WO2006058943A1 - Method of obtaining purified pravastatin sodium - Google Patents

Abstract

The invention relates to a method of obtaining purified pravastatin sodium from a fermentation broth. The inventive method is simple, fast and cost effective and can be easily performed on an industrial scale. According to the invention, the method comprises the following step, namely: formation of a pravastatin-enriched aqueous solution, production and isolation of crude pravastatin sodium or pravastatin calcium, and transformation of same into purified pravastatin sodium by means of suspension in water, adjustment to acid pH, extraction with organic solvent such as methyl isobutyl ketone or ethyl acetate, addition of a carboxylic acid sodium salt solution in low-molecular-weight alcohol, such as sodium octanoate in methanol, and isolation of the filtration-purified pravastatin sodium, thereby producing a pharmaceutical grade end product, with the optional application of a process involving the recrystallisation of the purified pravastatin sodium thus obtained.

Description

 PROCEDURE FOR OBTAINING PRAVASTATIN

PURIFIED SOUND

D E S C R I P C I Ó N

OBJECT OF THE INVENTION

The present invention relates to a new method for the isolation and purification of pravastatin sodium, from a fermentation broth.

The object of the invention is to provide a process that allows obtaining pravastatin sodium, from a fermentation broth, in a simple, fast and at the same time economical way, thereby obtaining a high quality final product. Procedure that is easy to scale industrial and very clean from an environmental point of view.

The present invention falls within the scope of the pharmaceutical industry.

BACKGROUND OF THE INVENTION

Pravastatin is a well known compound, belonging to the family of so-called statins, which are compounds that inhibit the enzyme HMG-CoA reductase. This enzyme acts as a catalyst for the mevalonic acid formation reaction, which is the limiting stage of cholesterol biosynthesis. Pravastatin, chemically referred to as 3,5-dihydroxy-7- [6-hydroxy-2-methyl-8- (2-methylbutyryloxy) -1, 2,6,7,8,8a-hexahydro-l acid -naphthyl] heptanoic, is used as an antihypercholesterolemic agent in the form of sodium salt, and has the following formula:

Pravastatin was initially isolated from canine urine as a compactin metabolite during a study of compactin metabolism (Tanaka and cois .; unpublished results), and subsequently structurally elucidated. (Haruyama.H and cois; Chemical & Pharmaceutical

Bulletin (1986), 34 (4), 1459).

This compound can also be obtained by enzymatic hydroxylation of the compactin, through the use of strains of various microorganisms, as shown in US Patent 4346227 of the Sankyo company, in which, in addition, its properties are described as inhibitor of the enzyme HMG-CoA reductase .

Several procedures for obtaining pravastatin sodium from a fermentation broth have been published. Thus, in US 4346227, pravastatin is extracted from the fermentation broth at acidic pH with ethyl acetate, previously separating the biomass by filtration. To the Pravastatin extract obtained is added a catalytic amount of trifluoro acetic acid, neutralized with sodium bicarbonate and concentrated to obtain a residue of pravastatin in its lactone form, which is purified by HPLC.

In US patent 5202029 a process of purification of a crude HMG-CoA reductase inhibitor by HPLC is described. Once the HMG-CoA reductase inhibitor is eluted in the column, the eluent is partially removed and by addition of water, its crystallization is achieved.

In another US patent 6306629, once the biomass is separated, pravastatin is adsorbed from the fermentation broth by means of a polymeric adsorbent resin, and subsequently washed and eluted with acetone or methanol. Once the eluent is concentrated, a residue is obtained which is purified by reverse phase HPLC.

A method of purifying a crude HMG-CoA reductase inhibitor by displacement chromatography is described in US Patent 6695969. The HMG-CoA reductase inhibitor is dissolved in a mobile phase and seeded on a column. Said column is washed with a second mobile phase that displaces the HMG-CoA reductase inhibitor through the column. Fractions that are analyzed by HPLC are collected and the HMG-CoA reductase inhibitor is obtained by lyophilization or recrystallization.

