FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
PROCESS FOR THE PREPARATION OF ATORVASTATIN HEMI-CALCIUM
FORM I
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
This invention relates to an improved process for the preparation crystalline Form I of atorvastatin hemi-calcium.
BACKGROUND OF THE INVENTION
Atorvastatin hemi-calcium is chemically known as [R-(R*. R*)]-2-(4-fluorophenyl)-(3, 6-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-hep-tanoic acid, calcium salt (2:1) trihydrate.
Atorvastatin hemi-calcium is a HMG-CoA reductase inhibitor which is used as lipid lowering agent. It is commercially available under the brand name LIPITOR in the form of tablets in USA.
Many polymorphicforms of atorvastatin hemi-calcium are known in the art. Form I of atorvastatin hemi-calcium was first described in EP 848705 B1. The process for the preparation of Form I is also described in the above European Patent.
According to one of the exemplified processes for the preparation of Form I of atorvastatin hemi-calcium, atorvastatin lactone was dissolved in a mixture of methyl tert-butyl ether (MTBE) and methanol and reacted with aqueous solution of sodium hydroxide at 48-58 °C for 40-60 minutes to form sodium salt of atorvastatin. The reaction mixture was then cooled to 25-35 °C and the organic layer was discarded. The MTBE saturated aqueous solution of sodium salt was heated to 40-75 °C. This solution was added to a aqueous solution of calcium acetate dropwise. The reaction mixture is then seeded with atorvastatin calcium Form I. The reaction mixture was then heated to 51-57 °C and then cooled to 15-40 °C. The precipitated atorvastatin hemi-calcium Form I was filtered, washed with water and methanol and dried at 60-70 °C for 3-4 days.

In another method for the preparation of Form I of atorvastatin hemi-calcium amorphous and crystalline form of atorvastatin in a ratio of 9:1 was stirred in a mixture of water and methanol for 17 hours. The precipitated atorvastatin hemi-calcium Form I was filtered, rinsed with water and dried at 70 °C under reduced pressure.
WO 02/43732 A1 claims a process for the preparation of atorvastatin hemi-calcium Form I by suspending any other form of the compound in water for sufficient time and recovering Form I of the compound.
US 2007032665 A1 describes a process for the preparation of Form I of atorvastatin hemi-calcium from Form VI or Form VII of atorvastatin hemi-calcium. According to the process, atorvastatin hemi-calcium Form VI or Form VII was dissolved in methanol and treated with basic charcoal. The reaction mixture was then filtered through celite and the filtrate was added to water seeded with Form I of atorvastatin hemi-calcium. The separated solid was filtered, washed with water and dried at 65-75 °C for 60 hours.'
We found that when an aqueous solution of calcium acetate, seeded with Form I of atorvastatin hemi-calcium to which an aqueous solution of atorvastatin sodium is added at elevated temperature and the reaction mixture is cooled after completion of addition, atorvastatin hemi-calcium Form I separated out.
SUMMARY OF THE INVENTION
In one embodiment, the specification discloses a process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising adding aqueous solution of atorvastatin sodium to aqueous solution of calcium acetate.
In another embodiment, the specification discloses a process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising the steps of:

(a) mixing calcium acetate in water;
(b) raising the temperature of the mixture of step (a) to 40-75 °C;
(c) seeding the mixture of step (b) with Form 1 of atorvastatin hemi-calcium;
(d) adding an aqueous solution of atorvastatin sodium of pH 8.8-9.2 to the mixture of step (c);
(e) stirring the reaction mixture of step (d) for 10-60 minutes;
(f) cooling the reaction mixture to 0-35 °C;
(g) stirring the cooled reaction mixture of step (f) for 1-3 hours;
(h) recovering the precipitated Form I of atorvastatin hemi-calcium.
In yet another embodiment, the specification discloses a process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising the steps of:
(a) dissolving (4R-cis)-1,1 -dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-( 1 -methyleth-yl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-lyl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate in acetonitrile;
(b) raising the temperature of the reaction mixture of step (a) to 30-70 °C;
(c) cooling the mixture of step (b) to 0-30 °C;
(d) adding dilute hydrochloric acid to the reaction mixture of step (c) drop wise;
(e) stirring the reaction mixture of step (d) for 1-3 hours;
(f) adding aqueous solution of sodium hydroxide to the reaction mixture of step (e);
(g) raising the temperature of the reaction mixture of step (f) to 30-70 °C;
(h) stirring the reaction mixture of step (g) for 1-3 hour;
(i) removing the solvent from the reaction mixture of step (h);
(j) charging methanol to the reaction mixture of step (i);
(k) stirring the reaction mixture of step (j) for 15-50 minutes below 45 °C;
(I) removing the solvent from the reaction mixture of step (k);
(m) charging tert-butyl methyl ether to the reaction mixture of step (I);
(n) stirring the reaction mixture of step (m) for 10-30 minutes;
(o) settling the reaction mixture of step (n) for 1 hour;
(p) separating the lower aqueous layer from the reaction mixture of step (o);

