Crystal forms of anamorelin

Abstract

Crystalline forms of anamorelin which are useful as pharmaceutical agents are disclosed. Methods of production and isolation of these polymorphs and pharmaceutical compositions which include these polymorphs and pharmaceutical methods of treatment are also disclosed. The crystalline polymorphs of the present invention are useful as they act directly on the pituitary gland cells to release growth hormone.

1 . Crystalline anamorelin clathrate having an X-ray powder diffraction pattern having at least four 2θ values measured using Cu K α  radiation selected from the group consisting of 10.1, 11.1, 17.6, 20.0, and 20.8. 
     
     
         2 . The crystalline anamorelin clathrate of  claim 1  having a degree of hydration of from 0.5 to 2.5. 
     
     
         3 . The crystalline anamorelin clathrate of  claim 1  having a degree of hydration of from 1.0 to 2.0. 
     
     
         4 . The crystalline anamorelin clathrate of  claim 1  comprising methanol as an organic volatile impurity. 
     
     
         5 . A process for preparing the crystalline anamorelin clathrate of  claim 1  comprising: a) producing a mixture of anamorelin and a solvent comprised of methanol and water, b) precipitating crystalline anamorelin clathrate hydrate from the solvent; and c) isolating the crystalline anamorelin clathrate. 
     
     
         6 . The process of  claim 5 , wherein the solvent is a mixture of water and methanol and the volume percentage of methanol in the mixture is from about 5% to about 95%. 
     
     
         7 . The process of  claim 5 , wherein the solvent is a mixture of water and methanol and the volume percentage of methanol in the mixture is from about 20% to about 80%. 
     
     
         8 . The process of  claim 5 , wherein the solvent is a mixture of water and methanol and the volume percentage of methanol in the mixture is from about 40% to about 60%. 
     
     
         9 . The process of  claim 5 , wherein the solvent is at an elevated temperature while combining with the anamorelin in step a), or the solvent is heated to an elevated temperature after combining with the anamorelin in step a). 
     
     
         10 . The process of  claim 9 , wherein said elevated temperature is from about 40° C. to about 100° C. 
     
     
         11 . The process of  claim 9 , wherein said elevated temperature is from about 50° C. to about 80° C. 
     
     
         12 . The process of  claim 9 , wherein said elevated temperature is from about 65° C. to about 75° C. 
     
     
         13 . The process of  claim 5 , wherein the crystals are precipitated in step b) by cooling the solvent. 
     
     
         14 . A process for preparing the crystalline anamorelin clathrate hydrate of  claim 1  comprising: a) combining {1-[(1R)-2-](3R)-3-Benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl-]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester (protected anamorelin) with a solvent; b) combining the mixture from step a) with an acid; c) neutralizing the mixture formed in step b); d) precipitating crystals of anamorelin clathrate hydrate from the solvent; and e) isolating the crystals. 
     
     
         15 . The process of  claim 14 , wherein the solvent in step a) is methanol, and the mixture is neutralized in step c) with a mixture of potassium hydroxide and water. 
     
     
         16 . The process of  claim 14 , wherein the acid is methanesulfonic acid. 
     
     
         17 . The process of  claim 14 , wherein the solvent is at an elevated temperature while combining with said protected anamorelin in step a), or the solvent is heated to an elevated temperature after combining with said protected anamorelin in step a). 
     
     
         18 . The process of  claim 17 , wherein the elevated temperature is from about 50° C. to about 75° C. 
     
     
         19 . The process of  claim 14 , wherein the crystals are precipitated in step d) by cooling the solvent. 
     
     
         20 . A method of making a pharmaceutically acceptable salt of anamorelin comprising reacting the crystalline anamorelin clathrate of  claim 1  with hydrochloric acid.