The present invention relates to a process for the preparation of pure Pravastatin sodium.
Pravastatin sodium is chemically 1-naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-p,6,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [lS-[la(pS*,8S*),2a,6a,8p(R*),8aa]]- of structural Formula I:
(Formula Removed)
FORMULA I
Pravastatin sodium is available in the market to reduce the risk of myocardial infarction and to reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes. Pravastatin sodium is also useful as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hyper-cholesterolemia.
US 4,346,227 provides a process for purification of pravastatin sodium by HPLC methods. EP 1,481,674 B1 provides a process for the preparation of pravastatin sodium having purity above 99% from pravastatin ammonium using sodium hydroxide and subsequent treatment with resin and purification by crystallization methods.
US 6,695,969 provides a process for purification of pravastatin sodium by chromatographic methods, wherein the final pravastatin sodium is obtained with a purity up to 99.9%.
Similar methods for the purification of pravastatin sodium are provided in US 4,537,859, US 6,790,984, US 7,189,558, US 2006/0281155, EP 1,477,471 A1, WO 02/030415, WO 04/087935, WO 05/121062, WO 06/046130, WO 06/058943 and WO 06/086680.
EP 1,054,993 B1 and EP 0,832,108 B1 mention about the use of reverse-osmosis for isolating antihypercholesterolemics or HMG-CoA reductase inhibitors in general from fermentation broth. However, there is no specific method disclosed or suggested in these references about obtaining pure pravastatin sodium.
The present inventors have surprisingly observed that the purity of pravastatin sodium can be tremendously increased by employing reverse osmosis method. Further, by employing this method, multiple crystallization steps, salt exchange and chromatographic methods need not be employed to improve the purity of pravastatin sodium. Thus the present invention is simple, efficient and economic to obtain pure pravastatin sodium.
A first aspect of the invention provides a process for the preparation of pure pravastatin sodium, wherein the process comprises,
a) dissolving crude pravastatin sodium in a solvent,
b) concentrating the solution obtained in step a) by reverse osmosis, and
c) isolating pure pravastatin sodium from the mixture thereof.
The crude pravastatin sodium can be the product isolated from the fermentation broth according to the methods provided in the prior art references, for example, US 6,566,120, US 7,223,590, EP 1,452,602 A1 and WO 99/10499. The crude pravastatin sodium has a purity of about 97% or below. The crude pravastatin sodium is dissolved in a solvent. The solvent is water or an organic solvent, or a mixture thereof. The organic solvent is selected from a group consisting of Ci.3 alkanols. The solvent is more preferably water. The dissolution of crude pravastatin sodium in the solvent is carried out at a temperature of about 5°C to
about 60°C. The dissolution is preferably carried out at a temperature of about 15°C to about 30°C. The solution so obtained is optionally subjected to carbon treatment. The carbon treatment can be carried out by treating the solution with about 10% to about 30% of activated charcoal to the weight of pravastatin sodium followed by stirring and filtration. The solution obtained is concentrated by reverse osmosis. The concentration can be partial or complete. The solution is preferably partially concentrated by reverse osmosis. The solution is more preferably concentrated by reverse osmosis to obtain a volume of about 10% to about 50% from the initial volume. A suitable membrane, which is compatible with the solvent system, is used for reverse osmosis. The parameters of reverse osmosis system including transmembrane pressure, effective surface area, permeate flux and cross flow rate can be optimized to obtain pure pravastatin sodium. The transmembrane pressure is employed in the range of about 4 Kg to about 20 Kg. The effective surface area can be about 3 to about 5 square feet, the permeate flux can be about 10 to about 30 L/h, and the cross flow rate can be about 3 to about 5 L/minute. Pure pravastatin sodium is isolated from the concentrated mixture subsequent to reverse osmosis. The isolation can be carried out by the methods including solvent precipitation, distillation, evaporation, filtration, decantation and centrifugation, or a combination thereof. The isolation is preferably carried out by solvent precipitation using an antisolvent. The antisolvent is preferably selected from a group consisting of acetonitrile, ethyl acetate, acetone, ethyl methyl ketone, methyl isobutyl ketone, chloroform and ether, and mixtures thereof. The antisolvent is more preferably acetonitrile. After treating with antisolvent, the pure pravastatin sodium is isolated by filtration, concentration, distillation, evaporation, decantation and centrifugation, or a combination thereof. The pure pravastatin sodium is optionally crystallized further using water or an organic solvent. The organic solvent can be alkanols, esters, ethers, ketones, amides, hydrocarbons, or mixtures thereof. The pure pravastatin sodium so obtained has a purity of about 99% or above. The pure pravastatin sodium so obtained preferably has a purity of about 99.5% or above.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE PREPARATION OF PURE PRAVASTATIN SODIUM:
Crude pravastatin sodium (100 g, HPLC Purity: 95.8%) was dissolved in de-ionised water (0.3 L) at about 25°C. Activated charcoal (10 g) was added to the solution and stirred for 30 minutes. The solution was filtered through Celite bed and subsequently through 0.5 micron filter, and the bed was washed with de-ionised water (100 ml). The filtrate was diluted with water to 4 L and added into reverse osmosis reservo-r (MILLIPORE, Type: Helicon - RO4, Nanomax-50 Catalogue No: CDRN50004). The solution was concentrated to 300 ml at 4 to 5 kg/cm2 pressure by reverse osmosis. The following parameters were controlled while employing reverse osmosis:
Effective surface area: 4.0 square feet
Permeate flux: 15 to 26 L/h
Cross flow rate: 4 L/minute
Quantity of water used for diafiltration: 2000 ml
Pressure : 4-5 kg/cm2
Subsequent to reverse osmosis, the membrane was washed with de-ionised water (100 ml). The concentrate and membrane washing were mixed and distilled under vacuum (20 torr) at a temperature not exceeding 55°C (Bath Temperature). Methanol (50 ml) was added to the concentrated mass and the methanol was distilled off under vacuum below 55°C (Bath temperature). The
concentrated mass was dissolved in Methanol (400 ml). Activated carbon (10 g) was added to the solution and stirred for 30 minutes. The solution was filtered through Celite bed and subsequently through 0.5 micron filter, and the bed was washed with methanol (100 ml). The solution was concentrated under vacuum at a temperature not exceeding 55°C (Bath Temperature). The concentrated mass was dissolved in water (300 ml). Acetonitrile (4 L) was added to the solution in 2 h duration accompanied by stirring at about 25°C. The mass was stirred for 15 h at 25°C, the reaction mixture was cooled to 0° to 5°C and stirred for 2 h. The solid obtained was filtered, washed with acetonitrile (100 ml), and dried under vacuum at 35° to 40°C. The dried product (40 g) was dissolved in methanol (120 ml), filtered through 0.5u filter and concentrated under vacuum at a temperature not exceeding 55°C (Bath Temperature). The concentrated mass was dissolved with water (120 ml) and acetonitrile (1.2 L) was added to the solution in 2 h duration accompanied by stirring at about 25°C. The mixture was further stirred for 15 h at 25°C. The reaction mixture was cooled to 0° to 5°C and stirred for 2 h. The solid obtained was filtered, washed with acetonitrile (40 ml), and dried under vacuum at 35° to 40°C to obtain the title compound.
Yield: 28.8 g HPLC Purity: 99.5% Moisture content: 4% w/w