(q) adjusting pH of the reaction mixture of step (p) to 8.8-9.2 by adding dliute
hydrochloric acid; (r) adding the reaction mixture of step (q) to adueous calcium acetate solution
seeded with Form-! of atorvastatin hemi-calcium;
(s) stirring the reaction mixture of step (r) for 10-60 minutes;
(t) cooling the reaction mixture of step (s) to 0-30 °C;
(u) stirring the cooled reaction mixture of step (t) for 1-3 hours;
(v) recovering the precipitated Form I of atorvastatin hemi-calcium.
The Form I of atorvastatin hemi-calcium obtained by the process of this invention is

substantially pure.

A pharmaceutical compostion comprising Form I of atorvatatin hemi-calcium

obtained by the process of this invention and one or more pharmaceutically

acceptable excipients.

A method for tracting hypercholesterolemia comprising administering the

pharmaceutical composition comprising Form I of atrvastatin hemi-calcium obtained

by the process of this invention and one more phrmaceutically acceptable

excipients to a patient in need thereof.

DESCRIPTION OF THE DRAWINGS

Figure 1: An X-ray poder diffraction pattern of crystalline atorvastatin hemi-calcium

Form I.

DETAILED DESCRIPTION OF THE INVENTION

The term 'substantially pure' as used herein means that atorvastatin hemi-calcium

Form I isolated by the process as described and exemplified herein, is substanitially
3

free from any other polymorph of atorvastatin hemi-calcium as well as other impurities.
In one embodiment, the specification discloses a process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising adding aqueous solution of atorvastatin sodium to aqueous solution of calcium acetate.
In another embodiment, the specification discloses a process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising the steps of:
(a) mixing calcium acetate in water;
(b) raising the temperature of the mixture of step (a) to 40-75 °C;
(c) seeding the mixture of step (b) with Form I of atorvastatin hemi-calcium;
(d) adding an aqueous solution of atorvastatin sodium of pH 8.8-9.2 to the mixture of step (c);
(e) stirring the reaction mixture of step (d) for 10-60 minutes;
(f) cooling the reaction mixture to 0-30 °C;
(g) stirring the cooled reaction mixture of step (f) for 1-3 hours;
(h) recovering the precipitated Form I of atorvastatin hemi-calcium.
Atorvastatin base can be prepared by the method described in Tetrahedron Letters, Vol. 33, No. 17, pp 2283-2284, 1992. The base can then be converted to sodium salt by any conventional method.
The process for the preparation of Form I of atorvastatin hemi-calcium comprises dissolving calcium acetate in water and heating to 40-75 °C. Preferably the solution is heated to 40-55 °C, more preferably to 50-55 °C. The solution is then seeded with Form I of atorvastatin hemi-calcium. An aqueous solution of atorvastatin sodium is added drop wise to the above solution for a period of 1 hour. The reaction mixture is then stirred for 10-60 minutes, preferably for 20-40 minutes and more preferably for 30 minutes. The reaction mixture is then cooled to 0-30 °C, preferably to 10-30 "C, more preferably to 25-30 °C. The reaction mixture is then stirred for 1-3 hours,