On the other hand, US 5616595 provides a process for the isolation of different water-insoluble compounds, which are present in a fermentation broth, by tangential filtration.

The above method is applicable to a wide variety of - A - compounds, among which is pravastatin. The fermentation broth is passed through a filter cyclically, so that it loses water, until the desired concentration is achieved. Next, the desired compound is isolated from the filtrate by extraction with a solvent, subsequently subjecting it to a purification process.

US 6583295 describes the preparation of a series of amine salts of HMG-CoA reductase inhibitors, including pravastatin, and their subsequent conversion to their pharmaceutically acceptable salts or to their lactone forms. In the examples of the patent, pravastatin sodium is obtained from the tert-butylamine salt, by dissolving said salt in ethanolic sodium hydroxide solution or in aqueous sodium carbonate solution.

There are, on the other hand, several methods of isolating pravastatin from a fermentation broth of the Mortierella maculata strain, which are described in US Patent 6682913. The fermentation broth, once it has been filtered, is loaded into a strong basic type anion exchange resin. After elution in the column, pravastatin is extracted at acidic pH with ethyl acetate or isobutyl acetate. Subsequently, lactonization occurs by adding a catalytic amount of trifluoroacetic acid. After recrystallization of the lactone form of pravastatin, the sodium salt is formed by the addition of sodium hydroxide and purified on an HP-20 molecular exclusion chromatography column. After eluting from the column with a mixture of acetone and water, finally pravastatin sodium is isolated by lyophilization.

Alternatively, after extraction of the broth at acidic pH, pravastatin can be converted into its corresponding secondary amine salt by the addition of a suitable amine. After recrystallization, this pravastatin amine salt is transformed into sodium salt by the addition of sodium ethoxide. By recrystallization or lyophilization, pravastatin sodium is obtained.

Another option for obtaining pravastatin sodium, after the extraction of the broth at acidic pH, consists in re-extracting the pravastatin contained in the organic phase of ethyl acetate or butyl acetate, in the form of sodium salt by contact with a solution aqueous alkaline A subsequent purification by chromatography on non-ionic adsorbent resin allows the sodium pravastatin obtained to be of high purity.

EPI 190087 describes pravastatin isolation methods similar to those of the previous patent, with the difference that they refer to fermentation broths of the Micromonospora strain. Pravastatin is separated from the fermentation broth by adsorption in an anionic resin or by extraction with an organic solvent immiscible in water, followed by its conversion into its lactone form or into a secondary amine salt or by purification of the aqueous alkaline extract obtained from the organic extract from the fermentation broth, by chromatography on a non-ionic resin.

Another process of isolation of pravastatin sodium from a fermentation broth is described in US patent 6444452. Said process consists in obtaining an aqueous or organic solution enriched with pravastatin and by adding ammonium hydroxide or ammonia respectively, obtaining ammonium salt. of pravastatin, which is purified by recrystallization. This ammonium salt of pravastatin is subsequently dissolved in water, pravastatin is extracted with isobutyl acetate at acidic pH, and converted into sodium pravastatin by re-extraction with an aqueous solution of sodium hydroxide. The excess sodium ions are removed by treating the aqueous solution of pravastatin sodium with a water-insoluble cation exchange resin, for example, with a weak acid cationic resin, Amberlite IRC-50. Finally, the isolation of pravastatin sodium is produced by lyophilization or recrystallization.

Patent application WO 0232847 describes a method of purification of an aqueous solution of pravastatin sodium, called ^" salting out. ^" The fermentation broth is extracted at acidic pH with ethyl acetate and re-extracted by contact with an aqueous solution of sodium hydroxide.

To the aqueous solution of pravastatin sodium thus obtained, various inorganic salts are added, for example, sulfate, nitrate, or ammonium acetate or sodium chloride and the resulting mixture is heated to 20-60 ° C. After allowing to cool to 0 ^or C precipitation of pravastatin sodium is achieved with a purity of about 90%.

