Methods of Producing Anamorelin Hydrochloride Having Controlled Chloride Content
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.