FIELD OF THE INVENTION

The present invention relates to novel polymorphic forms of (3S,8S,9S,12S)-3,12-Bis(1,1- dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester and process for the preparation thereof.

BACKGROUND OF THE INVENTION
Atazanavir sulfate is an azapeptide inhibitor of HIV-1 protease. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6- [4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-entaazatetradecan6dioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C3BH52N607'H2S04, trade name is REYATAZ®. Atazanavir sulfate has the following structural formula:

Atazanavir sulfate has a good oral bioavailability and its favorable pharmacokinetic profile enabled it to be the first once-a-day protease inhibitor to treat AIDS (Acquired Immunodeficiency Syndrome).

The synthesis of Atazanavir was disclosed in WO 97/40029, J. Med. Chem. 1996, 39, 3203-3216, J. Med. Chem. 1998, 41, 3387-3401 and Org. Proc. Res. Dev. 2002, 6, 323-328. Several limitations of this original process presented scale-up challenges. An updated process was disclosed in WO 97/46514 and Org. Proc. Res. Dev. 2002, 12, 323-328, but scale-up challenges were still present as environmentally unfriendly solvents, such as highly flammable diethyl ether, were used.

U.S. Patent No. 6087383 assigned to Singh et al. disclosed the crystalline bisulfate salt of the azapeptide HIV protease inhibitor known as Atazanavir bisulfate form A. Also disclosed in Example 3 of Singh et al. is the preparation of atazanavir bisulfate in the form of Type-ll crystals which are hydrated, hygroscopic and crystalline in nature and Type-I crystals which appears to be an anhydrous/desolvated crystalline form.

U.S. publication No.200500256202 disclosed crystalline polymorphic forms of Atazanavir bisulfate form E3, Pattern C and process for the preparation of Atazanavir bisulfate form A, Form E3 and Pattern C material.

It has now been unexpectedly discovered that (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8- hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13- pentaazatetradecanedioic acid dimethyl ester (Atazanavir freebase) exhibited excellent solid state characteristics. A systematic study of the physicochemical properties of the Atazanavir freebase revealed that it existed in two different polymorphic forms designated as Form-I and Form-ll. The various solid state techniques have been tested such as X-ray powder diffraction (PXRD), Differential scanning calorimetry (DSC), Thermogravimetric Analyzer (TGA) and Single crystal
analysis.

Thus the present invention leads to a novel crystalline polymorphic of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester and process for the preparation thereof.

OBJECT OF THE INVENTION:
The main object of the present invention relates to a novel crystalline forms of (3S,8S,9S,12S)- 3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester (Atazanavir freebase) and process for their preparation thereof.

SUMMARY OF THE INVENTION:
The main aspect of the present invention relates to a novel crystalline forms of (3S,8S,9S,12S)- 3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester (Atazanavir freebase) and process for their preparation thereof.

Yet another aspect of the present inventionrelates to a crystalline (3S,8S,9S,12S)-3,12-Bis(1,1- dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, designated as Form I.

Yet another aspect of the present invention relates to a process for the preparation of crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6- [[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

Yet another aspect of the present invention relates to a process for purification of crystalline form I of (3S,8S,9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

Yet another aspect of the present invention relates to crystalline (3S,8S,9S,12S)-3,12-Bis(1,1- dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, designated as Form II.

Yet another aspect of the present invention relates to a process for the preparation of crystalline Form II of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

Yet another aspect of the present invention relates to single crystal structure of crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4.11-dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyOphenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the X-ray powder diffraction pattern of an Atazanavir freebase Form I.
Figure 2 illustrates the Differential scanning calorimetry thermo gram of an Atazanavir freebase form I.
Figure 3 illustrates TGA profile of Atazanavir freebase form I.
Figure 4 illustrates FT-IR spectrum of an Atazanavir freebase form I.
Figure 5 illustrates the X-ray powder diffraction pattern of an Atazanavir freebase Form II.
Figure 6 illustrates the Differential scanning calorimetry thermo gram of an Atazanavir freebase form II.
Figure 7 illustrates TGA profile of Atazanavir freebase form II.
Figure 8 illustrates FT-IR spectrum of an Atazanavir freebase form II.
Figure 9 illustrates single crystal structure of Atazanavir Form-I.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel Crystalline (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8- hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methylJ-2,5,6,10,13- pentaazatetradecanedioic acid dimethyl ester.

