Processes for preparing crystalline and amorphous mupirocin calcium

Abstract

Processes are provided for preparing mupirocin calcium dihydrate from pseudomonic acid in a two phase system by using an organic carboxylate. A highly pure composition of amorphous mupirocin calcium is provided, and processes for its preparation by solvent removal, lyophilization and precipitation with use of an anti-solvent. Pharmaceutical compositions of amorphous form, and methods of using them to treat infections are also provided. Also provided are combined processes for preparing mupirocin calcium dihydrate and amorphous, by producing amorphous form first, followed by conversion of amorphous form into the dihydrate through crystallization from an aqueous solution. Also provided are processes for removing the water of crystallization of the dihydrate to obtain mupirocin calcium anhydrate.

1 . A process for preparing crystalline mupirocin calcium dihydrate or an anhydrate thereof comprising the steps of:
 a) preparing a solution of pseudomonic acid in a water-immiscible solvent;   b) combining the solution with a suspension or solution of a calcium C 2  to C 12  organic carboxylate in an aqueous solvent, to form an aqueous phase and a non-aqueous phase, wherein mupirocin calcium dihydrate precipitates from the aqueous phase;   c) separating the precipitate; and   d) optionally converting the dihydrate to the anhydrate.   
     
     
         2 . The process of  claim 1 , wherein the aqueous solvent is water free of a co-solvent. 
     
     
         3 . The process of  claim 1 , wherein the aqueous solvent is a mixture of water and a C 1  to a C 4  alcohol. 
     
     
         4 . The process of  claim 1 , wherein the organic carboxylate is 2-ethyl-hexanoate. 
     
     
         5 . A process for preparing crystalline mupirocin calcium dihydrate or an anhydrate thereof comprising the steps of:
 a) adding pseudomonic acid and a calcium C 2  to C 8  organic carboxylate to an aqueous solvent to form a solution, wherein a C 2  to C 8  organic carboxylic acid forms;   b) removing the carboxylic acid;   c) separating the mupirocin calcium dihydrate as a precipitate from the aqueous solvent; and   d) optionally converting the dihydrate to the anhydrate.   
     
     
         6 . The process of  claim 5 , wherein the aqueous solvent is a mixture of water and a C 1  to a C 4  alcohol. 
     
     
         7 . The process of  claim 6 , further comprising a step of increasing the water content of the aqueous solvent before step (c). 
     
     
         8 . The process of  claim 5 , wherein the removing step is carried out by extraction. 
     
     
         9 . The process of  claim 5 , wherein the organic carboxylate is 2-ethyl-hexanoate. 
     
     
         10 . A process for preparing crystalline mupirocin calcium dihydrate or an anhydrate thereof comprising the steps of:
 a) adding pseudomonic acid and calcium oxide to water free of a co-solvent to form a solution, wherein mupirocin calcium dihydrate precipitates from the solution;   b) separating the mupirocin calcium dihydrate; and   c) optionally converting the dihydrate to the anhydrate.   
     
     
         11 . A process for preparing amorphous mupirocin calcium comprising the steps of:
 a) adding pseudomonic acid, a base, and a source of calcium ions to a C 1  to a C 4  alcohol to form a solution; and   b) removing the alcohol.   
     
     
         12 . The process of  claim 11 , wherein the alcohol is substantially anhydrous. 
     
     
         13 . The process of  claim 12 , wherein the alcohol has less than about 1% (vol/vol) water content. 
     
     
         14 . The process of  claim 11 , wherein the alcohol is selected from the group consisting of methanol and ethanol. 
     
     
         15 . The process of  claim 11 , wherein the removing step is carried out by evaporating the alcohol. 
     
     
         16 . A process for preparing amorphous mupirocin calcium comprising the steps of:
 a) adding pseudomonic acid, a base and a source of calcium ions to a C 1  to a C 4  alcohol to form a solution;   b) combining the solution with an anti-solvent to precipitate amorphous mupirocin calcium; and   c) separating the precipitate.   
     
     
         17 . The process of  claim 16 , wherein the alcohol has less than about 1% (vol/vol) water content. 
     
     
         18 . The process of  claim 16 , wherein the alcohol is selected from the group consisting of ethanol and methanol. 
     
     
         19 . The process of  claim 16 , wherein the anti-solvent is selected from the group consisting of esters and ethers. 
     
     
         20 . The process of  claim 19 , wherein the anti-solvent as an ether is selected from the group consisting of methyl-t-butyl ether and diisopropylether. 
     
     
         21 . The process of  claim 19 , wherein the anti-solvent as an ester is i-butyl acetate. 
     
     
         22 . The process of  claim 16 , wherein combining is carried out by adding the solution to the anti-solvent. 
     