preferably for 2 hours. Atorvastatin hemi-calcium Form I is separated out from the reaction mixture and recovered by any method known in the art.
One of the preferred methods of recovering atorvastatin hemi-calcium Form I from the reaction mixture comprises centrifuging the reaction mixture and washing the residue with a mixture of water and alcohol. The most preferred alcohol for this purpose is methanol. Atorvastatin hemi-calcium Form I obtained thus is the spin dried for 10-60 minutes, preferably for 30 minutes and then dried under vacuum at 30-35 °C.
In yet another embodiment, the specification discloses a process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising the steps of:
(a) dissolving (4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methyleth-
yl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-lyl]ethyl}-2,2-dimethyl-1,3-
dioxane-4-acetate in acetonitrile;
(b) raising the temperature of the reaction mixture of step (a) to 30-70 °C;
(c) cooling the mixture of step (b) to 0-30 °C;
(d) adding dilute hydrochloric acid to the reaction mixture of step (c) drop wise;
(e) stirring the reaction mixture of step (d) for 1-3 hours;
(f) adding aqueous solution of sodium hydroxide to the reaction mixture of step
(e);
(g) raising the temperature of the reaction mixture of step (f) to 30-70 °C;
(h) stirring the reaction mixture of step (g) for 1-3 hour;
(i) removing the solvent from the reaction mixture of step (h);
(j) charging methanol to the reaction mixture of step (i);
(k) stirring the reaction mixture of step (j) for 15-50 minutes below 45 oC;
(I) removing the solvent from the reaction mixture of step (k);
(m)charging tert-butyl methyl ether to the reaction mixture of step (I);
(n) stirring the reaction mixture of step (m) for 10-30 minutes;
(o) settling the reaction mixture of step (n) for 1 hour;
(p) separating the lower aqueous layer from the reaction mixture of step (o);

(q) adjusting pH of the reaction mixture of step (p) to 8.8-9.2 by adding dilute
hydrochloric acid; (r) adding the reaction mixture of step (q) to aqueous calcium acetate soiution
seeded with Form-I of atorvastatin hemi-calcium; (s) stirring the reaction mixture of step (r)for10-60 minutes; (t) cooling the reaction mixture of step (s) to 0-30oC (u) stirring the cooled reaction mixture of step (t) for 1-3 hours; (v) recovering the precipitated Form I of atorvastatin hemi-calcium.
(4R-cis)-1,1-Dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(ph-
enylamino)-carbonyl]-1H-purrol-lyl]ethyl}-2,2-dimrthyl-1,3-dioxane-4-acetate can be made by the method described in Tetrahedron Letters. Vol 33 No 17 pp 2283-2284, 1992.
(4R-cis)-1-Dimethylethyl-6-{2-[2-(4-flurophenyl)-5-(1-methylethyl)-3-phenyl-4-[(ph-
enylamino)-carbonyl]-1H-pyrrol-lyl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate is
dissolved in acetonitrile and heatede to 30-70 oC preferably to 30-45 oC, more

preferably to 40-45°C. The reaction mixture is coored to 0-30 oC, preferably to 25-30 °C. Dilute hydrochloric acid is added drop wise the above solution in a period of 30 minutes. The reaction mixture is then stirred for 1-3 hours preferably for 2 hours. Aqueous solution of sodium hydroxide was added to the reaction mixture until the pH becomes 12.0. The reaction mixture is again heated to 30.70 °c preferably to 30-45 °C, more preferably to 40-45 °C and stirred for 1-8 hours preferably for 1 hour. The organic solvents were distilled out from the reaction, mixture under vacuum, Methanol was added to the reaction mixture below 45 °C and stirred for 30 minutes. Methanol was distilled out from the reaction mixture under vacuum. This operation was repeated twice. Then tert-butyl methyl ether is added to the reaction mixture and stirred for 10-30 minute, preferably for 15 minutes and the reaction mixture is allowed to settle for 1 hour. The lower aqueous layer is collected and its pH is adjusted to 8.8-9.2 by the addition of dilute hydrochloric acid. This solution is assed to calcium acetate solution seeded with Form-I of atorvastatin hemi-calcium. The resulting

