This invention relates to "Novel Crystalline Forms Of Atorvastatin Calcium And Processes For Preparing Them".
FIELD OF THE INVENTION:
This invention particularly relates to novel crystalline polymorphs of Atorvastatin Calcium, which have been designated by us sas M-2, M-3 and M-4. The new crystalline polymorphs of the present invention may be anhydrous or trihydrate and could contain up to 4.5 to 8 % water. The invention also provides processes for the preparation of these novel polymorphs, which are simple, cost effective, reproducible, environment friendly and easy to scale up for industrial manufacture while maintaining the quality of the title product. The process more particularly results in the title compound with superior filtration characteristics.
BACKGROUND OF THE INVENTION
Atorvastatin Calcium is a member of the class of drug called statins, which are
considered to be the therapeutically most effective drugs available for the treatment of
hyperlipidemia and hypocholesterolemia. Atorvastatin calcium is an orally active
hypocholesterolaemic, a liver-selective HMG-CoA reductase inhibitor. Atorvastatin
Calcium is known by its chemical name as [R-(R*,R*)]-2-(4-fluorophenyl)-p,5-
dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-(phenylamino) carbonyl]-1 H-pyrrole-1 -
heptanoic acid hemi calcium salt tri-hydrate and is marketed under the brand name LIPITOR. It is an optically active molecule with two asymmetric centers and its reported optical rotation [ajo is -7.4 ° (C = 1, DMSO). The empirical formula of Atorvastatin Calcium is C66H6gCaF2N4O10. Atorvastatin Calcium is a white to off white amorphous or crystalline powder that is soluble in water and alcohols like methanol, ethanol, aliphatic ketones like acetone, tetrahydrofuran, dimethylformamide, dimethylacetamide and dimethylsulfoxide etc. Atorvastatin calcium (I) is displays the following Chemical Structure as shown in Fig.. I
(FIGURE REMOVED)

The present invention is directed to new crystalline forms of Atorvastatin Calcium and processes for the preparation thereof.
It has been reported in a number of publications and patents that both the crystalline and amorphous forms of several drugs exhibit distinct dissolution characteristics and bioavailability patterns. Depending upon the nature of the structure, the dissolution rate may favour one formulation over the other as a result of which, for some therapeutic indications, one specific formulation may be favored over another. (See, T. Konno, Chem. Pharm. Bull., 38, 2003-2007, 1990). Similarly, one formulation may be more suitable for treating certain patient populations. Therefore it is desirable to develop methodologies for converting crystalline and amorphous forms of active pharmaceutical ingredients into one another. In addition it is desirable to prepare fast melt tablet formulations for quick action and relief to the patients.
The formation of different polymorphic forms can be achieved by crystallising the compound from different solvents under varying conditions. Polymorph formation is influenced by temperature of the solution, rate of stirring, rate of precipitation, mode of mixing and rate of addition of the mixing of solvents and time of stirring. Very often the different polymorphs can be isolated from the same solvent system by simply stirring the mixture for different period of times and one form can be converted into another. In view of the very tight limits of residual solvent specification norms as per ICH guidelines for the Active Pharmaceutical Ingredient (API), only a limited number of solvents, preferably C class solvents are being used for generating the new polymorphs. Thus choice is narrowed down to very few solvent systems. Also seeding plays a important role in crystallizing a specific form of a polymorph from same or different solvent systems in higher yields
Processes for the preparation of Atorvastatin and its hemi calcium salts are described in U.S. 5,273,995; U.S. 5,298,627; US 5,003,080; 5,097045; US 5,124,482; US
5,149,837; US 5,216,174; US 5,245,047; US 5,280,126; U.S. 6,087,511; U.S. 6,274,740; PCT WO 97/03960; PCT WO 02/059087; US 6,777,552 B2 and in the publications by P. L. Brower et al. in Tetrahedron Letters 33, 2279-2282, ((1992); K. L. Baumann et al. in Tetrahedron Letters, 33, 2283-2284 ((1992) and A. Graul et al. in Drugs of the Future, 22, 956-968 (1997). 073 which are all incorporated here by reference.
