Crystals of the sodium salt of pravastatin

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and cervastatin and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis (simvastatin) or they are the products of total chemical synthesis (fluvastatin, atorvastatin and cervastatin). The present invention relates to a crystalline form of the sodium salt of pravastatin, which is known by the chemical name 1-naphthaleneheptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, mono sodium salt, which is useful as a pharmaceutical substance. The present invention further relates to the method for its preparation and isolation, to a pharmaceutical formulation containing the sodium salt of pravastatin in the crystalline form and a pharmaceutically acceptable carrier, and to a pharmaceutical method of treatment. The novel crystalline form of the sodium salt of pravastatin is useful in the treatment of hypercholesterolemia and hyperlipidemia.

1 . The sodium salt of pravastatin in a crystalline form.  
     
     
         2 . The sodium salt of pravastatin according to  claim 1 , wherein the crystals exhibit a colorless or pale yellow appearance.  
     
     
         3 . The sodium salt of pravastatin according to  claim 1 , wherein the crystals clearly appear in the form of needles or radiating clusters.  
     
     
         4 . The sodium salt of pravastatin according to  claim 1 , wherein the melting point is in the range of from 170° C. to 174° C.  
     
     
         5 . The sodium salt of pravastatin according to  claim 1 , wherein the crystals in an X-ray diffraction measurement produce distinct peaks (2θ) 15 having a half-value width below 2°.  
     
     
         6 . The sodium salt of pravastatin in a crystalline form, wherein the crystals in an X-ray diffraction measurement produce a signal sufficiently comparable to that illustrated in the diffractogram shown in  FIG. 2 .  
     
     
         7 . A process for the preparation of the sodium salt of pravastatin in a crystalline form, comprising the steps of: 
 (a) providing a solution containing pravastatin and sodium cations in a lower aliphatic alcohol;    (b) addition of ethyl acetate to said alcoholic solution;    (c) cooling of said alcohol/ethyl acetate mixture; and    (d) crystallization.    
     
     
         8 . The process according to  claim 7  additionally comprising after a first crystallization stage the steps of: 
 (e) addition of further ethyl acetate to the alcohol/ethyl acetate mixture; and    (f) further crystallization.    
     
     
         9 . The process according to  claim 7 , wherein the lower aliphatic alcohol is ethanol or methanol.  
     
     
         10 . The process according to  claim 7 , wherein the lower aliphatic alcohol is methanol.  
     
     
         11 . The process according to  claim 7 , wherein the addition of ethyl acetate is exhibited while the alcoholic solution of the sodium salt of pravastatin is stirred continually.  
     
     
         12 . The process according to  claim 7 , wherein the concentration of the sodium salt of pravastatin in the alcoholic solution of step (a) is between 0.03 and 0.3 g/ml.  
     
     
         13 . The process according to  claim 7 , wherein the volume of added ethyl acetate in step (b) does not exceed the 15-fold volume of the initial alcoholic solution of the sodium salt of pravastatin.  
     
     
         14 . The process according to  claim 8 , wherein the volume of further added ethyl acetate in step (e) is in the range of from 25 to 75% by volume based on the volume of ethyl acetate added in step (b).  
     
     
         15 . The process according to  claim 7 , wherein the alcohol/ethyl acetate mixture is cooled to a temperature below 15° C.  
     
     
         16 . The process according to  claim 7 , wherein the total crystallization time is between 3 and 20 hours.  
     
     
         17 . The process according to  claim 7 , wherein the formed crystals are filtered, ethyl acetate washed and dried.  
     
     
         18 . A pharmaceutical formulation containing the sodium salt of pravastatin in a crystalline form.  
     
     
         19 . The pharmaceutical formulation according to  claim 18  containing the sodium salt of pravastatin in a crystalline form according to any one of  claims 2  to  5 .  
     
     
         20 . A pharmaceutical formulation of the sodium salt of pravastatin in a crystalline form, wherein the crystals in an X-ray diffraction measurement produce a signal sufficiently comparable to that illustrated in the diffractogram shown in  FIG. 2 .  
     
     
         21 . A process for preparing pharmaceutical products for the treatment of hypercholesterolemia and hyperlipidemia comprising the step of adding the active agent pravastatin as crystalline sodium salt with a pharmaceutically acceptable carrier.