Methods of producing anamorelin hydrochloride having controlled chloride content

Patent metadata

Field	Value
Publication number	US-10905737-B2
Application number	US-202016751836-A
Country	US
Kind code	B2
Filing date	Jan 24, 2020
Priority date	Apr 20, 2012
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

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.

First claim

The invention claimed is:

1. Anamorelin monohydrochloride having a chloride content ranging from 5.8 to 6.2%, a residual organic solvent concentration less than 5000 ppm, and an inter-batch chloride content that varies by no more than 7%.

2. The anamorelin monohydrochloride of claim 1 in an amorphous state.

3. The anamorelin monohydrochloride of claim 1 , in an isolated state.

4. The anamorelin monohydrochloride of claim 1 , comprising less than 0.5% impurities.

5. The anamorelin monohydrochloride of claim 1 , comprising from 1 to 3% water.

6. The anamorelin monohydrochloride of claim 4 , wherein the impurities are selected from by-products, contaminants, and degradation products.

7. The anamorelin monohydrochloride of claim 6 , comprising a residual organic 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.

8. The anamorelin monohydrochloride of claim 7 , wherein the residual organic solvent is isopropyl acetate.

9. The anamorelin monohydrochloride of claim 1 , having a purity greater than 99%, based on impurities selected from by-products, contaminants other than residual organic solvents and water, and degradation products.

10. A composition comprising anamorelin monohydrochloride and one or more pharmaceutically acceptable excipients, wherein the composition comprises a chloride content ranging from 5.8 to 6.2%, a residual organic solvent concentration less than 5000 ppm, and an inter-batch chloride content that varies by no more than 7%.

11. The composition of claim 10 , in the substantial absence of anamorelin hydrochloride other than anamorelin monohydrochloride.

12. A process for preparing multiple batches of 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) isolating said anamorelin monohydrochloride from said aqueous phase; and
e) repeating steps (a)-(d) multiple times to produce multiple batches of anamorelin monohydrochloride having an inter-batch chloride content that varies by no more than 7%.

13. The process of claim 12 , wherein said water and hydrochloric acid in step b) are added sequentially or concurrently to said solution.

14. The process of claim 12 , 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.

15. The process of claim 14 , wherein said organic solvent is isopropyl acetate.

16. The process of claim 12 wherein the anamorelin monohydrochloride is isolated from said aqueous phase by spray drying.

17. The process of claim 12 , further comprising processing the anamorelin monohydrochloride into a finished dosage form.

18. The process of claim 12 , wherein said anamorelin monohydrochloride comprises less than 5000 ppm residual organic solvents.

19. The process of claim 12 , wherein said anamorelin monohydrochloride comprises less than 1% impurities selected from contaminants, by-products, and degradation products, other than residual organic solvents and water.

20. The anamorelin monohydrochloride of claim 1 , in an amorphous state, comprising less than 1% impurities selected from by-products, contaminants, and degradation products.

Assignees

• Helsinn Healthcare Sa
• Ono Pharmaceutical Co

Inventors

• Kuwabe Shin-Itsu
• Yanagimachi Takehiko
• Yoshiyama Hideyuki
• Pines Seemon
• De Groot Eleanor
• Garcia Rubio Silvina
• Manini Peter

Classifications

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61K38/05 Primary

  Dipeptides · CPC title

• C07K5/06034

  the side chain containing 2 to 4 carbon atoms · CPC title

• A61K9/1682

  Processes · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title