So far more than 40 crystalline forms and processes for their preparation have been claimed in several patents. The prior art known to the inventor include Warner Lambert's (Pfizer's) US 6,121,461 and US 5, 969, 156 (WO A 97/03958 & WO A 97/03959), which describe the isolation of crystalline Atorvastatin calcium with the polymorphic forms III, and I, II, and IV, respectively, US 6,605, 729 Bl claims the crystalline Atorvastatin calcium with the polymorphic Forms V to XII, whereas PCT WO 02/051,804 claims the polymorphic forms A, Bl, B2, C, D and E. Teva's patent applications PCT WO 01/36384 Al and US 6,605,636 B2 claim Form V and Form VII respectively, PCT WO 2004/043,918 Al and US 2003/0,212,279 Al claim new forms VI to IX, IXa, X, XI, XII, XIV, XVI and XVII whereas PCT WO 2004/050618 A2 claims form F. In addition, there are reports from other Pharmaceutical companies claiming new polymorphic forms of Atorvastatin calcium. These include Dr. Reddy's Form VI and Form VII as described in PCT WO 03/011862 Al, Ivax corporation's Form Fa and Form Je as mentioned in PCT WO 03/050085 Al and Morepen's Form VI that is claimed in PCT WO 2004/022053 Al. In almost all these cases, mixtures of polar organic solvents such as methanol, ethanol, isopropanol, butanol or aliphatic ketones like acetone and methyl isobutyl ketone and ethers like methyl tertiary butyl ether (MTBE), diisopropyl ether or tetrahydrofliran (THF) or acetonitrile in pure form or in combination, preferably with water have been used for generating the different crystalline forms.
Although some of the crystalline forms mentioned above, more specifically Form I overcomes some of the deficiencies of the amorphous forming terms of filterability, flowability and stability, there is still a need for new crystalline forms which could lead to the preparation finished pharmaceutical dosage forms displaying superior biological and clinical efficiency than those of the existing ones.
In an earlier disclosure in PCX application No WO 04/022,053 Al, we have described that a new polymorphic Form VI of Atorvastatin Calcium can be isolated from a mixture of acetone and water at around 50°C which displays distinctly different XRD pattern and solid state 13C-NMR spectra from at the reported forms of Atorvastatin Calcium. This form has been redesignated as M-1 and its characteristic 20 (± 0.2) values are incorporated in Table below by way of reference in this specification. However, there is still a need to produce Atorvastatin calcium in a reproducible, pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications. Furthermore, it is economically desirable that the product is stable for extended periods of time without the need for specialised storage conditions and can be produced by the processes that can be easily scale up for industrial manufacture. Moreover, the product thus produced can be isolated easily minimising losses as it has better filterability. This leads to higher yields.
In continuation of our studies on the synthesis of new crystalline forms of Atorvastatin Calcium, we have discovered that new crystalline forms herein designated as Forms M-2, M-3 and M-4 can be isolated from ecological friendly solvents such as lower aliphatic ketones and has a good thermal stability combined with good solubility characteristics. Moreover new form M-4 have also been isolated from the solution of dichloromethane.
BRIEF DESCRIPTION OF THE DRAWING:
FIG I displays chemical structure of Atorvastatin calcium FIG II displays XRD pattern of crystalline Form M-1 of Atorvastatin Calcium FIG III displays XRD pattern of crystalline Form M-2 of Atorvastatin Calcium FIG IV displays XRD pattern of crystalline Form M-3 of Atorvastatin Calcium FIG V displays XRD pattern of crystalline Form M-4 of Atorvastatin Calcium.
SUMMARY OF THE INVENTION:
The present invention provides new crystalline forms of Atorvastatin Calcium designated by us as M-2, M-3 and M-4 and methods for preparing them in anhydrous as well as hydrated forms. The new crystalline forms of Atorvastatin Calcium are generally trihydrate with water content around 4.0 to 6.0%, but may also exhibit water content up to 8.0 % w/w. or more.
The main object of the present invention is to provide novel crystalline polymorphs of
Atorvastatin Calcium and processes for preparing the said polymorphs.
Another object is to provide new polymorphic forms of Atorvastatin Calcium having
higher purity and stability.
Yet another object is to provide new crystalline polymorphic form of Atorvastatin
Calcium that is easy to filter, has superior texture, and displays reduced residual
solvent.
Still another object of the invention is also to provide a process for the preparation of a
new crystalline which are simple, cost effective, involving less number of steps, high
yielding, precise, reproducible, environment friendly and easy to scale up for industrial
manufacture while maintaining the quality of the title product. The processes for the
new crystalline forms of Atorvastatin Calcium have merits of residual solvent limits,
which are well below ICH guidelines.
STATEMENT OF INVENTION:
Accordingly the present invention is directed to new crystalline polymorphs designated as M-2, M-3 and M-4.
Thus the invention provides new polymorph of Atorvastatin designated as M-2 exhibits a characteristic X-ray powder diffraction pattern obtained using conventional CuKα radiation with characteristic sharp peaks expressed in 20 values at 8.64, 10.16, 19.38 and specific peak at 29.34. It further exhibits Powder X ray diffraction (PXRD) pattern as shown in FIG III with additional characteristic peaks at 20 (± 0.2) values of 8.24, 16.94, 17.66, 18.14, 18.42, 20.10, 20.36, 20.82, 27.10 and 32.80.
