Methods of Producing Anamorelin Hydrochloride Having Controlled Chloride Content

Abstract

The present invention relates to particulate forms of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having controlled chloride content, preferably isolated in an amorphous and/or fine particulate state, processes for making the particulate forms, and pharmaceutical compositions comprising the particulate forms.

1 ) Anamorelin monohydrochloride having a chloride content ranging from 5.8 to 6.2%. 
     
     
         2 ) Anamorelin monohydrochloride comprising a chloride:anamorelin molar ratio of from 0.9 to 0.99. 
     
     
         3 ) Anamorelin monohydrochloride in an amorphous state. 
     
     
         4 ) The anamorelin monohydrochloride of  claim 1 , in an isolated state. 
     
     
         5 ) The anamorelin monohydrochloride of  claim 1 , comprising less than 0.5% impurities. 
     
     
         6 ) The anamorelin monohydrochloride of  claim 1 , comprising from 1 to 3% water. 
     
     
         7 ) The anamorelin monohydrochloride of  claim 5 , wherein the impurities are selected from by-products, contaminants, degradation products and residual solvents. 
     
     
         8 ) The anamorelin monohydrochloride of  claim 7 , comprising a residual solvent selected from methanol, butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate, methylethyl ketone, methylisobutyl ketone, 2-methyltetrahydrofuran and combinations thereof in an amount less than 1000 ppm. 
     
     
         9 ) The anamorelin monohydrochloride of  claim 8 , wherein the residual solvent is isopropyl acetate. 
     
     
         10 ) The anamorelin monohydrochloride of  claim 1 , having a purity greater than 99%. 
     
     
         11 ) A composition comprising anamorelin monohydrochloride, wherein the composition comprises a chloride content ranging from 5.8 to 6.2%. 
     
     
         12 ) A composition comprising anamorelin monohydrochloride, wherein the composition has a chloride:anamorelin molar ratio of from 0.9 to 0.99. 
     
     
         13 ) The composition of  claim 11 , in the substantial absence of anamorelin hydrochloride other than anamorelin monohydrochloride. 
     
     
         14 ) A process for preparing anamorelin monohydrochloride comprising:
 a) dissolving anamorelin free base in an organic solvent to form a solution;   b) mixing said solution with water and hydrochloric acid for a time sufficient to:
 i) react said anamorelin free base with said hydrochloric acid, and 
 ii) form an organic phase and an aqueous phase; 
   c) separating the aqueous phase from the organic phase; and   d) isolating said anamorelin monohydrochloride from said aqueous phase.   
     
     
         15 ) The process of  claim 14 , wherein said water and hydrochloric acid in step b) are added sequentially or concurrently to said solution. 
     
     
         16 ) The process of  claim 14 , wherein said organic solvent is selected from butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate, methylethyl ketone, methylisobutyl ketone and 2-methyltetrahydrofuran. 
     
     
         17 ) The process of  claim 16 , wherein said organic solvent is isopropyl acetate. 
     
     
         18 ) The process of  claim 14  wherein the anamorelin monohydrochloride is isolated from said aqueous phase by spray drying. 
     
     
         19 ) The process of  claim 14 , wherein said anamorelin monohydrochloride is combined with from 0.9 to 1.0 molar equivalents of hydrochloric acid. 
     
     
         20 ) The process of  claim 14 , further comprising processing the anamorelin monohydrochloride into a finished dosage form. 
     
     
         21 ) Anamorelin monohydrochloride produced by the method of  claim 14 . 
     
     
         22 ) A pharmaceutical composition comprising:
 a) a therapeutically effective amount of the anamorelin monohydrochloride of  claim 1 ; and   b) one or more pharmaceutically acceptable excipients.   
     
     
         23 ) A method of making a pharmaceutical dosage form comprising:
 a) combining a therapeutically effective amount of the anamorelin monohydrochloride of  claim 1  with one or more pharmaceutically acceptable excipients to form a mixture; and   b) processing said mixture into a finished dosage form.