INTRODUCTION:
The present invention relates to novel crystalline forms of anastrozole and processes for their preparation. Anastrozole is useful, as an anti-neoplastic agent in treatment of breast cancer. The novel forms have been designated by us as Forms I & Form II.
Patent EP 296,749 (corresponding US pat 4,935,437) describes (substituted-aralkyl) heterocyclic compounds useful as inhibitors of the enzyme aromatase. These compounds are useful in treatment of cancer. Notable among them is the compound a,a,a',a'- tetramethyl-5-( 1H, 1,2,4-triazol-1 -ylmethyl)-1,3-benzenediacetonitrile, of formula-I,

This compound is known by the name anastrozole and is marketed as an anti-neoplastic in treatment of breast cancer.
The aforesaid European patent describes the preparation of anastrozole by N-alkylating sodium 1,2,4-triazole with a,a,a',a'-tetramethyl-5-bromomethyl-l,3-benzene- diacetonitrile. Crude anastrozole thus obtained is reciystallized from a mixture of ethyl acetate and cyclohexane. No crystalline forms of anastrozole have been reported till date.
We have prepared two novel crystalline forms of anastrozole. These novel forms are found to be stable, reproducible, and useful for treatment of breast cancer as such and / or as suitable pharmaceutical preparations.
Accordingly, the main objective of the present invention is to provide stable, novel crystalline Forms I & II (designated by us) of anastrozole useful for the treatment of breast cancer.
Another objective of the present invention is to provide a process for the preparation of stable, novel crystalline forms I & II of anastrozole useful for the treatment of breast cancer.
SUMMARY OF THE INVENTION:
Accordingly the present invention provides novel, stable, and crystalline forms of anastrozole having the formula I,

designated by us as Form I, characterized by an X-ray powder diffraction pattern having peaks expressed as 29 (intensity in %) 9.83 (37.8), 16.77 (21.8), 18.45 (13.2), 18.81 (100), 22.95 (10.7), 29.38 (3.1), 29.86 (3.3), 33.83 (4.0), and 43.94 (26.1) degrees as shown in Figure 1 of the drawing accompanying this specification
According to another aspect of the present invention there is provided a process for preparation of novel, stable, and crystalline Form I of anastrozole having the formula I and characteristics given above which comprises crystallizing pure anastrozole of the formula I from a mixture of ethyl acetate / hexane (1:1) to get the Form I of anastrozole.
The anastrozole used in the process of the present invention can be prepared according to the process given in EP 296,749. The anastrozole so prepared may be purified to get high (>99.5%) purity anastrozole by following the process disclosed in our pending patent application No. 406/CHE/2004 (corresponding PCT Appln. No. IN05/00140).
Another aspect of the present invention is to provide another novel, stable, and crystalline form of anastrozole, of the formula I designated by us as Form II, characterized by an X- ray powder diffraction pattern having peaks expressed as 20 (intensity in %) 9.64 (92.7), 10.92 (9.9), 12.48 (4.9), 16.58 (28.7),' 17.07 (11.9), 18.58 (100), 19.56 (26.4), 21.19 (7.8), 21.51 (6.2), 22.12 (17.1), 22.74 (37.8), 25.59 (8.7), 26.10 (6.1), 28.90 (12.1), 29.27 (13.1), 29.78 (10.5), 30.09 (6.6), 30.64 (6.1), 312.67 (5.3), 33.64 (7.3), and 35.25 (6.1) degrees as shown in Figure 2
According to yet another aspect of the present invention there is provided a process for the preparation of Form II of anastrozole of the formula I having the characteristics given above which comprises crystallizing anastrozole from a group of solvents consisting of hydrocarbon solvents at a temperature in the range of 0-30°C, excluding 1:1 mixtures of ethyl acetate / hexane, cooling the resulting solution and partially removing of the solvent(s) by distilling under vaccum below the boiling point of the solvents) or without vaccum at the boiling point of the solvents)
It should be noted that when the mixtures of the solvents is used care should be taken to avoid the 1: 1 mixture of ethyl acetate / hexane, as the use of such a mixture results in the formation of Form I
The preferred solvent which can be used are toluene, hexane, cyclohexane; nitriles such as acetonitrile; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters like ethyl acetate, and alcohols like methanol, ethanol, isopropanol or the mixtures thereof is used
The temperature used may be preferably in the range of 20-30°C.
The anastrozole used in the process can be prepared according to the process given in EP 296,749. The anastrozole thus obtained can be further purified to get high purity (>99.5%) anastrozole by following the process disclosed in our co-pending patent application No. 406/CHE/2004 (corresponding PCT Appln. No. IN05/00140).