For its part, patent application WO 0232848 provides another method of isolation and purification of pravastatin sodium from a fermentation broth. The procedure consists in separating the mycelium and adding an inorganic base to the filtered broth, for example sodium hydroxide, and refluxing at basic pH. Next, an extraction of pravastatin at acidic pH is carried out using propyl acetate or butyl acetate. The enriched organic phase is re-extracted with an aqueous solution of sodium hydroxide at pH 8-9. To this aqueous phase of pravastatin sodium is added an inorganic acid and heated at a temperature of between 20 and 50 ° C and at pH between 2 and 5. High purity pravastatin is isolated by subsequent crystallization.

The procedures for obtaining pravastatin described in the different patents described above are difficult to implement at an industrial level, since they involve the use of HPLC chromatographic columns and, often, high volumes of solvent, which implies a high economic cost.

There are also problems with the fermentation broth of heading, since as is well known in the field of work to which the invention belongs, fermentation broths contain a large number of substances, necessary for the fermentation process, which, however, constitute potential impurities of the active ingredients. In addition, fermentation broths generally have very low concentrations of the active substance, which forces the treatment of large volumes of broth and hinders the subsequent isolation of the active substances.

Part of the problem is solved through the application of successive extraction and re-extraction operations, to obtain organic or aqueous solutions enriched with the active ingredients, while achieving partial removal of impurities contained in the fermentation broth. However, subsequent purification operations are usually required by chromatographic methods or isolation of intermediate products to obtain an active principle of the quality required in the pharmaceutical industry.

DESCRIPTION OF THE INVENTION

The procedure for obtaining purified pravastatin sodium from a fermentation broth that the invention proposes, solves in a completely satisfactory way the problem previously stated, in the different aspects mentioned. It is a simple method, which can be easily adapted to an industrial scale and that does not cause environmental problems.

Specifically, the process object of the present invention comprises the formation of an enriched aqueous solution of pravastatin from a fermentation broth, the obtaining and isolation of raw sodium pravastatin or calcium pravastatin, and its conversion into pravastatin sodium purified, as can be seen in the following scheme:

Fermentation broth

Miceli Organic Extract

Enriched aqueous solution

Pravastatin Sodium Pravas Itatina Calcium Raw

Pravastatin purified sodium

The process that the invention provides begins with the formation of an enriched aqueous solution of pravastatin from a fermentation broth. For this, the fermentation broth of pravastatin is adjusted to basic pH, preferably between 8.5 and 9.5, by using an aqueous solution of an inorganic base, for example sodium hydroxide. Once the pH has been adjusted, a polyamine type coagulant, preferably cationic and a cationic or anionic polyacrylamide type flocculant, is added. Coagulant addition is optional and can also be done prior to the pH adjustment of the fermentation broth. After the addition of a coagulant and a flocculant, and after a brief period of stirring, the separation of the fermentation broth is achieved, by centrifugation. An effluent free of solid particles is obtained and the separation of the mycelium from the broth is achieved with a recovery yield of pravastatin greater than 97%, also achieving the elimination of immiscible little polar impurities in aqueous medium.

The clarification of the fermentation broth through the use of coagulants and flocculants and the consequent centrifugation has important competitive advantages over other methods of separating the mycelium, such as conventional filtration, for example, by a filter press. These advantages are: reduction in solid-liquid separation times, with a broth flow rate of 10,000 1 / h, higher separation yields, greater than 97%, and obtaining a cleaner filtered broth, which favors extraction later of the broth with an organic solvent, since the formation of emulsions in the liquid-liquid interface is avoided.

Once the mycelium separation operation is carried out, the broth is adjusted to an acidic pH, preferably between 3.5 and 5.5, by using inorganic or organic acids, preferably inorganic, and more preferably hydrochloric acid, sulfuric acid or phosphoric acid. Pravastatin is extracted from the acidified broth ^"by üή ^~ solvent with a high yield, so that an organic solution of the compound. The solvent used is an organic solvent immiscible in water, such as alkyl carboxylic esters, halogenated hydrocarbons and ketones, such as ethyl acetate, propyl acetate, butyl acetate, methylene chloride and methyl isobutyl ketone Preferred solvents are ethyl acetate and methyl isobutyl ketone. The next operation to achieve the formation of the enriched aqueous solution of pravastatin is the re-extraction of the organic solution by contact with a basic aqueous solution, in the form of alkaline or ammonium salt. The base used is an alkali hydroxide or ammonium hydroxide, preferably sodium hydroxide. The pH of the basic aqueous solution must be between 8 and 13, preferably between 9 and 11. Pravastatin is preferably extracted in the form of sodium salt, while achieving the elimination of potential non-polar organic impurities.

