Methods of making L-ornithine phenyl acetate
View Patent ↗Disclosed herein are processes for making L-ornithine phenyl acetate. The process may include, for example, inter-mixing a halide salt of L-ornithine with silver phenyl acetate. The process may also include forming a phenyl acetate salt in situ. The present application also relates to various compositions obtained from these processes, including crystalline forms.
1. A process for making L-ornithine phenyl acetate salt comprising:
preparing a solution of phenyl acetate salt by mixing a phenyl acetic acid and a base in a solvent;
intermixing L-ornithine benzoate with the solution of phenyl acetate salt; and
isolating a composition comprising L-ornithine phenyl acetate.
2. The process of claim 1 , further comprising forming L-ornithine benzoate, wherein forming L-ornithine benzoate comprises intermixing an L-ornithine salt, a benzoate salt and a first solvent to form an intermediate solution.
3. The process of claim 2 , further comprising removing at least a portion of a salt from said intermediate solution before intermixing with the phenyl acetate salt, wherein said removed salt is not an L-ornithine salt.
4. The process of claim 3 , wherein said removed salt comprises an anion derived at least in part from the L-ornithine salt and a cation derived at least in part from the benzoate salt.
5. The process of claim 4 , wherein the L-ornithine salt is L-ornithine hydrochloride and said anion is chloride.
6. The process of claim 4 , wherein the benzoate salt is silver benzoate and the cation is a silver ion.
7. The process of claim 3 , wherein the process further comprises adding hydrochloric acid before said removing at least a portion of the salt.
8. The process claim 3 , wherein at least about 90% by weight of said removed salt is removed.
9. The process of claim 1 , further comprising forming L-ornithine benzoate, wherein forming L-ornithine benzoate comprises:
intermixing an L-ornithine salt, a benzoate salt and a first solvent to form an intermediate solution; and
isolating L-ornithine benzoate from said intermediate solution.
10. The process of claim 9 , further comprising removing at least a portion of a salt from said intermediate solution before isolating the L-ornithine benzoate, wherein said removed salt is not an L-ornithine salt.
11. The process of claim 10 , wherein the process further comprises adding hydrochloric acid before said removing at least a portion of the salt.
12. The process of claim 9 , wherein isolating L-ornithine benzoate comprises crystallizing L-ornithine benzoate from said intermediate solution.
13. The process of claim 1 , wherein the base is selected from the group consisting of an alkali metal hydroxide and an alkali metal alkoxide.
14. The process of claim 1 , further comprising forming L-ornithine benzoate, wherein forming L-ornithine benzoate comprises intermixing an L-ornithine salt, a benzoate salt and a second solvent to form an intermediate solution.
15. The process of claim 1 , wherein said composition comprises at least about 0.10% by weight benzoate salt and no more than 5% by weight benzoate salt.
16. The process of claim 14 , wherein the L-ornithine salt is L-ornithine hydrochloride.
17. The process of claim 14 , wherein the benzoate salt is silver benzoate.
18. The process of claim 17 , wherein said composition further comprises at least 10 ppm silver and no more than 600 ppm silver.
19. The process of claim 1 , wherein the phenyl acetate salt is an alkali metal salt.
20. The process of claim 19 , wherein the alkali metal salt is sodium phenyl acetate.
21. The process of claim 20 , wherein said composition comprises no more than 100 ppm sodium.
22. The process of claim 21 , wherein said composition comprises no more than 20 ppm sodium.
23. The process of claim 1 , wherein the composition comprises no more than 0.1% by weight chloride.
24. The process of claim 1 , wherein the composition comprises a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein said characteristic peak is selected from the group consisting of approximately 6.0°, 13.9°, 14.8°, 17.1°, 17.8° and 24.1° 2θ.
25. A process for making L-ornithine phenyl acetate salt comprising:
intermixing an L-ornithine salt, silver phenyl acetate and a solvent to form a solution; and
isolating a composition comprising L-ornithine phenyl acetate from said solution.
26. The process of claim 25 , wherein the L-ornithine salt is a halide salt.
27. The process of claim 26 , wherein the L-ornithine salt is L-ornithine hydrochloride.
28. The process of claim 25 , further comprising preparing the silver phenyl acetate by mixing a phenyl acetic acid and a base in a solvent.
29. The process of claim 25 , wherein the process further comprises adding hydrochloric acid to the solution before isolating L-ornithine phenyl acetate from the solution.
30. The process of claim 25 , wherein said composition further comprises at least 10 ppm silver and no more than 600 ppm silver.
31. The process of claim 25 , wherein said composition comprises no more than 100 ppm sodium.
32. The process of claim 31 , wherein said composition comprises no more than 20 ppm sodium.
33. The process of claim 25 , wherein the composition comprises no more than 0.1% by weight chloride.
34. The process of claim 25 , wherein the composition comprises a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein said characteristic peak is selected from the group consisting of approximately 6.0°, 13.9°, 14.8°, 17.1°, 17.8° and 24.1°2θ.