FIELD OF THE INVENTION

The present invention relates to an improved process for preparing amorphous form of pitavastatin calcium salt of Formula I.

BACKGROUND OF THE INVENTION

Pitavastatin calcium, chemically known as (3,55',6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid calcium (2:1) salt, is a synthetic lipid lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase).

Pitavastatin is being marketed under the brand name Livalo®, as an oral tablet in 1 MG, 2 MG and 4 MG strengths. Pitavastatin calcium is used to lower the lipid levels including cholesterol in blood and can be used for the prevention or treatment of hyperlipidemia and atherosclerosis.

Pitavastatin was disclosed for the first time in US patents US 4,761,419, US 5,011,930 and US 5,753,675.

US 2009/0182008 Al discloses crystalline polymorphic forms A, B, C, D, E, F and an amorphous form of pitavastatin calcium. This patent publication also discloses different processes to prepare amorphous pitavastatin calcium.

The process to prepare amorphous pitavastatin calcium comprises the addition of non-solvent to a concentrated solution of pitavastatin caJcium in an organic solvent.

The amorphous form can also be prepared according to prior art process by lyophilization of an aqueous solution of pitavastatin calcium.

The above process does not provide a direct process for the preparation of amorphous form of pitavastatin calcium salt and lyophilization technique is not economically feasible and not industrially applicable.

US 2009/0176987 AI discloses Crystalline Form A of pitavastatin calcium. This patent publication also stated that if pitavastatin calcium (crystal Form A) is subjected to drying in a usual manner, the crystallinity will decrease to a state close to amorphous state.

The present inventors have now found a process for preparing amorphous pitavastatin calcium, which is industrially feasible and economically viable.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a process for the preparation of amorphous pitavastatin calcium, which is simple, industrially applicable and economically viable.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of amorphous form of pitavastatin calcium of Formula I,

which comprises:

a) reacting a CM alkyl ester of pitavastatin of formula II,

wherein R represents C1.4 alkyl group, preferably selected from methyl, ethyl and tert-butyl with a base in the presence of alcohol solvent to obtain a solution;

b) concentrating the solution to obtain a residue;

c) combining the residue with water to obtain an aqueous solution;

d) washing the aqueous solution with a water immiscible organic solvent;

e) optionally, treating with carbon enoanticromos;

f) partially concentrating the content to remove dissolved organic solvents;

g) adding a source of calcium ions to the solution to precipitate amorphous pitavastatin calcium; and

h) isolating pitavastatin calcium salt in amorphous form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the powder x-ray diffractogram of the wet pitavastatin calcium. FIG. 2 shows the powder x-ray diffractogram of the dry pitavastatin calcium.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process to prepare amorphous form of pitavastatin calcium which comprises, reacting a CM alkyl ester of pitavastatin of formula II with a base in the presence of alcoholic solvent to obtain a solution. The base is selected from alkali and alkaline earth metal bases other than calcium hydroxide such as sodium hydroxide, potassium hydroxide and barium hydroxide. The base is preferably added portion wise in the presence of alcohol solvent such as methanol, ethanol, n-propanol, isopropanol or mixtures thereof preferably ethanol to obtain a solution.

The resulting solution is stirred for at least 5 minutes, more preferably for about 2 hours. The solution is then evaporated under reduced pressure at a temperature of 25-80°C, most preferably at 30-45°C to obtain a residue.

The obtained residue is combined with water to obtain a solution and which is then washed with organic solvent. The organic solvent is water immiscible and is selected from C4-7 esters, ketones, C1.5 ethers such as methyl tert-butyl ethers, aliphatic or aromatic hydrocarbons such as hexane and toluene or mixtures thereof. After washing with organic solvent, optionally carbon enoanticromos is added to the aqueous salt solution of pitavastatin and the resulting aqueous solution is stirred for 1-5 hours, preferably for 30 minutes to 1 hour at ambient temperature and thereafter, carbon is filtered. The traces of organic solvent remaining may be removed by conventional techniques known in the art, such as evaporation under reduced pressure at a temperature of about 5-80°C, more preferably at 50-60°C temperature.

The resulting solution is added to the source of calcium ions such as calcium chloride or vice versa, preferably at ambient temperature to yield wet pitavastatin calcium. The wet pitavastatin calcium obtained through above process is amorphous.

The wet pitavastatin calcium is then dried at 40-45°C till moisture content is less than 0.5% w/w. The pitavastatin calcium obtained after drying is also amorphous in nature, which is confirmed by Powder X-ray Diffraction Pattern.