Finally, the aqueous extract is concentrated to obtain an enriched aqueous solution of pravastatin. This concentration of the aqueous extract is carried out by partial distillation under vacuum of water, so that the removal of a residual volume of organic solvent is also achieved.

The procedure proposed by the invention continues with a step for obtaining and isolating raw sodium pravastatin or calcium pravastatin from the previously enriched aqueous pravastatin solution obtained.

Generally, in compounds containing a carboxylic acid group capable of forming salts, such as pravastatin, the process for the isolation of a given salt of said compound, with good purity, is difficult. Particularly difficult is the isolation ^{"of the"} active ingredient in aqueous medium, since, usually alkali metal salts and ammonium are water soluble. Therefore, the formation and isolation of ammonium salts or amine salts, commonly used to purify pravastatin, is carried out from an enriched organic phase of the compound. The enriched aqueous pravastatin extract of the present invention, obtained from a fermentation broth, can be extracted with a water immiscible organic solvent, to obtain an enriched pravastatin organic solution. The solvents used for extraction are alkyl esters of carboxylic acid, halogenated hydrocarbons and ketones, such as ethyl acetate, propyl acetate, butyl acetate, methylene chloride and methyl isobutyl ketone. Preferred solvents are ethyl acetate and methyl isobutyl ketone. The extraction is carried out after an adjustment at acidic pH, preferably between 3.5 and 5.5, by using inorganic or organic acids, preferably inorganic acids, and more preferably hydrochloric acid, sulfuric acid or phosphoric acid.

It has been found that from the enriched organic solution, raw sodium pravastatin of good purity can be obtained by adding a solution of sodium salt of carboxylic acid in low molecular weight alcohol, preferably a solution of sodium octanoate in methanol. After several hours of maturation at low temperature, preferably between 0 ^o C and 10 ° C, filtered raw pravastatin sodium is obtained using a filter press, for example.

Alternatively to obtaining raw pravastatin sodium, calcium pravastatin can be obtained and isolated directly from the enriched pravastatin aqueous solution. By adding an aqueous solution of calcium chloride to the enriched aqueous solution of pravastatin, it is possible to isolate calcium pravastatin of good purity. The method of obtaining pravastatin calcium salt is simple, since it precipitates in aqueous medium and is easily isolated by filtration, for example by means of a filter press. The calcium salt of pravastatin can be used as an intermediate for obtaining pravastatin sodium of adequate purity.

The procedure described in the invention ends with obtaining of purified pravastatin sodium from raw pravastatin sodium or calcium pravastatin obtained.

For this, raw pravastatin sodium or calcium pravastatin is suspended in water and, after adjusting the solution to acidic pH, pravastatin is extracted with an organic solvent immiscible in water, preferably with ethyl acetate or methyl isobutyl ketone. The adjustment of the solution to acidic pH, preferably between 3.5 and 5.5, is carried out by using inorganic or organic acids, preferably inorganic acids, and more preferably hydrochloric acid, sulfuric acid or phosphoric acid.

The organic pravastatin extract may, optionally be discolored with activated carbon and washed with an aqueous saline solution, preferably with sodium chloride. The process is continued with the addition of a solution of sodium salt of carboxylic acid in low molecular weight alcohol, preferably a solution of sodium octanoate in methanol, the precipitation of sodium pravastatin being observed. After several hours of maturation, preferably between 3 and 8 hours, at low temperature, preferably between 0 ^or C and 10 ° C, finally purified pravastatin is isolated by filtration.