The new polymorph M-3 displays a broad peak at 8.0, sharp peaks at 18.22 surrounded by broad peaks in the region of 19 to 22 and a very strong peak at 29.26. Its powder XRD spectrum is reproduced in FIG IV displays additional characteristic 20 (± 0.2) values of 8.30, 8.58, 18.76, 19.46, 20.16 and 36.00.
Crystalline Form M-4 is shows sharp peaks at 5.52, 8.20 (100%), 18.30, 19.00 and a very strong unique peak at 31.68. Additionally, it displays characteristic 20 (± 0.2)
values of 2.72, 10.90, and 20.04 which are shown in the powder XRD spectrum in FIGV.
In accordance with this invention, there is provided a process for preparing polymorphs
designated as M-2, M-3 and M-4.
The process comprises crystallizing from a mixture of aliphatic ketone and water at 0 to
55°C under stirring, while allowing the ketone to evaporate till thick precipitate is
obtained if so desired, followed by drying.
The ketone used is acetone, diethyl ketone or ethyl methyl ketone using quantities
varying between 10 times and 150 times, preferably 70 to 100 times w. r. t. the
Atorvastatin calcium used, the ratio of acetone and water used ranging from 0.25:1.0 to
1.0 to 0.25, preferably 0.75:1.0 to 1.0 to 0.75, the crystallization being carried out
preferably at 20 to 40°C, with stirring over a period of 50 to 250 hrs, preferably over 75
to 125 hrs and the sample being dried at 20 to 70°C, preferably at 50 to 60°C to desired
level of moisture.
Alternately, a process comprising slow crystallization of Atorvastatin calcium in
dichloromethane that is dissolved at reflux temperature followed by isolation and
drying to get polymorph M-4.
The quantity of dichloromethane used varies between 3 to 100 times, preferably 10 to
20 times v/w w. r. t. the starting material and refluxing is effected over a period of 3 to
96 hrs, preferably 18 to 30 hrs at 40 to 45''C under stirring.
Surprisingly, we have now found that Atorvastatin Calcium can be isolated as novel crystalline in anhydrous and hydrated forms at different temperatures by varying the rate of addition, ratio of ingredients, and time of stirring of the reaction mixture. Generally Atorvastatin calcium, either in form of solution or solid, is mixed with anti-solvent optionally in presence of water. The solvent used for preparing solution of Atorvastatin calcium may be such as aliphatic ketones preferably acetone, diethyl ketone and ethyl methyl ketone and the like. This solution was added to anti-solvent i.e. water. Alternately Atorvastatin calcium may be added to a mixture of the ketone and water.
The details of the synthesis and identification of the new polymorphic forms are delineated in the following paragraphs.
Stirring a solution of Atorvastatin Calcium in of a mixture acetone and water for 150 or more results in the isolation a powder which after drying in oven affords crystalline Form M-2.
Alternatively, stirring a solution of Atorvastatin Calcium in acetone and water mixture for over 100 or more hrs and allowing the acetone to evaporate over a period of time leads to the crystallization of thick precipitate which after filtration and drying affords Form M-3. The amount of acetone and water used may vary between 10 times to 150 times, preferably 70 to 100 times w. r. t. the Atorvastatin calcium used. The ratio of acetone and water used may be between 0.25:1.0 to 1.0 to 0.25, preferably between 0.75:1.0 to 1.0 to 0.75 and the crystallization is carried out at 0 to 55''C, preferably at 20 to 40 °C, the stirring is performed over a period of 48 to 250 hrs, preferably over 125 to 200 hrs and the sample is dried at 20 to 70 °C, preferably at 50 to 60 °C.
It was observed that slow crystallization of Atorvastatin calcium from a solution of dichloromethane results in the formation of crystalline Form M-4 as shown in FIG V. The quantity of dichloromethane in which Atorvastatin calcium is dissolved may be between 3 to 100 times, preferably 10 to 20 times v/w w. r. t. the starting material and the solvent is slowly allowed to evaporate from the reaction flask over a period of 3 to 96 hrs, preferably 24 to 30 hrs at +5 to 35°C under slow stirring.