In another aspect of the present invention, the process to prepare amorphous form of pitavastatin calcium comprises combining a suspension of pitavastatin tert-butyl ester in ethanol with sodium hydroxide to obtain a solution and stirring during or after combining, evaporating the solvent under reduced pressure to obtain a residue, combining the residue with water to obtain an aqueous solution, washing the aqueous solution with methyl tert-butyl ether, evaporating traces of methyl tert-butyl ether under reduced pressure, adding calcium chloride to the solution to precipitate pitavastatin calcium and isolating pitavastatin calcium salt in amorphous form.

In another aspect of the present invention, the process to prepare amorphous form of pitavastatin calcium comprises combining a suspension of pravastatin ethyl ester in ethanol with sodium hydroxide to obtain a solution and stirring during or after combining, evaporating the solvent under reduced pressure to obtain a residue, combining the residue with water to obtain an aqueous solution, washing the aqueous solution with methyl tert-butyl ether, evaporating traces of methyl tert-butyl ether under reduced pressure, adding calcium chloride to the solution to precipitate pitavastatin calcium and isolating pitavastatin calcium salt in amorphous form.

Unless otherwise specified, the term 'ambient temperature' refers to a temperature of from about 5°C to 30°C. Most preferably, 'ambient temperature' refers to a temperature of about 25°C. The term 'reduced pressure' generally refers to a pressure of about 10 mm Hg to about 50 mm Hg.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF AMORPHOUS (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3-YLJ-3,5-DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT
Ethyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate (25 g, 0.055 mole) was suspended in ethanol (125 ml) and cooled to 0-5°C. Sodium hydroxide (2.28 g, 97% w/w assay, 0.055 mole) in water (50 ml) was added to the above suspension at 0-5°C and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, solvent was evaporated and water (240 ml) was added to it. The resulted aqueous layer was extracted with methyl tert-butyl ether (2 x 50 ml). Carbon (1 g) was added to the aqueous layer and stirred for -30 min. It was filtered through hyflo, the filtrate was partially concentrated to remove dissolved organic solvents and thereafter a solution of calcium chloride (4.5 g, 0.030 mole) in water (25 ml) was added to it. The pitavastatin calcium, which precipitated out was filtered and washed with water (2 x 25 ml). The product was dried under vacuum at 40-45°C for 8 h. Yield: 22 g (90%). Purity: 99.5%.

EXAMPLE 2

PREPARATION OF AMORPHOUS (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)-QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT
Tert-Butyl(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy -6-heptenoate (25 g, 0.052 mole) was suspended in ethanol (125 ml) and cooled to 0-5°C. Sodium hydroxide (2.09 g, 97% w/w assay, 0.052 mole) in water (50 ml) was added to the above suspension at 0-5°C and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, solvent was evaporated and water (240 ml) was added to it. The resulted aqueous layer was extracted with methyl tert-butyl ether (2 x 50 ml). Carbon (1 g) was added to the aqueous layer and stirred for -30 min. It was filtered through hyflo, filtrate was partially concentrated under vacuum to remove dissolved organic solvents and thereafter a and a solution of calcium chloride (4.23 g, dihydrate, 0.029 mole) in water (25 ml) was added to it. The pitavastatin calcium, which precipitated out was filtered and washed with water (2 x 25 ml). The product was dried under vacuum at 40-45 °C for 8 h. Yield: 22 g (90%). Purity: 99.8%.

WE CLAIM:

1. A process for the preparation of amorphous pitavastatin calcium of formula I, comprising:

a) reacting a compound of formula II,

wherein R represents CM alkyl group
with a base in the presence of alcohol solvent to obtain a solution;

b) concentrating the solution to obtain a residue;

c) combining the residue with water to obtain an aqueous solution;

d) washing the aqueous solution with a water immiscible organic solvent;

e) optionally, treating with carbon enoanticromos;

f) partially concentrating the filtrate to remove dissolved organic solvents;

g) adding a source of calcium ions to the solution to precipitate amorphous pitavastatin calcium; and

h) isolating amorphous pitavastatin calcium.

2. The process according to claim 1, wherein base is selected from alkali and alkaline earth metal bases other than calcium hydroxide.

3. The process according to claim 2, wherein base is selected from the group consisting of sodium hydroxide, potassium hydroxide and barium hydroxide.

4. The process according to claim 1, wherein alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol and isopropanol.

5. The process according to claim 4, wherein alcohol solvent is ethanol.

6. The process according to claim 1, wherein water immiscible organic solvent is selected from the group consisting of C4.7 esters, ketones, C1.5 ethers and aliphatic and aromatic hydrocarbons.

7. The process according to claim 6, wherein water immiscible organic solvent is methyl tert-butyl ether.

8. The process according to claim 1, wherein calcium ion source is calcium chloride.

9. A process for preparing amorphous pitavastatin calcium substantially as described herein.