Pravastatin sodium purified of the present invention may be recrystallized to obtain pravastatin pharmaceutical grade, by any of the methods known in the art, such as recrystallization from a mixture of ethanol and ^"acetate" I acetate, or ^{"récristalizaciórT} by addition of ethyl acetate to a solution of pravastatin sodium in ethanol and water.

DESCRIPTION OF THE DRAWINGS To complement the description that is being made and in order to help a better understanding of the characteristics of the invention, in accordance with a preferred example of practical realization thereof, a single sheet of plans is attached as an integral part of said description. which, with an illustrative and non-limiting nature and in its only figure, appears a representation of a spectrum of X-ray diffraction of purified sodium pravastatin obtained according to an embodiment of the present invention.

EXAMPLES OF EMBODIMENT OF THE INVENTION

The following examples illustrate the preferred embodiments of the present invention and are not intended to limit the scope thereof.

Example 1: Obtaining raw pravastatin sodium from a fermentation broth.

From an initial volume of 7 m ³ of pravastatin fermentation broth, it is diluted with 4 m ³ of water and 105 1 of coagulant is added. The broth is adjusted to pH 9.5 by the addition of 10% sodium hydroxide, and then a flocculant solution is added and the biomass is removed by centrifugation, obtaining 14 m ³ of broth.

The broth is adjusted to pH 3.5 with 10% hydrochloric acid and extracted with 3500 1 of methyl isobutyl ketone. The organic pravastatin extract is re-extracted by contact with 1050 1 of an aqueous solution of sodium hydroxide at pH 9.5. The aqueous extract is distilled under vacuum until an enriched aqueous solution of pravastatin is obtained.

Then, the enriched aqueous solution is adjusted to pH 4. with hydrochloric acid and extracted with 600 1 of methyl isobutyl ketone. The organic phase is washed with a saturated solution of sodium chloride and decanted. A solution of 11.5 kg of sodium octanoate dissolved in 100 1 of methanol is added to the organic phase and the mixture is completed with the addition of 500 1 of methyl isobutyl ketone. The mixture is cooled to 5 ^o C and kept ripening for 5 hours. After this period, the mixture is filtered and the product obtained is washed with 50 1 of methyl isobutyl ketone. After drying under vacuum at 50 ° C, 21.5 kg of raw sodium pravastatin are obtained.

Example 2: Obtaining calcium pravastatin from a fermentation broth.

It starts from an initial volume of 5,000 ml of pravastatin fermentation broth, which is adjusted to pH 9.5 by the addition of sodium hydroxide. Next, a polyamine type coagulant and a polyacrylamine type flocculant are added and the biomass is removed by centrifugation.

Then, the broth obtained is adjusted to pH 4 with hydrochloric acid and extracted with 2,000 ml of ethyl acetate. The organic pravastatin extract is re-extracted by contact with 350 ml of aqueous sodium hydroxide solution at pH 9.5. The aqueous extract is distilled under vacuum until an enriched pravastatin solution is obtained.

To the enriched aqueous solution of pravastatin is added 10 g of calcium chloride. After 4 hours of stirring at 15 ° C, a solid is obtained which is filtered and dried under vacuum at 50 ° C. 17 g of calcium pravastatin are obtained.

Example 3: Obtaining purified pravastatin sodium from calcium pravastatin. This process starts from 50 g of pravastatin calcium obtained previously. 1000 ml of ethyl acetate and 250 ml of water are added and the pH of the mixture is adjusted to 3.5 with phosphoric acid. After an hour of stirring, the organic phase, which contains pravastatin, is separated by decantation.

The solution of pravastatin in ethyl acetate prepared above is washed with 200 ml of a saturated solution of sodium chloride, decolorized with activated carbon and filtered. Then, 19.5 g of sodium octanoate dissolved in 200 ml of methanol are added on the organic phase and completed with the addition of 1000 ml more of ethyl acetate.

The mixture is allowed to cool to 5 ^o C and is kept ripening for a period of approximately 4 hours. After this time, the solid obtained is filtered and dried under vacuum. Finally, 40 g of purified pravastatin sodium are obtained.

