Preparation of orlistat and orlistat crystalline forms

Abstract

The present invention is directed to a process of converting lipstatin to orlistat by catalytic hydrogenation. The present invention further discloses novel crystalline solid orlistat forms, designated form I and form II and methods for their preparation.

What is claimed is:  
     
         1 . A process of preparing orlistat, comprising the steps of hydrogenating lipstatin in an organic solvent in the presence of a catalyst to obtain orlistat.  
     
     
         2 . The process of  claim 1 , wherein the organic solvent is selected from the group consisting of acetonitrile, alcohol, and acetone.  
     
     
         3 . The process of  claim 2 , wherein the alcohol is methanol.  
     
     
         4 . The process of  claim 1 , wherein the catalyst is selected from the group consisting of palladium and nickel.  
     
     
         5 . The process of  claim 1 , wherein the hydrogenating step is performed at a temperature between about 10° C. to about 50° C.  
     
     
         6 . The process of  claim 1 , wherein the hydrogenating step is performed at pressure of less than 5 bar.  
     
     
         7 . The process of  claim 1 , wherein the hydrogenating step is performed at pressure between about 1 to about 3 bar.  
     
     
         8 . The process of  claim 1 , wherein the hydrogenating step is performed at pressure of about 1 bar.  
     
     
         9 . A crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta and a DSC melting endotherm at about 46.7° C.  
     
     
         10  The crystalline solid orlistat of  claim 9 , wherein the crystalline solid orlistat is characterized by the XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta.  
     
     
         11 . The crystalline solid orlistat of  claim 10 , wherein the crystalline solid orlistat is further characterized by a XRD pattern substantially as depicted in FIG. 1.  
     
     
         12 . The crystalline solid orlistat of  claim 9 , wherein the crystalline solid orlistat is characterized by the DSC melting endotherm at about 46.7° C.  
     
     
         13 . A crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSC melting endotherm at about 46.6° C.  
     
     
         14 . The crystalline solid orlistat of  claim 13 , wherein the crystalline solid orlistat is characterized by the XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta.  
     
     
         15 . The crystalline solid orlistat of  claim 14 , wherein the crystalline solid orlistat is further characterized by a XRD pattern substantially as depicted in FIG. 2.  
     
     
         16 . The crystalline solid orlistat of  claim 13 , wherein the crystalline solid orlistat is characterized by a DSC melting endotherm at about 46.6° C.  
     
     
         17 . A process of preparing crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta and a DSC melting endotherm at about 46.7° C., comprising the steps of: 
 (a) dissolving orlistat in a solvent;  
 (b) adding an anti-solvent or water to the solvent; and  
 (c) isolating the crystalline solid orlistat.  
 
     
     
         18 . The process of  claim 17 , wherein the solvent is a lower alkyl alcohol, acetone, acetonitrile, acetone, ethyl acetate, isobutyl acetate, methyl isobutyl ketone, and hexane.  
     
     
         19 . The process of  claim 18 , wherein the lower alkyl alcohol is selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.  
     
     
         20 . The process of  claim 17 , wherein the anti-solvent is a hydrocarbon.  
     
     
         21 . The process of  claim 20 , wherein the hydrocarbon is selected from the group consisting of hexane, cyclohexane and heptane.  
     
     
         22 . The process of  claim 17 , wherein the solvent is methanol and the anti-solvent is hexane.  
     
     
         23 . The process of  claim 17 , wherein the steps (a) to (c) are repeated at least once to increase the purity of the crystalline solid orlistat.  
     
     
         24 . The crystalline solid orlistat prepared in accordance with the process of  claim 17 .  
     
     
         25 . The crystalline solid orlistat of  claim 24 , wherein the crystalline solid orlistat is characterized by a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta.  
     
     
         26 . The crystalline solid orlistat of  claim 25 , wherein the crystalline solid orlistat is further characterized by a XRD pattern substantially as depicted in FIG. 1.  
     
     
         27 . The crystalline solid orlistat of  claim 24 , wherein the crystalline solid orlistat is characterized by a DSC melting endotherm at about 46.7° C.  
     
     
         28 . A process for preparing a crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSC melting endotherm at about 46.6° C., comprising the steps of: 
 (a) mixing orlistat in hexane to form a mixture at a first temperature;  
 (b) lowering the first temperature of the mixture sufficiently to precipitate; and  
 (c) isolating crystalline solid orlistat.  
 
     
     
         29 . The process of  claim 28 , wherein the steps (a) to (c) are repeated at least once to increase the purity of the crystalline solid orlistat.  
     
     
         30 . The crystalline solid orlistat prepared in accordance with the process of  claim 28 .  
     
     
         31 . The crystalline solid orlistat of  claim 30 , wherein the crystalline solid orlistat is characterized by the XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta.  
     
     
         32 . The crystalline solid orlistat of  claim 31 , wherein the crystalline solid orlistat is further characterized by a XRD pattern substantially as depicted in FIG. 2.  
     
     
         33 . The crystalline solid orlistat of  claim 30 , wherein the crystalline solid orlistat is characterized by the DSC melting endotherm at about 46.6° C.  
     
     
         34 . A process of preparing a mixture of crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3±0.2 degrees two-theta, a DSC melting endotherm at about 46.7° C., a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0±0.2 degrees two-theta, and a DSC melting endotherm at about 46.6° C., comprising the steps of: 
 (a) dissolving orlistat in a solvent; and  
 (b) inducing crystallization to obtain the mixture of crystalline solid orlistat.  
 
     
     
         35 . The process of  claim 34 , wherein the solvent is at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol, 1-propanol, 2-propanol, isopropanol, 1-butanol, i-butanol, sec-butanol, tert-butanol, N,N-dimethyl formamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, isobutyl acetate, methyl isobutyl ketone, and acetic acid.  
     
     
         36 . The process of  claim 34 , wherein solvent is an aliphatic hydrocarbon.  
     
     
         37 . The process of  claim 36 , wherein the aliphatic hydrocarbon is selected from the group consisting of hexane, pentane and heptane.  
     
     
         38 . The process of  claim 34 , wherein the solvent contains water.  
     
     
         39 . The process of  claim 34 , wherein the solvent is methanol.  
     
     
         40 . The process of  claim 34 , wherein the mixture of methanol and water is present in a v/v ratio of about 1:0.3.  
     
     
         41 . The process of  claim 35 , wherein the solvent is a mixture of a first alcohol in combination with a second alcohol selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and t-butanol.  
     
     
         42 . The process of  claim 34 , wherein the crystallization step is induced by adding an anti-solvent.  
     
     
         43 . The process of  claim 34 , wherein the crystallization step is induced by cooling.  
     
     
         44 . The crystalline solid orlistat as prepared by the process of one of claims  17 ,  28 , and  34 , wherein the crystalline solid orlistat has a purity of at least about 95%.  
     
     
         45 . The crystalline solid orlistat as prepared by the process of one of claims  17 ,  28  and  34 , wherein the crystalline solid orlistat has a purity of at least about 98%.  
     
     
         46 . A process of preparing orlistat, comprising the steps of: 
 a) preparing fermentation broth containing lipstatin;    b) extracting lipstatin from the fermentation broth;    c) hydrogenating the lipstatin to obtain orlistat; and    d) separating the orlistat.    
     
     
         47 . The process of  claim 46 , wherein the hydrogenating step a) is carried out in an organic solvent in the presence of a catalyst to obtain orlistat.