reaction mixture is then stirred for 10-60 minutes, preferably for 20-40 minutes and more preferably for 30 minutes. The reaction mixture is then cooled to 0-30 °C, preferably to 10-30 °C, more preferably to 25-30 °C. The reaction mixture is then stirred for 1-3 hours, preferably for 2 hours. Atorvastatin hemi-calcium Form I is separated out from the reaction mixture and recovered by any method known in the art.
One of the preferred methods of recovering atorvastatin hemi-calcium Form I from the reaction mixture comprises centrifuging the reaction mixture and washing the residue with a mixture of water and alcohol. The most preferred alcohol for this purpose is methanol. Atorvastatin hemi-calcium Form I obtained thus is the spin dried for 10-60 minutes, preferably for 30 minutes and then dried under vacuum at 30-35 °C.
Atorvastatin hemi-calcium is known to exist in a number of polymorphic forms. Any skilled person would appreciate that even a minor change e.g. rate of heating, rate of cooling, strirring speed etc. in the process parameters may ultimately change the polymorphic form of atorvastatin hemi-calcium. The process of the present invention does not employ any organic solvent as taught fn the prior art.
Thus, the major advantage of the process of instant invention is that it does not employ any organic solvent for the preparation of crystalline form I of atorvastatin hemi-calcium. Hence, the process becomes cost-effective, eco-friendly and commercially more suitable than any other prior art processes.
The process of the present application produces a stable, substantially pure crystalline Form I of atorvastatin hemi-calcium which can be used for the preparation of pharmaceutical composition comprising crystalline Form I of atorvastatin hemi-calcium. The pharmaceutical composition comprising crystalline Form I of atorvastatin hemi-calcium obtained by the process of this invention may be used for treating hypercholesterolemia.

The atorvastatin hemi-calcium crystalline Form I prepared according to the present invention is characterized by its X-ray diffraction pattern. Atorvastatin hemi-calcium crystalline Form I has an XRPD pattern having significant characteristics peaks at about 3.0, 6.0, 9.0, 9.3, 9.4, 10.1, 10.4, 11.7, 12.0, 13.8, 15.1, 16.9, 17.1, 17.8, 18.2, 18.7, 19.3, 19.7, 20.5, 21.1, 21.5, 21.8, 22.5, 23.2, 23.5, 24.2, 24,5, 25.0, 26.2, 27.3, 28.1, 28.6, 29.0, 30.1, 31.7, 33.1, 33.8, 35.0, 36.0, 37.1, 38.4 and 39.1, ±0.2 6. An XRPD pattern of Form I of atorvastatin calcium is shown in Fig. 1.
The Form I of atorvastatin hemi-calcium is substantially free of other polymorphs and may be formulated into a dosage form, like tablet, capsule, etc., by combining with one or more pharmaceutically acceptable excipients. The dosage form may be oral or parenteral.
The following examples illustrate preparation of atorvastatin hemi-calcium Form I, and is not intended to limit the scope of the invention.
Example 1:
Atorvastatin sodium is dissolved in water in a reactor. The pH of the aqueous solution is adjusted to 8.8-9.2 by the addition of dilute hydrochloric acid at 25-35 °C. In another reactor, aqueous solution of calcium acetate is charged and heated to 50-55 °C. Atorvastatin calcium crystalline Form-I is added to the aqueous solution of calcium acetate in one lot. The aqueous solution of atorvastatin sodium prepared above is added drop-wise in a period of 1 hour at 50-55 °C. The reaction mixture is stirred for 30 minutes and cooled to 25-30 °C. The reaction mixture was further stirred for 2 hours at this temperature. The reaction mass is centrifuged and washed with aqueous methanol. The material was spin dried for 30 minutes and dried in a vacuum oven at 30-35 °C.
Example 2:
(4R-cis)-1,1-Dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[{ph-enylamino)-carbonyl]-1H-pyrrol-lyl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (1.1 Kg)

is dissolved in acetonitrile (7.5 L) and heated to 40-45 °C. The reaction mixture was then cooled to 25-30 °C and dilute hydrochloric acid was added to the reaction mixture drop wise over a period of 30 minutes. The reaction mixture was stirred for 2 hours and sodium hydroxide solution (0.2 Kg sodium hydroxide in 0.5 L water) was added to the reaction mixture and heated to 40-45 °C again. The reaction mixture was stirred for 1 hour. The organic solvent was distilled out completely in vacuum. Methanol was charged in the reaction mixture for stirred for 30 minutes. Then methanol was distilled off completely under vacuum. The operation was repeated twice. Then tert-butyl methyl ether (12 L) was charged to the reaction mixture and stirred for 15 minutes. The reaction mixture was allowed to settle for 1 hour and the lower aqueous layer was taken adjusted its pH to 8.8-9.2 by the addition of dilute hydrochloric acid. Calcium acetate was dissolved in water in a separate reactor and heated to 50-55 °C. Crystalline form I of atorvastatin hemi-calcium was seeded to the aqueous solution of atorvastatin hemi-calcium, The above aqueous solution of atorvastatin sodium was added drop wise to aqueous solution of calcium acetate seeded with crystalline Form-I of atorvastatin hemi-calcium over a period of 1 hour at 50-55 °C. The reaction mixture is stirred for 30 minutes and cooled to 25-30 °C. The reaction mixture was further stirred for 2 hours at this temperature. The reaction mass is centrifuged and washed with aqueous methanol. The material was spin dried for 30 minutes and dried in a vacuum oven at 30-35 °C.

