about 30min. Initially gummy residue was formed which on further stirring at 25-30°C converts to a free solid. The solid obtained was filtered and identified as crystalline Lopinavir form A.

Example 2: Preparation of Lopinavir higher hydrate by drying Lopinavir form A

2g of Lopinavir form A obtained as described in example 1 was kept in a static dryer and heated at 50°C under vacuum for 24 hours. The resulting solid was identified as Lopinavir higher hydrate.

Example 3: Preparation of Lopinavir form B

Lopinavir (l0g) is suspended in formic acid (5ml) and stirred at 25-30°C for l0min. The slurry is then heated at 60-65°C to get the clear solution. The resulting solution is then slowly cooled to 25-30°C and water (200ml) is added in about 30min. Initially gummy residue was formed which on further stirring at 25-30°C converts to a free solid. The solid obtained was filtered and identified as crystalline Lopinavir form B.

Example 4: Preparation of Lopinavir form B

Lopinavir (25g) is suspended in formic acid (12.5ml) and stirred at 25-30°C for lmin. The slurry is then heated at 60-65 °C to get a clear solution. The resulting solution is then slowly cooled to 25-30°C and isopropyl ether (IPE, 750ml) is added in lh. Initially gummy residue was formed which on further stirring at 25-30°C for 16h converts to a free solid. The solid obtained was filtered and identified as crystalline Lopinavir form B.

Example 5: Preparation of Lopinavir form B

Lopinavir (l0g) is suspended in Formic acid (5ml) and stirred at 25-30°C for l0min. The slurry is then heated at 60-65°C to get a clear solution. The resulting solution is slowly cooled to 25-30°C and water (200ml) is added in 30min. Initially gummy residue was formed which on further stirring at 25-30°C converts to a free solid. The solid obtained was filtered. The solid was then suspended in water (100 ml) and maintained under stirring for 30min at 25-30°C. The resulting solid was filtered and dried at 50°C under vacuum for 40hrs. The solid obtained was identified as crystalline Lopinavir form B.

Example 6: Preparation of Lopinavir Form C by drying Lopinavir form B

2g of Lopinavir form B obtained as described in example 3 was kept in a static dryer and heated at 50°C under vacuum for 5-6 days. The resulting solid was identified as crystalline Lopinavir form C.

Example 7: Preparation of Amorphous Lopinavir by drying Lopinavir Form B

2g of Lopinavir form B obtained as described in example 3 was kept in a static dryer and heated at 65°C under vacuum for 3-5hr. The resulting solid was identified as amorphous Lopinavir.

We Claim:

1. Crystalline Lopinavir form-A, characterized by powder X-ray diffraction pattern as shown in Figure 1 and having the characteristic peaks at 7.09, 14.21, 17.21, 21.40, 21.74±0.2, 20 values.

2. A process for the preparation of crystalline Lopinavir form-A comprising steps of;

a. dissolving Lopinavir in acetic acid,

b. adding water and

c. isolating crystalline Lopinavir form-A.

3. Crystalline Lopinavir form-B, characterized by powder X-ray diffraction pattern as shown in Figure 2 and having the characteristic peaks at 9.60, 11.79, 12.39, 13.46, 15.88±0.2,20 values.

4. A process for the preparation of crystalline Lopinavir form-B comprising steps of;

a. dissolving Lopinavir in formic acid,

b. adding anti-solvent and

c. isolating crystalline Lopinavir form-B.

5. A process according to claim 4, wherein the anti-solvent is selected from water, ether solvent or mixtures thereof, ether solvent is selected from isopropyl ether.

6. Crystalline Lopinavir form-B, characterized by a DSC as shown in Figure 3.

7. Crystalline Lopinavir form-C, characterized by powder X-ray diffraction pattern as shown in Figure 5 and having the characteristic peaks at 9.71,12.39,15.72, 16.58, 25.02± 0.2, 20 values.

8. Process for the preparation of crystalline Lopinavir form-C, which comprising the steps of,

a. drying crystalline Lopinavir Form-B at 40-50°C and

b. isolating crystalline Lopinavir form-C.

9. Process for the preparation of amorphous Lopinavir ,which comprising the steps of

a. drying crystalline Lopinavir Form-B at 55-65 °C and

b. isolating amorphous Lopinavir.

10. Process for the preparation of Lopinavir higher hydrate comprising the steps of

a. drying Lopinavir form-A at 40-50°C and

b. isolating Lopinavir higher hydrate.