One embodiment the present invention related to crystalline forms of (33,88,93,12S)-3,12- Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, designated as Form I and Form II.

Another embodiment of the present invention relates to crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, characterized by X-ray diffraction having 2e-peaks at 6.8°, 8.3°, 10.6°, 11.9°, 12.8°, 17.5°, 18.5°, 19.2°, 22.8° and 23.3° ±0.2°.

Yet another embodiment of the present invention relates to PXRD pattern of crystalline Form I of (3S, 8S,9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, substantially as shown in Figure 1.

Yet another embodiment of the present invention relates to crystalline Form I (3S,8S,9S,12S)- 3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by a DSC thermogram exhibiting a single sharp melting at 212°C, substantially as shown in Figure 2.

Yet another embodiment of the present invention relates to Anhydrous crystalline form of (3S, 8S,9S, 12S)-3,12-Bis( 1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester

Yet another embodiment of the present invention relates to TGA thermogram of crystalline Form- (3S, 8S,9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyi)phenyi] methyi]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, showing weight loss of approximately around 0.7%, substantially as shown in Figure 3.

Another embodiment of the present invention relates to the FT-IR spectrum of crystalline Form I of (3S,8S,9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2- pyridinyOphenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester showing characteristic absorption bands at 1061, 1239, 1512, 1651, 1670, 1724, 3309, 3428 cm-1 substantially as shown in Figure 4

Yet another embodiment of the present invention relates to a process for the preparation of crystalline form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9- (phenylmethyl)-6-[[4-{2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester comprising the steps of i) dissolving Atazanavir sulphate in first solvent, ii) optionally adding second solvent and ill) isolating crystalline form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

In one embodiment, Atazanavir sulfate is dissolved in first solvent, optionally added with a second solvent for complete dissolution and isolated atazanavir free base.

According to the present invention, the first solvent is selected from Acetonitrile, n-Hexane, n-Pentane, Chloroform and Ethylacetate, 1,4 Dioxane, N-methyl pyrollidine. Acetone, Dimethyl sulfoxide, Dimethyl formamide or a mixture thereof and the second solvent is methanol.

According to the present invention, second solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; or a mixture thereof.

Yet another embodiment of the present invention relates to process for purification of crystalline form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethy!ethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester comprising the steps of i) adding atazanavir crystalline form 1 to an organic solvent and ii) isolating atazanavir crystalline form I.

According to the present invention the organic solvent used in the purification step is selected from water; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary- butyl alcohol, cyclohexanol; chlorinated solvents such as dichloromethane, chloroform, carbon I tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof.

Yet another embodiment of the present invention relates to crystalline Form II of (3S,8S,9S,12S)-3,12-Bis{1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by X-ray diffraction having 2e-peaks at 6.8°, 8.3°, 10.0°, 12.8°, 14.3°, 17.5°, 18.5°, 19.2°, 20.4°, 20.9° and 22.7°± 0.2 °

Yet another embodiment of the present invention relates to PXRD pattern of crystalline Form II of (3S,8S,9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyOphenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, substantially as shown in Figure 5.

Yet another embodiment of the present invention relates to crystalline Form-ll of (3S,8S,9S,12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by a DSC thermogram showing a broad endotherm peak at about 130°-160°C followed by the phase transition and then a single sharp endotherm at 210°C, substantially as shown in Figure 6.

