Vareniciline compound and process of manufacture thereof
The present disclosure relates to the field of synthesizing substantially pure varenicline and its intermediates. It also relates to the pharmaceutical compositions comprising varenicline and the method of use of these pharmaceutical compositions for smoking cessation.
1. A pharmaceutical composition in the form of a tablet, comprising varenicline tartrate, wherein the tablet comprises less than 50 ppm of N-nitroso-varenicline (7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino [2,3-h][3] benzazepine) impurity as measured by LC-ESI-HRMS (U.S. FDA Method) and less than 0.15% (w/w) of diamide (Bis (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]-benzazepine)-amide) impurity as measured by RS Method-II.
2. The composition of claim 1 , further comprising one or more excipients chosen from: maltodextrin, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, a starch, alginic acid, polyvinylpyrrolidone, sucrose, gelatin, acacia, a silicate, magnesium stearate, sodium lauryl sulfate, talc, lactose, polyethylene glycol, hydroxypropyl cellulose, hypromellose, titanium dioxide, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, or mixtures of any of the foregoing.
3. The composition of claim 1 , wherein the tablet comprises between about 0.85 mg and about 1.7 mg of the varenicline tartrate, and comprises less than 25 ppm of the N-nitroso-varenicline impurity per tablet as measured by LC-ESI-HRMS (U.S. FDA Method).
4. The composition of claim 1 , wherein the tablet comprises between about 0.85 mg and about 1.7 mg of the varenicline tartrate, and comprises less than 19 ppm of the N-nitroso-varenicline impurity per tablet as measured by LC-ESI-HRMS (U.S. FDA Method).
5. The composition of claim 1 , wherein the tablet comprises between about 0.85 mg and about 1.7 mg of the varenicline tartrate, and comprises about 5 ppm or less of the N-nitroso-varenicline impurity per tablet as measured by LC-ESI-HRMS (U.S. FDA Method).
6. The composition of claim 1 , wherein the tablet further comprises less than 0.15% (w/w) of monomethyl tartrate (tartaric acid monomethyl ester) impurity per tablet as measured by LCMS-ESI.
7. The composition of claim 1 , wherein the tablet further comprises less than 0.15% (w/w) of dimethyl tartrate (tartaric acid dimethyl ester) impurity per tablet as measured by LCMS-APCI.
8. The composition of claim 1 , wherein the tablet further comprises less than 0.15% (w/w) of N-methyl varenicline (7,8,9,10-tetrahydro-8-methyl-6,10-Methano-6H-pyrazino[2,3-h][3] benzazepine) impurity per tablet as measured by RS Method-III.
9. The composition of claim 1 , wherein the tablet further comprises less than 0.15% (w/w) of N-formyl varenicline (6,7,9,10-Tetrahydro-6,10-methano-8H-pyrazino[2,3-h][3]benzazepine-8-carboxaldehyde) impurity per tablet as measured by RS Method-II.
10. The composition of claim 1 , wherein the tablet further comprises less than 0.15% (w/w) of varenicline N-glucoside impurity per tablet as measured by RS Method-III.
11. The composition of claim 1 , wherein the tablet further comprises less than 50 ppm of dinitro nitrosoamine (4,5-Dinitro-10-nitroso-10-aza-tricyclo[6.3.1.0 2,7 ] dodeca-2,4,6-triene) impurity per tablet as measured by LCMS Method-I.
12. The composition of claim 1 , wherein the tablet further comprises less than 50 ppm of diamino nitrosoamine (10-nitroso-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2,4,6-triene-4,5-diamine) impurity per tablet as measured by LCMS Method-II.
13. A pharmaceutical composition in the form of a tablet, comprising between about 0.85 mg and about 1.7 mg varenicline tartrate, wherein the varenicline tartrate comprises less than 50 ppm of N-nitroso-varenicline (7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino [2,3-h][3] benzazepine) impurity as measured by LC-ESI-HRMS (U.S. FDA Method) and less than 0.15% (w/w) of varenicline N-glucoside impurity as measured by RS Method-III.
14. The composition of claim 13 , further comprising one or more excipients chosen from: maltodextrin, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, a starch, alginic acid, polyvinylpyrrolidone, sucrose, gelatin, acacia, a silicate, magnesium stearate, sodium lauryl sulfate, talc, lactose, polyethylene glycol, hydroxypropyl cellulose, hypromellose, titanium dioxide, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, or mixtures of any of the foregoing.
15. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 0.15% (w/w) of monomethyl tartrate (tartaric acid monomethyl ester) impurity as measured by LCMS-ESI.
16. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 0.15% (w/w) of dimethyl tartrate (tartaric acid dimethyl ester) impurity as measured by LCMS-APCI.
17. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 0.15% (w/w) of N-methyl varenicline (7,8,9,10-tetrahydro-8-methyl-6,10-Methano-6H-pyrazino[2,3-h][3] benzazepine) impurity as measured by RS Method-III.
18. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 0.15% (w/w) of N-formyl varenicline (6,7,9,10-Tetrahydro-6,10-methano-8H-pyrazino[2,3-h][3]benzazepine-8-carboxaldehyde) impurity as measured by RS Method-II.
19. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 0.15% (w/w) of diamide (Bis (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]-benzazepine)-amide) impurity as measured by RS Method-II.
20. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 50 ppm of dinitro nitrosoamine (4,5-Dinitro-10-nitroso-10-aza-tricyclo[6.3.1.0 2,7 ] dodeca-2,4,6-triene) impurity as measured by LCMS Method-I.
21. The composition of claim 13 , wherein the varenicline tartrate further comprises less than 50 ppm of diamino nitrosoamine (10-nitroso-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2,4,6-triene-4,5-diamine) impurity as measured by LCMS Method-II.
22. The composition of claim 13 , wherein the varenicline tartrate comprises less than 25 ppm of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS (U.S. FDA Method).
23. The composition of claim 13 , wherein the varenicline tartrate comprises less than 19 ppm of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS (U.S. FDA Method).
24. A pharmaceutical composition in the form of a tablet, comprising between about 0.5 mg and about 1 mg varenicline free base and tartaric acid as a counterion to the varenicline free base, wherein the tablet comprises less than 50 ppm of N-nitroso-varenicline (7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino [2,3-h][3] benzazepine) impurity as measured by LC-ESI-HRMS (U.S. FDA Method) and less than 0.15% (w/w) diamide (Bis (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]-benzazepine)-amide) impurity as measured by RS Method-II.
25. The composition of claim 24 , wherein the tablet comprises less than 30 ppm of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS (U.S. FDA Method).
26. The composition of claim 24 , wherein the tablet comprises less than 20 ppm of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS (U.S. FDA Method).
27. The composition of claim 24 , wherein the tablet comprises less than 10 ppm of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS (U.S. FDA Method).
28. A pharmaceutical composition in the form of a tablet, comprising between about 0.5 mg and about 1 mg varenicline free base and tartaric acid as a counterion to the varenicline free base, wherein the varenicline free base comprises less than 50 ppm of N-nitroso-varenicline (7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino [2,3-h][3] benzazepine) impurity as measured by LC-ESI-HRMS (U.S. FDA Method), and the tablet comprises less than 0.15% (w/w) diamide (Bis (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]-benzazepine)-amide) impurity as measured by RS Method-II.
29. The composition of claim 28 , wherein the varenicline free base comprises less than 25 ppm of the N-nitroso-varenicline impurity.
30. The composition of claim 28 , wherein the varenicline free base comprises less than 15 ppm of the N-nitroso-varenicline impurity.