TABLE
XRD PATTERN OF THE CRYSTALLINE FORMS M-1 TO M-4

(TABLE REMOVED)


R. I. = Relative Intensity
The process is further illustrated by following examples. However, this should not construe the scope of the invention
EXAMPLE 1 : Preparation of Crystalline polymorphic Form M-2
To a stirred mixture of acetone( 430 ml) and water ( 430 ml) at 30 to 35°C, amorphous Atorvastatin calcium (5.0 g) was added and the mixture was then stirred at 30 to 35°C for 115 hrs during which time the product slowly crystallizes out. The resulting precipitate was filtered and dried at 40 to 45°C to obtain white crystalline solid, which displayed XRD pattern as shown in FIG III. The 20 values along with the intensity are shown in Table. Yield = 3.4 g (68 % recovery) EXAMPLE 2 : Preparation of Crystalline polymorphic form M-3 : To a stirred mixture of acetone (8.0 Itl ) and water (7.5 It) at 25 to 30''C, amorphous Atorvastatin calcium (90.0 g) was added and the mixture. The mixture was then stirred at 25 to 30°C and acetone was slowly allowed to evaporate over a period of 145 hrs during which time the product slowly crystallizes out. The product was filtered to and dried to afford off white crystalline form M-3, which displayed XRD pattern as shown in FIG IV. The 20 values along with the intensity are shown in Table. Yield = 68.5 g (76.11 % recovery)
EXAMPLE 3: Preparation of Crystalline form M-4:
Amorphous Atorvastatin calcium (9.0 g) was refluxed at 42 to 45°C in dichloromethane ( 100 ml ) and after complete dissolution had taken place, the solution was filtered through hyfiow bed to remove the suspended particles. The mixture was then stirred for 17 hrs at 10 to 15°C and the resulting solid was filtered off and dried at 45 to 50°C to obtain crystalline form M-4 which displayed XRD pattern as shown in FIG V. The 20 values along with the intensity are shown in Table. Yield = 4.2 g (( 46.67% recovery)

WE CLAIM:
1. A new crystalline Form M-2 of Atorvastatin hemi-calcium and solvates there of characterized by powder X ray pattern as depicted and expressed in 20 values in FIG in with sharp peaks at 8.64, 10.16, 19.38 and specific peak at 29.34 and additional characteristic peaks at 8.24, 16.94, 17.66, 18.14, 18.42, 20.10, 20.36, 20.82, 27.10 and 32.80 20 (± 0.2).
2. A new crystalline Form M-3 of Atorvastatin hemi-calcium and solvates there of characterized by powder X ray pattern as depicted and expressed in 20 values in FIG IV with sharp peaks at 18.22 surrounded by broad peaks in the region of 19 to 22 and a very strong peak at 29.26 and additional characteristic 20 (± 0.2) values of 8.30, 8.58, 18.76, 19.46, 20.16 and 36.00.
3. A new crystalline Form M-4 of Atorvastatin hemi-calcium and solvates there of characterized by powder X ray pattern as depicted and expressed in 20 values in FIG V with sharp peaks at .52, 8.20 18.30, 19.00 and 31.68 and additional characteristic 20 (± 0.2) values of 2.72, 10.90 and 20.04.
4. New crystalline polymorphs M-2, M-3 & M-4 as claimed in preceding claims are trihydrate and contain up to 8% water.
5. A process for the preparation of crystalline polymorph M-2 as claimed in claim 1 comprises crystallizing from a mixture of aliphatic ketone and water at 0 to 55°C under stirring followed by drying.
6. A process for the preparation of crystalline polymorph M-3 as claimed in claim 2 comprises crystallizing from a mixture of aliphatic ketone and water at 0 to 55oC under stirring while allowing the ketone to evaporate till thick precipitate is obtained followed by drying.
7. A process as claimed in claim 5 wherein the ketone used is acetone, diethyl ketone or ethyl methyl ketone using quantities varying between 10 times and 150 times, preferably 70 to 100 times w. r. t. the Atorvastatin calcium used, the ratio of acetone and water used ranging from 0.25:1.0 to 1.0 to 0.25, preferably 0.75:1.0 to 1.0 to 0.75, the crystallization being carried out preferably at 20 to 40°C, with stirring over a period of 50 to 250 hrs, preferably over 75 to 125 hrs and the sample being dried at 20 to 70''C, preferably at 50 to 60°C to desired level of moisture.
8. A process for the preparation of crystalline polymorph M-4 as claimed in claim 3 comprising slow crystallization of Atorvastatin calcium in dichloromethane that is dissolved at reflux temperature followed by isolation and drying.
9. A process as in claimed in claim 8 wherein the quantity of dichloromethane used varies between 3 to 100 times, preferably 10 to 20 times v/w w. r. t. the starting material and refluxing is effected over a period of 3 to 96 hrs, preferably 18 to 30 hrs at 40 to 45°C under stirring.
10. A new crystalline Forms of Atorvastatin calcium designated as M-2, M-3, and M-4, solvates there of and a process therefore substantially as herein desribed.