Yet another embodiment of the present invention relates to Hydrated crystalline Form of (3S,8S,9S, 12S)-3,12-Bis( 1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

Yet another embodiment of the present invention relates to TGA thermogram of crystalline Form-II of (3S,8S,9S, 12S)-3,12-Bis(1,1 -dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester showing weight loss around 2-3%, substantially as shown in figure 7. The Form-ll weight loss is attributed to hydrated form of Atazanavir base.

Yet another embodiment of the present invention relates to the FT-IR spectrum of crystalline Form-ll of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[{4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester showing characteristic absorption bands at 1061, 1239, 1512, 1651, 1670, 1724, 3309, 3428 cm"\ substantially as shown in Figure 8.

Yet another embodiment of the present invention relates to a process for the preparation of crystalline form II of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9- 1 {phenylmethyl)-6-l[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester comprising the steps of i) dissolving Atazanavir form I in an a solvent and ii) isolating Atazanavir form II.

According to the present invention, Atazanavir form II is dissolved in a solvent selected from water; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; balcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitrites such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof.

Yet another embodiment of the present invention relates to single crystal structure of crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester. Single crystals of Atazanavir were grown from Dimethyl sulphoxide by slow evaporation method. Single crystal X-ray diffraction measurements for Atazanavir base Form-I were made using Bruker SMART Apex CCD diffractometer. The Single crystal data is collected with Molybdenum-anode X-ray tube is operated at 50kV and 35mA. Atazanavir base Form-I crystallizes into a monoclinic crystal system with a space group of P21. The stereochemistry (absolute configuration) at four chiral centers were confirmed as C (14)-S, C(22)-S, C(23)-S and C(32)-S as observed using PLATON :A.L. SPEK. J.APPL.CRYST. 36, 7-13, 2003). The crystallographic data is tabulated in Table 1.

Yet another embodiment of the present invention relates to single crystal structure of crystalline Form I of {3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6- [[4-(2-pyridinyl)phenyl] methyi]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, substantially as shown in Fig. 9.

The Powder X-ray diffraction (PXRD) measurements were made using PANalytical X'Pert PRO powder diffractometer equipped with a goniometer of 6/6 configuration and X'celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 26 range of 2.0°-50.0° with 0.030° step size and 50.0 seconds step time.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the in any way.

EXAMPLES:

Example 1: Preparation of Atazanavir Base Form-I
To 5.0ml of N-methyl pyrrolidine taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir sulphate. Added few drops of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 2:
To a 5.0ml of Dimethyl sulphoxide taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir sulphate. Added few drops of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 3: To 5.Gml of Dimethyl formamide taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir sulphate and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 4: To 5.0ml of 1,4 Dioxane taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir sulphate and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 5: To 5.0ml of methanol taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 5OOmg of Atazanavir base Form-I and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 6: To 5.0ml of Ethanol taken in a 3-neck round bottom flask fitted with mechanical stirrer added about SOOmg of Atazanavir base Form-I and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 7: To 5.0ml of Isopropyl alcohol taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir base Form-I and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 8: To 5.0ml of Acetonitrile taken in a 3-neck round bottom flask fitted with mechanical stirrer added about SOOmg of Atazanavir base Form-I and stirred the reaction mixture at ambient conditions for 2-3lirs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 9: To 5.0ml of water taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir base Form-I. Added few drops of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 10: To 5.0ml of Ethylacetate taken in a 3-neck round bottom flask fitted with
mechanical stirrer added about 500mg of Atazanavir base Form-I. Added few drops of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 11: To 5.0ml of 1,4 Dioxane taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir base Form-i and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid formed in a clean filtration flask under vacuum to afford crystalline form I of atazanavir base.
Example 12: To 5.0ml of water taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir base Form-I and added 5.0ml of Isopropyl alcohol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2- 3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 13: To 5.0ml of water taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir base Form-I and added 5.0ml of acetonitrile to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid formed under vacuum to afford crystalline form I of atazanavir base.

