Trientine tetrahydrochloride and a method of preparation and a pharmaceutical composition thereof
A method of preparation of trientine tetrahydrochloride crystals in which an anti-solvent at a feeding temperature is added into a trientine tetrahydrochloride solution and stirred for crystallization wherein the feeding temperature ranges from 50° C. to 75° C. and the anti-solvent is an alcohol solvent. A novel trientine tetrahydrochloride featuring XRPD peaks detected at 21.9, 24.8, 25.2, 28.0 and 35.6±0.1° 2θ for stable storage of a pharmaceutical composition manufactured with the trientine tetrahydrochloride.
1. A method of preparation of trientine tetrahydrochloride crystals, comprising:
step 1: adding an anti-solvent at a feeding temperature into a trientine tetrahydrochloride solution and stirring for crystallization;
wherein the feeding temperature ranges from 50° C. to 75° C. and the anti-solvent is an alcohol solvent,
wherein the stirring is made for a duration of at least one hour at a temperature ranging from 5° C. to 25° C.,
wherein the method does not require a use of seed crystals, and
wherein the trientine tetrahydrochloride crystals feature X-Ray Powder Diffraction (XRPD) peaks detected at 21.9, 24.8, 25.2, 28.0 and 35.6±0.1° 2θ.
2. The method of preparation as claimed in claim 1 , wherein the anti-solvent is methanol.
3. The method of preparation as claimed in claim 2 , wherein the step 1 further comprises drying crystals for LOD (loss on drying) of crystals <1%.
4. The method of preparation as claimed in claim 1 , wherein the step 1 further comprises:
pre-step 1: preparing a reaction fluid by mixing a trientine dihydrochloride (TETA·2HCl) solution and an acidic solution for acidification; and
pre-step 2: adding an alcohol anti-solvent to the reaction fluid and stirring the reaction fluid for crystallization of crude trientine tetrahydrochloride.
5. The method of preparation as claimed in claim 4 , wherein the reaction fluid has a pH value ≤2.0.
6. The method of preparation as claimed in claim 4 , wherein the alcohol anti-solvent in the pre-step 2 is methanol.
7. The method of preparation as claimed in claim 4 , wherein the stirring in the pre-step 2 is made for a duration of at least two hours at a temperature ranging from 15° C. to 35° C.
8. The method of preparation as claimed in claim 4 , wherein the pre-step 2 further comprises drying the crude trientine tetrahydrochloride such that LOD (loss on drying) of the crude trientine tetrahydrochloride is <10%.
9. A pharmaceutical composition, comprising the trientine tetrahydrochloride prepared by the method of preparation as claimed in claim 4 .
10. The pharmaceutical composition as claimed in claim 9 , wherein the pharmaceutical composition further comprises a vehicle pharmaceutically acceptable.
11. The pharmaceutical composition as claimed in claim 10 , wherein the vehicle comprises a dissolving agent, a diluent, a lubricant, a binding agent, a depolymerizing agent, an effervescent mixture, a dye, a sweetening agent, a wetting agent, or a nontoxic and pharmaceutically inactive substance for pharmaceutical concoction.
12. The pharmaceutical composition as claimed in claim 9 , wherein a formulation of the pharmaceutical composition is a solution, an emulsion, a suspension, powders, a tablet, a pill, a troche or a capsule.
13. The trientine tetrahydrochloride prepared by the method of preparation as claimed in claim 5 for preparation of a pharmaceutical composition with which a Wilson's disease is prevented or treated.
14. A pharmaceutical composition, comprising trientine tetrahydrochloride crystals, wherein the trientine tetrahydrochloride crystals feature X-Ray Powder Diffraction (XRPD) peaks detected at 21.9, 24.8, 25.2, 28.0 and 35.6±0.1° 2θ.
15. The pharmaceutical composition as claimed in claim 14 , wherein the pharmaceutical composition further comprises a vehicle pharmaceutically acceptable.
16. The pharmaceutical composition as claimed in claim 15 , wherein the vehicle comprises a dissolving agent, a diluent, a lubricant, a binding agent, a depolymerizing agent, an effervescent mixture, a dye, a sweetening agent, a wetting agent, or a nontoxic and pharmaceutically inactive substance for pharmaceutical concoction.
17. The pharmaceutical composition as claimed in claim 14 , wherein a formulation of the pharmaceutical composition is a solution, an emulsion, a suspension, powders, a tablet, a pill, a troche or a capsule.