Example 4: Obtaining raw sodium pravastatin from a fermentation broth.

The process begins with adjusting an initial volume of 5,000 ml of pravastatin fermentation broth to pH 9.5 by adding sodium hydroxide. Next, a polyamine type coagulant and a polyacrylamine type flocculant are added and the biomass is removed by centrifugation.

The broth obtained is filtered, adjusted to pH 4 with phosphoric acid and extracted with 2,000 ml of ethyl acetate. This organic pravastatin extract is re-extracted by contact with 350 ml of aqueous sodium hydroxide solution at pH 9.5. The new aqueous extract is distilled under vacuum until an enriched pravastatin solution is obtained. To the enriched aqueous solution is added 350 ml of ethyl acetate and adjusted to pH 4 with hydrochloric acid. The organic phase is then separated, decolorized with activated carbon and filtered. To this solution, 8 g of sodium octanoate dissolved in 80 ml of methanol are added and the mixture is completed with the addition of 500 ml of ethyl acetate. The mixture is cooled to

5 ^o C and remains in maturation for 4 hours. After this period, the solid obtained is filtered and dried under vacuum. 16 g of raw pravastatin sodium are obtained.

Example 5: Obtaining purified pravastatin sodium from raw pravastatin sodium.

A sample of 15O g of raw pravastatin sodium is taken to which 2250 ml of ethyl acetate and 450 ml of water are added, subsequently the pH of the solution is adjusted to 3.4 with hydrochloric acid. After 15 minutes of stirring, the organic phase, which contains pravastatin, is separated by decantation.

The solution of pravastatin in ethyl acetate obtained is decolorized with 15 g of activated carbon, filtered and washed with 375 ml of 25% sodium chloride. Next, 67.5 g of sodium octanaoate dissolved in 675 ml of methanol are added on the organic phase and the solution is diluted with the addition of 4500 ml more of ethyl acetate.

The mixture is allowed to cool to 10 ° C and is maintained in maturation for a time of approximately 8 hours. After this period, the solid obtained is filtered and dried under vacuum. 100 g of purified pravastatin sodium are thus obtained.

Example 6: Obtaining pharmaceutical grade sodium pravastatin from purified sodium pravastatin. Once the purified sodium pravastatin has been obtained, according to the previous example, 10 g of it are dissolved in 20 ml of ethanol and 10 ml of water, and the resulting solution is decolorized with activated carbon, then washed with 5 ml of a mixture of ethanol and water, and filtered.

Then, the clarified solution is heated to 50 ° C and 420 ml of ethyl acetate is added, keeping the mixture under stirring for a period of approximately one hour.

After this time, the solution is cooled by maintaining it at a temperature of 10 ° C and is subjected to a maturation period for 2 hours. Then, the solid obtained is filtered and finally dried under vacuum at 50 ° C. As a final result, 6.7 g of pharmaceutical grade sodium pravastatin are obtained.

The pravastatin sodium obtained is subjected to a spectroscopic analysis, whose X-ray diffraction spectrum is represented in the figure that accompanies this description.