Example 14: To 5.0ml of acetone taken in a 3-neck round bottom flask fitted with mechanical stirrer added about SOOmg of Atazanavir base Form-I and stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid formed under vacuum.

Example 15: To 5.0ml of water adjusted to alkaline pH taken in a 3-neck round bottom flask fitted with mechanical stirrer added about SOOmg of Atazanavir base Form-i. Added S.Omi of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitated out. Filtered the solid formed under vacuum to afford crystalline form I of atazanavir base.

Example 16: To 5.0ml of Hexane taken in a 3-neck round bottom flask fitted with mechanical stirrer added about SOOmg of Atazanavir base Form-I. Added few drops of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2- 3hrs until the white solid precipitates out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 17: To 5.0ml of n-pentane taken in a 3-neck round bottom flask fitted with mechanical stirrer added about 500mg of Atazanavir base Form-I. Added few drops of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2- 3hrs until the white solid precipitated out. Filtered the solid under vacuum to afford crystalline form I of atazanavir base.

Example 18: Preparation of Atazanavir Base Form-ll:
To a 5.0mi of n-Heptane taken in a 3-neck round bottom flask fitted with mechanical stirrer. Added about 500mg of Atazanavir base Form-I sample and 1.5ml of methanol to dissolve the sample totally to get a clear solution. Stirred the reaction mixture at ambient conditions for 2-3hrs until the white solid precipitates out. Filtered the solid formed under vacuum to afford crystalline form II of atazanavir base.

We claim:

1. Crystalline (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)- 6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

2. Crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by an X-ray powder diffraction pattern having 26 values at: 6,8°, 8.3°, 10.6°, 11.9°, 12.8°, 17.5°, 18.5°, 19.2°, 22.8° and 23.3° ± 0.2 °C

3. Crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by an X-ray powder diffraction as shown in Fig. 1.

4. Crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9- (phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by Differential scanning calorimetry thermo gram as shown in Fig 2.

5. Anhydrous crystalline form of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11- dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester

6. A Process for the preparation of Crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1- dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester comprising the steps of
i) dissolving atazanavir bisulfate In a first solvent
ii) optionally adding second solvent, and
iii) Isolating crystalline form I of atazanavir free base.

7. The process according to claim 6, wherein the first solvent is selected from DMSO, DMF, Acetonitrile, n-Hexane, n-Pentane, Chloroform and Ethylacetate, 1,4 Dioxane, N-methyl pyrollidine, acetone. Methylene dihydrochloride or a mixture thereof and the second solvent is methanol.

8. A Process for purification of crystalline form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11 -dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester comprising the steps of
i) adding atazanavir crystalline form I to an organic solvent and
ii) isolating atazanavir crystalline form I.

9.The process according to claim 8, wherein the organic solvent is selected from water, acetone, methanol, ethanol, isopropyl alcohol, n-hexane, n-heptane, ethyl acetate, dioxane, acetonitrile or their mixtures thereof.

l0.Crystalline polymorphic Form II of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyllmethyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester characterized by X-ray diffraction pattern reflections exhibited characteristic 2e-peaks at 6.8°, 8.3°, 10.0°, 12.8°, 14.3°, 17.5°, 18.5°, 19.2°, 20.4°, 20.9° and 22.7°± 0.2 °C.

11.Hydrated crystalline Form of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester.

12. A Process for the preparation of Crystalline Form II of (3S,8S,9S,12S)-3,12-Bis(1,1- dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]- 2,5,6,10,13-penta-azatetradecanedioic acid dimethyl ester comprising the steps of
l) dissolving atazanavir free base crystalline Form 1 in a first solvent
ii) optionally adding second solvent, and
iii) Isolating atazanavir free base crystalline Form II.

13. The process according to claim 12, wherein the first solvent is selected from n-hexane, n-Heptane, and the second solvent is selected from methanol, ethanol, isopropylalcohol.

14. Single Crystal structure of Crystalline Form I of (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-penta-azatetradecanedioic acid dimethyl ester as shown in Fig 9.