     
         23 . A process for preparing amorphous mupirocin calcium comprising the steps of:
 a) adding pseudomonic acid, a base and a source of calcium ions to a solvent selected from the group consisting of water, a C 1  to a C 4  alcohol, or mixtures thereof to form a solution; and   b) lyophilizing the solution.   
     
     
         24 . The process of  claim 23 , wherein the alcohol is methanol. 
     
     
         25 . The process of  claim 23 , further comprising a step, before the lyophilization step, of removing solvents other than water and optionally adding water. 
     
     
         26 . A process for preparing crystalline mupirocin calcium hydrate or an anhydrate thereof comprising the steps of:
 a) dissolving pseudomonic acid in a water-immiscible solvent to form a solution;   b) combining the solution with a suspension or solution of a base and a source of calcium ions in an aqueous solvent, to form an aqueous and a non-aqueous phase, wherein mupirocin calcium dihydrate precipitates from the aqueous phase;   c) separating the dihydrate; and   d) optionally converting the dihydrate to the anhydrate.   
     
     
         27 . The process of  claim 26 , wherein the water-immiscible solvent is selected from the group consisting of esters and ketones. 
     
     
         28 . The process of  claim 27 , wherein the water-immiscible solvent as an ester selected is iso-butyl acetate. 
     
     
         29 . The process of  claim 27 , wherein the water-immiscible solvent as a ketone is isobutyl methyl ketone. 
     
     
         30 . A process for preparing crystalline mupirocin calcium dihydrate comprising the steps of:
 a) adding pseudomonic acid, a base and a source of calcium ions to a C 1  to a C 4  alcohol to form a solution;   b) adding the solution to an ether or an ester as an anti-solvent to precipitate amorphous mupirocin calcium;   c) dissolving the amorphous mupirocin calcium in a solvent selected from the group consisting of water, and a mixture of water and a C 1  to a C 4  alcohol to form a solution, wherein the dihydrate precipitates from the solution; and   d) separating the dihydrate.   
     
     
         31 . A process for preparing crystalline mupirocin calcium dihydrate comprising the steps of:
 a) adding pseudomonic acid, a base and a source of calcium ions to a C 1  to a C 4  alcohol to form a solution;   b) evaporating the alcohol to obtain amorphous mupirocin calcium;   c) dissolving the amorphous mupirocin calcium in a solvent selected from the group consisting of water, and a mixture of water and a C 1  to a C 4  alcohol to form a solution, wherein the dihydrate precipitates from the solution; and   d) separating the dihydrate.   
     
     
         32 . A process for preparing crystalline mupirocin calcium dihydrate comprising the steps of:
 a) adding pseudomonic acid, a base and a source of calcium ions to a solvent selected from the group consisting of water, and a mixture of water and a C1 to a C4 alcohol to form a solution;   b) lyophilizing the solution to obtain amorphous mupirocin calcium;   c) dissolving the amorphous mupirocin calcium in a solvent selected from the group consisting of water and a mixture of water and a C 1  to a C 4  alcohol to precipitate the dihydrate; and   d) separating the dihydrate as a precipitate.   
     
     
         33 . A process for preparing amorphous mupirocin calcium comprising the steps of:
 a) reacting pseudomonate ions and calcium ions in solution in a C 1  to a C 4  alcohol; and   b) evaporating the alcohol.   
     
     
         34 . A process for preparing amorphous mupirocin calcium comprising the steps of:
 a) reacting pseudomonate ions and calcium ions in solution in a C1 to a C4 alcohol;   b) adding the solution to an ester or an ether as an anti-solvent to precipitate amorphous mupirocin calcium; and   c) separating the precipitate.   
     
     
         35 . A process for preparing amorphous mupirocin calcium comprising the steps of:
 a) reacting pseudomonate ions and calcium ions in solution in a solvent selected from the group consisting of water and a mixture of water and a C 1  to a C 4  alcohol; and   b) lyophilizing the solution.   
     
     
         36 . A process for preparing crystalline mupirocin calcium dihydrate or an anhydrate thereof comprising the steps of:
 a) providing pseudomonic acid and a calcium C 2  to C 12  organic carboxylate;   b) exchanging acidic proton of the pseudomonic acid with the calcium of the C 2  to C 12  organic carboxylate;   c) recovering the mupirocin calcium dihydrate; and   d) optionally converting the dihydrate to the anhydrate.   
     
     
         37 - 44 . (canceled) 
     
     
         45 . The process of  claim 11 ,  12 ,  31  or  33 , further comprising the step of drying amorphous form. 
     
     
         46 . The process of  claim 31  or  33 , wherein the alcohol is methanol or ethanol containing less than about 2% water by volume.