WE CLAIM:
1. A process for the preparation of pure pravastatin sodium, wherein the process
comprises,
a) dissolving crude pravastatin sodium in a solvent,
b) concentrating the solution obtained in step a) by reverse osmosis, and
c) isolating pure pravastatin sodium from the mixture thereof.

2. A process according to claim 1, wherein the crude pravastatin sodium has a
purity of about 97% or below.
3. A process according to claim 1, wherein the solvent is water or an organic
solvent, or a mixture thereof.
4. A process according to claim 3, wherein the organic solvent is selected from a
group consisting of Ci-3 alkanols.
5. A process according to claim 3, wherein the solvent is water.

6. A process according to claim 1, wherein the concentration is partial or
complete.
7. A process according to claim 1, wherein the isolation is carried out by the
methods including solvent precipitation, distillation, evaporation, filtration,
decantation and centrifugation, or a combination thereof.
8. A process according to claim 7, wherein the isolation is carried out by solvent
precipitation using an antisolvent.
9. A process according to claim 8, wherein the antisolvent is selected from a
group consisting of acetonitrile, ethyl acetate, acetone, ethyl methyl ketone,
methyl isobutyl ketone, chloroform and ether, and mixtures thereof.
10. A process according to claim 1, wherein the pure pravastatin sodium
obtained at step c) has purity of about 99% or above.