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. A process for preparing amorphous 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 amorphous anamorelin monohydrochloride from said aqueous phase.
2. A process for preparing amorphous 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;
d) removing residual organic solvent from said aqueous phase via distillation; and
e) isolating said amorphous anamorelin monohydrochloride from said aqueous phase;
wherein (i) anamorelin free base is more soluble in the organic solvent than in water, and (ii) amorphous anamorelin monohydrochloride is more soluble in water than the organic solvent.
3. A process for preparing amorphous anamorelin monohydrochloride comprising:
a) dissolving anamorelin free base in isopropyl acetate 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;
d) removing residual isopropyl acetate from said aqueous phase via azeotropic distillation; and
e) isolating said amorphous anamorelin monohydrochloride from said aqueous phase.
4. The process of claim 1 , further comprising removing residual solvent from said aqueous phase after step (c) via distillation.
5. The process of claim 1 , wherein said water and hydrochloric acid in step b) are added sequentially to said solution.
6. The process of claim 1 , wherein said water and hydrochloric acid in step b) are added concurrently to said solution.
7. The process of claim 1 , 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.
8. The process of claim 1 , wherein said organic solvent is isopropyl acetate.
9. The process of claim 1 , wherein the amorphous anamorelin monohydrochloride is isolated from said aqueous phase by spray drying.
10. The process of claim 1 , wherein said anamorelin free base is combined with from 0.9 to 1.0 molar equivalents of hydrochloric acid.
11. The process of claim 1 , further comprising processing the amorphous anamorelin monohydrochloride into a finished dosage form.
12. The process of claim 1 wherein the amorphous anamorelin monohydrochloride has a solubility in water greater than 333 mg/mL, and a stability defined by a percentage increase in impurities of no more than 114% when stored at 25° C. and a relative humidity of 60% for two years.
13. The process of claim 1 wherein the amorphous anamorelin monohydrochloride has a chloride content of from 5.6 to 6.2% and a residual solvent concentration excluding water less than 5000 ppm, a solubility in water greater than 333 mg/mL, and a stability defined by a percentage increase in impurities of no more than 114% when stored at 25° C. and a relative humidity of 60% for two years.
14. The process of claim 2 wherein the amorphous anamorelin monohydrochloride has a solubility in water greater than 333 mg/mL, and a stability defined by a percentage increase in impurities of no more than 114% when stored at 25° C. and a relative humidity of 60% for two years.
15. The process of claim 2 wherein the amorphous anamorelin monohydrochloride has a chloride content of from 5.6 to 6.2% and a residual solvent concentration excluding water less than 5000 ppm, a solubility in water greater than 333 mg/mL, and a stability defined by a percentage increase in impurities of no more than 114% when stored at 25° C. and a relative humidity of 60% for two years.
16. The process of claim 2 , wherein said water and hydrochloric acid in step b) are added sequentially to said solution.
17. The process of claim 2 , wherein said water and hydrochloric acid in step b) are added concurrently to said solution.
18. The process of claim 2 , 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.
19. The process of claim 2 , wherein said organic solvent is isopropyl acetate.
20. The process of claim 2 , wherein the amorphous anamorelin monohydrochloride is isolated from said aqueous phase by spray drying.
21. The process of claim 2 , wherein said anamorelin free base is combined with from 0.9 to 1.0 molar equivalents of hydrochloric acid.
22. The process of claim 2 , further comprising processing the amorphous anamorelin monohydrochloride into a finished dosage form.
23. The process of claim 3 , wherein said water and hydrochloric acid in step b) are added sequentially to said solution.
24. The process of claim 3 , wherein said water and hydrochloric acid in step b) are added concurrently to said solution.
25. The process of claim 3 , wherein the amorphous anamorelin monohydrochloride is isolated from said aqueous phase by spray drying.
26. The process of claim 3 , wherein said anamorelin free base is combined with from 0.9 to 1.0 molar equivalents of hydrochloric acid.
27. The process of claim 3 , further comprising processing the amorphous anamorelin monohydrochloride into a finished dosage form.
28. The process of claim 3 wherein the amorphous anamorelin monohydrochloride has a solubility in water greater than 333 mg/mL, and a stability defined by a percentage increase in impurities of no more than 114% when stored at 25° C. and a relative humidity of 60% for two years.
29. The process of claim 3 wherein the amorphous anamorelin monohydrochloride has a chloride content of from 5.6 to 6.2% and a residual solvent concentration excluding water less than 5000 ppm, a solubility in water greater than 333 mg/mL, and a stability defined by a percentage increase in impurities of no more than 114% when stored at 25° C. and a relative humidity of 60% for two years.