Claims

R E I V I N D I C A C I O N E S I ^a .- Procedure for obtaining purified sodium pravastatin, from a fermentation broth, characterized in that it comprises a first stage of formation of an enriched aqueous solution of pravastatin, followed by a process of obtaining and isolating raw or pravastatin sodium of calcium pravastatin, and finally a stage of conversion of raw sodium pravastatin or calcium pravastatin into purified sodium pravastatin. 2 .- A method for obtaining purified pravastatin sodium according ^to claim I, wherein the step of forming the enriched aqueous solution comprising the following steps: - adjustment of the fermentation broth to basic pH, between 8.5 and 9.5; - addition to the fermentation broth of a coagulant and a flocculant; - separation of the broth by centrifugation; adjustment of the broth at acidic pH, between 3.5 and 5.5; - extraction of pravastatin from the fermentation broth with water-immiscible organic solvent; - re-extraction of pravastatin from the organic solution by contact with a basic aqueous solution; - concentration of the aqueous extract to obtain the enriched aqueous solution, by vacuum distillation. 3 .- A process for preparing pravastatin sodium purified, according to claim 2, characterized in that the adjustment of the fermentation broth at basic pH is performed by adding an aqueous solution of an inorganic base, preferably sodium hydroxide. 4 .- Method for obtaining purified pravastatin sodium according ^to claim 2, wherein the coagulant added to the fermentation broth is preferably cationic polyamine and polyacrylamide flocculant, cationic or anionic. 5 .- A process for preparing pravastatin sodium purified, according to claim 2, characterized in that the adjustment of the fermentation broth at an acid pH is carried out by using inorganic or organic acids, preferably inorganic, and hydrochloric more preferably acid, sulfuric acid or phosphoric acid. 6 .- Method for obtaining purified pravastatin sodium according ^to claim 2, wherein the organic solvent used for extraction of pravastatin from the fermentation broth is selected from ethyl acetate or methyl isobutyl ketone. 7 .- Method for obtaining purified pravastatin sodium according ^to claim 2, wherein the basic aqueous solution used for reextraction of pravastatin is in salt form alkaline or ammonium. 8 .- Method for obtaining purified pravastatin sodium according ^to claim I, wherein the process of obtaining and isolating pravastatin sodium from the crude enriched aqueous solution, comprising the following steps: - adjustment of the enriched aqueous solution at acidic pH, between 3.5 and 5.5; - extraction of pravastatin with a water-immiscible organic solvent; - adding a solution of sodium salt of carboxylic acid in low molecular weight alcohol; - maturation of the solution at a temperature between 0 and 10 ° C; - obtaining raw pravastatin by filtration. 9 .- Method for obtaining purified pravastatin sodium according ^to claim 8, wherein the adjustment of the enriched aqueous solution at acid pH is carried out by using inorganic or organic acids, preferably inorganic, and more preferably hydrochloric acid, sulfuric acid or phosphoric acid. 10 .- Method for obtaining purified pravastatin sodium according ^to claim 8, wherein the organic solvent selected for extraction of pravastatin is selected from ethyl acetate or methyl isobutyl ketone. 11 .- Method for obtaining purified pravastatin sodium according ^to claim 8, wherein the solution of sodium salt of carboxylic acid alcohol of low molecular weight, is a solution of sodium octanoate in methanol. 12 .- Method for obtaining purified pravastatin sodium according ^to claim I, wherein the obtaining and isolating pravastatin calcic from the enriched aqueous solution is i produced by adding calcium chloride. 13 .- Method for obtaining purified pravastatin sodium according ^to claim I, wherein the conversion of raw pravastatin or pravastatin sodium calcic purified pravastatin comprises the following steps: - suspension of raw pravstatin sodium or calcium pravastatin in water; - adjustment of the solution at acidic pH, between 3.5 and 5.5; - extraction of pravastatin with a water immiscible organic solvent; addition of a solution of sodium salt of carboxylic acid in low molecular weight alcohol; - maturation of the solution at a temperature between 0 and 10 ° C; - Isolation of pravastatin sodium purified by filtration. 14 .- Method for obtaining pravastatin purified, according to claim 13, wherein adjusting the solution to acid pH is carried out by using inorganic or organic acids, preferably inorganic, and hydrochloric more preferably acid, sulfuric acid or phosphoric acid. 15 .- Method for obtaining purified pravastatin sodium according ^to claim 13, wherein the organic solvent used in the extraction of pravastatin is selected from ethyl acetate or methyl isobutyl ketone. 16 .- Method for obtaining purified pravastatin sodium according ^to claim 13, wherein the solution of sodium salt of carboxylic acid alcohol of low molecular weight, is a solution of sodium octanoate in methanol. 17 .- Method for obtaining purified pravastatin sodium according ^to claim I, wherein the pravastatin Purified sodium is optionally subjected to a recrystallization process to obtain pharmaceutical grade sodium pravastatin.