WE CLAIM:
1. A process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising adding aqueous solution of atorvastatin sodium to aqueous solution of calcium acetate seeded with crystalline Form I of atorvastatin hemi-calcium.
2. A process for the preparation of crystalline Form I of atorvastatin hemi-calcium comprising the steps of:

(a) mixing calcium acetate in water;
(b) raising the temperature of the mixture of step (a) to 40-75 °C;
(c) seeding the mixture of step (b) with Form I of atorvastatin hemi-calcium;
(d) adding an aqueous solution of atorvastatin sodium to the mixture of step (c);
(e) stirring the reaction mixture of step (d) for 30 minutes;
(f) cooling the reaction mixture to 0-35 °C;
(g) stirring the cooled reaction mixture of step (f) for 1-3 hours;
(h) recovering the precipitated Form I of atorvastatin hemi-calcium.
3. A process for the preparation of crystalline Form I of atorvastatin hemi-calcium
comprising the steps of:
(a) dissolving {4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methyleth-
yl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-lyl]ethyl}-2,2-dimethyl-1,3-
dioxane-4-acetate in acetonitrile;
(b) raising the temperature of the reaction mixture of step (a) to 30-70 °C;
(c) cooling the mixture of step (b) to 0-30 °C;
(d) adding dilute hydrochloric acid to the reaction mixture of step (c) drop wise;
(e) stirring the reaction mixture of step (d) for 1-3 hours;
(f) adding aqueous solution of sodium hydroxide to the reaction mixture of step
(e);
(g) raising the temperature of the reaction mixture of step (f) to 30-70 °C;
(h) stirring the reaction mixture of step {g)for 1-3 hour;
(i) removing the solvent from the reaction mixture of step (h);

(]) charging methanol to the reaction mixture of step (i);
(k) stirring the reaction mixture of step (j) for 15-50 minutes below 45 °C;
{I) removing the solvent from the reaction mixture of step (k);
(m) charging tert-butyl methyl ether to the reaction mixture of step (I);
(n) stirring the reaction mixture of step (m) for 10-30 minutes;
(o) settling the reaction mixture of step (n) for 1 hour;
(p) separating the lower aqueous layer from the reaction mixture of step (o);
(q) adjusting pH of the reaction mixture of step (p) to 8.8-9.2 by adding dilute
hydrochloric acid; (r) adding the reaction mixture of step (q) to aqueous calcium acetate solution
seeded with Form-I of atorvastatin hemi-calcium; (s) stirring the reaction mixture of step (r) for 10-60 minutes; (t) cooling the reaction mixture of step (s) to 0-30 °C; (u) stirring the cooled reaction mixture of step (t) for 1-3 hours; (v) recovering the precipitated Form I of atorvastatin hemi-calcium.
4. The process of claim 1, wherein Form-I of crystalline atorvastatin hemi-calcium is seeded.
5. The process of claim 1, 2 or 3, wherein precipitated Form I of atorvastatin is recovered by centrifugation.
6. The process of claim 1, 2 or 3, wherein aqueous solution of atorvastatin sodium is added to an aqueous solution of calcium acetate at a temperature of 50-55 °C.
7. The process of claim 2, wherein the reaction mixture of step (e) is stirred at 50-55 °C for 30 minutes.
8. The process of claim 3, wherein the reaction mixture of step (f) is stirred at 40-45 °C for 1 hour.

9. Substantially pure crystalline Form I of atorvastatin hemi-calcium prepared according to claim 2 or 3.
10. A pharmaceutical composition comprising crystalline Form I of atorvastatin hemi-calcium prepared according to the process of claim 2 or 3 and one or more pharmaceutically acceptable excipients.