The novel forms of anastrozole may be formulated in a form suitable for oral administration or injection.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1 is X-ray powder diffraction pattern of Form I anastrozole. Figure 2 is X-ray powder diffraction pattern of Form II anastrozole.
X-ray powder diffraction spectra were measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation (1.5406A).
The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1
Preparation of pure anastrozole of formula-I
(i) Preparation of crude anastrozole
Into a 1L, three-necked RB flask was charged 54g of sodium triazole monohydrate and 500ml of dry DMF under nitrogen atmosphere. The reaction mass was cooled to 25 °C. (2,2'-[5-Bromomethyl)-l,3-phenylene]di(2-methylpropio-nitrile was added to the reaction mass over a period of 2hr. The reaction mass was maintained at this temperature until the completion of reaction. The reaction mass was transferred into 3L flask containing 1.6L of water and stirred for 30min. Reaction mass was extracted with toluene (2 x 300ml and 1 x 100ml). Toluene layers were combined and washed with water (2 x 200ml). Toluene layer was treated with activated carbon (5g) and filtered. Toluene was distilled off from the filtrate under vaccum to get 98g of crude anastrozole.
(ii) Preparation of crude anastrozole p-toluenesulfonate salt
Acetone (400ml) was added to the residue at room temperature and stirred for 30min to get a clear solution. p-Toluenesulfonic acid monohydrate (65 g) was added to the reaction mass and stirred for lhr. Acetone was distilled of from the reaction mass and added 400ml of acetone. The reaction mass was stirred at 25 °C for 12hr. Filtered the solids and washed the wet cake with 100ml of acetone. Wet weight is 140g.
(iii) Recrystallization of anastrozole p-toluenesulfonate salt
The wet salt obtained above is taken into a 1L three-necked RB flask and added acetone (500ml). The reaction mass was heated to reflux temperature and maintained for lhr. The reaction mass was cooled to 25°C and maintained for 3hr. The solids were filtered of and washed with acetone. The salt was dried at 50°C. Yield is 120g. M. P. is 176 °C. Purity by HPLC is 99.7%. Isomeric impurity is 0.04%. IR (KBr): 3426, 3106, 3051, 2988, 2235, 1605, 1551, 1534, 1496, 1463, 1441, 1406, 1372, 1296, 1267, 1221, 1192, 1165,1121, 1031, 1009,932,912, 868,817, 760, 704, 685,644, and 565cm"1.
(iv) Preparation of pure anastrozole of formula-I
Water (200ml) and the p-toluenesulfonate salt of anastrozole (25g) prepared above in step (iii) is taken into a 500ml, three-necked RB flask and stirred for 30min. pH of the reaction mass was adjusted to 8.5-9.0 with aqueous ammonia. Ethyl acetate (150ml) was added to the reaction mass and stirred for 30min. Ethyl acetate layer was separated and the aqueous layer extracted with 150ml of ethyl acetate. Combined ethyl acetate layer was washed with 100ml of water. Ethyl acetate layer was dried with sodium sulfate partially distilled, cooled to 10 °C to get pure anastrozole of formula-I as white solid. Melting point is 86.3°C. Purity by HPLC is 99.6%. Isomeric impurity is 0.06%. IR (KBr): 3102, 2985, 2950, 2236, 1606, 1502, 1476, 1454, 1428, 1389, 1359, 1273, 1220, 1205, 1138, 1013, 956, 895, 876, 763, 713, 680, and 664cm-1. •H-NMR (300MHZ, CDCI3): 8.16 (s, 1H, -NCHN-); 8.01 (s 1H, -NCHN-); 7.34-7.54 (m, 3H, aromatic-H); 5.40 (s, 2H, A1CH2-); 1.73 (s, 12H, 4 x -CH3). 13C-NMR (75MHz, CDCI3): 152.07 (NCHN); 143.04 (NCHN); 136.44 (C-5); 123.99 (C-4 and C-6); 123.50 (C-2); 121.79(CN); 52.71(ArCH2); 36.99 (-CCH2); 28.76 (-CH3). Mass (EI-MS): 294([M + 1]+) ; 293 ([Mf); 292 ([M-l]+); 278 ([M - CH3]+); 266 ([M + if - CN); 225 ([M ]+ - triazole); 224 ([M -1]+ - triazole); 210 ([M + 1]+ - CH2-triazole); 209 ([M]+ - [-CH2- triazole]).
(v) Preparation of Form I crystals of anastrozole of formula-I The pure (>99.5%) anastrozole (27.5g) obtained as above was taken into a flask and added 55ml of ethyl acetate and 55ml of cyclohexane. The reaction mixture was heated to reflux temperature to get a clear solution. The solution was allowed to cool to 25-30 °C. After maintaining for lhr, the reaction mass was filtered and the resulting solid dried under vaccum at 45-50°C for lhr to get Form I crystals of anastrozole.
Example 2
Pure (>99.5%) anastrozole obtained by the process described in steps (i) to (iv) of the Example 1 (2g) was dissolved in 5ml of toluene at 55-60°C. The resulting solution was slowly allowed to reach 25-30°C and maintained for lhr before filtration. The wet solid was washed with hexane and dried under vaccum at 45-50°C to get Form II crystals of anastrozole.
Example 3
Pure anastrozole (>99.5%) (2g) prepared by the process described in steps (i) to (iv) of the Example 1 (2g) was dissolved in 5ml of isopropanol at 50-60°C. The resultant solution was allowed to reach 25-30°C and maintained for lhr. Crystals formed were filtered, washed with 5ml of hexane, and dried at 45-50°C to get Form II crystals of anastrozole.
Example 4
Pure anastrozole (>99.5%) prepared by the process described in steps (i) to (iv) of the Example 1 was dissolved in 2ml of acetonitrile at 55-60°C. The solution was allowed to reach 25-30°C and maintained for lhr. Crystals were filtered, washed with hexane, and dried at 45-50°C to get Form II crystals of anastrozole.
Example 5
Pure anastrozole (99.5%) (3.7g) prepared by the process described in steps (i) to (iv) of the Example 1 was dissolved in 5ml of tetrahydrofuran. The resultant solution was allowed to reach 25-30°C. Hexane (5ml) was added and stirred for lhr. The crystals formed were filtered, washed with hexane and dried under vaccum at 45-50°C to get Form II crystals of anastrozole.
Advantages of present invention:
1. Two novel crystalline forms of anastrozole designated by us as Form I and Form II which are stable, reproducible, and useful for the treatment of breast cancer.
2. The processes for the preparation of the novel crystalline forms, namely Form I, and Form II of anastrozole are simple and easy to adopt on a commercial scale.

We Claim:
1. Novel, stable, and crystalline Form I of anastrozole of the formula I,

characterized by an X-ray powder diffraction pattern having peaks expressed as 20 (intensity in %) 9.83 (37.8), 16.77 (21.8), 18.45 (13.2), 18.81 (100), 22.95 (10.7), 29.38 (3.1), 29.86 (3.3), 33.83 (4.0), and 43.94 (26.1) degrees as shown un Fig 1 of the drawings accompanying this specification.
2. Novel, stable, and crystalline Form II of anastrozole of the formula I given in claim 1 characterized by an X-ray powder diffraction pattern characterized by an X-ray powder diffraction pattern having peaks expressed as 20 (intensity in %) 9.64 (92.7), 10.92 (9.9), 12.48 (4.9), 16.58 (28.7), 17.07 (11.9), 18.58 (100), 19.56 (26.4), 21.19 (7.8), 21.51 (6.2), 22.12 (17.1), 22.74 (37.8), 25.59 (8.7), 26.10 (6.1), 28.90 (12.1), 29.27 (13.1), 29.78 (10.5), 30.09 (6.6), 30.64 (6.1), 312.67 (5.3), 33.64 (7.3), and 35.25 (6.1) degrees as shown in Figure 2 of the drawings accompanying this specification.
3. A process for preparation of novel, stable & crystalline Form I of anastrozole having the formula I and characteristics given in Fig 1 which comprises crystallizing pure anastrozole of the formula I from a mixture of ethyl acetate / hexane (1:1) to get the Form I anastrozole.
4. A process as claimed in claim 3 wherein the ratio between the ethyl acetate and cyclohexane used is 1:2 to 1:4, preferably 1: 1 and the resulting solution is heated at reflux temperature.
5. A process for the preparation of novel Form II of anastrozole of the formula I having the characteristics given above which comprises crystallizing anastrozole from a group of solvents consisting of hydrocarbon excluding 1:1 mixtures of ethyl acetate / hexane, at a temperature in the range of 0 to 30°C, cooling the resulting solution and partially removing of the solvent(s) by distilling under vaccum below the boiling point of the solvent(s) or without vaccum at the boiling point of the solvent(s).
6. A process as claimed in claims 3 to 5 wherein the anastrozole of the formula I used is prepared by the process disclosed in EP no 296,749 which further purified by the process disclosed in our pending patent application No. 406/CHE/2004 (corresponding PCT Appln. No. IN05/00140).
7. A process as claimed in claims 5 & 6 wherein the solvents such as toluene, hexane, cyclohexane; nitriles such as acetonitrile; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters like ethyl acetate, and alcohols like methanol, ethanol, isopropanol or the mixtures thereof is used.