VARENICLINE 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 .- 68 . (canceled)
69 . A method of treating nicotine dependency, addiction or withdrawal in a subject in need thereof, comprising orally administering a pharmaceutical composition comprising about 0.85 mg to about 1.7 mg substantially pure varenicline tartrate (equivalent to about 0.5 mg to about 1 mg substantially pure varenicline free base) in one or more daily doses;
wherein the substantially pure varenicline free base is obtained by an acid-base treatment to remove N-nitroso-varenicline (7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino [2,3-h][3] benzazepine) impurity to less than 50 ppm per dose as measured by LC-ESI-HRMS Method; and
wherein the subject receives a total of no more than about 37 ng of the N-nitroso-varenicline impurity per day as measured by LC-ESI-HRMS Method.
70 . The method of claim 69 , wherein the composition comprises less than 25 ppm of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS Method.
71 . The method of claim 69 , wherein the composition is orally administered one week before a date set by the subject to attempt to stop smoking.
72 . The method of claim 69 , wherein the subject quits smoking between about 8 to about 35 days after treatment.
73 . The method of claim 69 , wherein the acid-base treatment utilizes an organic solvent and an acid chosen from tartaric acid, fumaric acid, lactic acid, malic acid, malonic acid, hydrochloric acid, succinic acid, oxalic acid, citric acid, or mixtures thereof.
74 . The method of claim 69 , wherein the treatment comprises administering:
a) the equivalent of about 0.5 mg of the substantially pure varenicline free base once daily for days 1-3 of the treatment;
b) the equivalent of about 0.5 mg of the substantially pure varenicline free base twice daily for days 4-7 of the treatment; and
c) the equivalent of about 1 mg of the substantially pure varenicline free base twice daily after day 7 of the treatment.
75 . The method of claim 74 , wherein the subject is treated for about 12 weeks.
76 . A method of treating nicotine dependency, addiction or withdrawal in a subject in need thereof, comprising orally administering a pharmaceutical composition comprising about 0.85 mg to about 1.7 mg substantially pure varenicline tartrate in one or more daily doses;
wherein the substantially pure varenicline tartrate is obtained by combining substantially pure varenicline free base comprising less than 50 ppm of N-nitroso-varenicline impurity as measured by LC-ESI-HRMS Method with tartaric acid; and
wherein the subject receives a total of no more than 100 ppm of the N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
77 . The method of claim 76 , wherein the subject receives a total of no more than 75 ppm of the N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
78 . The method of claim 76 , wherein the subject receives a total of no more than 50 ppm of the N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
79 . The method of claim 76 , wherein the subject receives a total of no more than 25 ppm of the N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
80 . The method of claim 76 , wherein the subject receives a total of no more than 20 ppm of the N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
81 . A method of treating nicotine dependency, addiction or withdrawal in a subject in need thereof, comprising:
a) combining substantially pure varenicline free base with tartaric acid to form a pharmaceutical composition comprising about 0.85 mg to about 1.7 mg substantially pure varenicline tartrate;
b) combining the substantially pure varenicline tartrate with at least one excipient; and
c) orally administering the composition in one or more daily doses;
wherein the substantially pure varenicline free base is obtained by an acid-base treatment to remove N-nitroso-varenicline (7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino [2,3-h][3] benzazepine) impurity to less than 50 ppm per dose as measured by LC-ESI-HRMS Method;
wherein the subject receives a total of no more than 100 ppm of N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
82 . The method of claim 81 , wherein the varenicline tartrate pharmaceutical composition is equivalent to about 0.5 mg to about 1 mg of the substantially pure varenicline free base and is in the form of a tablet or capsule.
83 . The method of claim 81 , wherein the excipient is 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.
84 . The method of claim 81 , wherein the substantially pure varenicline free base is obtained by layer separation, basification and extraction.
85 . The method of claim 82 , wherein the tablet or capsule comprises about 25 ppm or less of the N-nitroso-varenicline impurity as measured by LC-ESI-HRMS Method.
86 . The method of claim 82 , wherein the tablet or capsule comprises about 1 mg of the substantially pure varenicline free base and about 50 ppm or less of the N-nitroso-varenicline impurity.
87 . The method of claim 82 , wherein the tablet or capsule comprises about 0.5 mg of the substantially pure varenicline free base and about 25 ppm or less of the N-nitroso-varenicline impurity.
88 . The method of claim 82 , wherein the tablet or capsule comprises about 1 mg of the substantially pure varenicline free base and about 25 ppm or less of the N-nitroso-varenicline impurity.
89 . The method of claim 84 , wherein the acid is chosen from tartaric acid, fumaric acid, lactic acid, malic acid, malonic acid, hydrochloric acid, succinic acid, oxalic acid, citric acid, or mixtures thereof.
90 . A method of treating nicotine dependency, addiction or withdrawal in a subject in need thereof, comprising:
a) providing a solid oral dosage form comprising about 0.85 mg to about 1.7 mg substantially pure varenicline tartrate wherein the dosage form comprises less than 25 ppm total of N-nitroso-varenicline, dinitro nitrosamine, and diamino nitrosamine impurities as measured by LC-ESI-HRMS Method and wherein the substantially pure varenicline tartrate is obtained by acid-base treatment and layer separation; and
b) orally administering the dosage form in one or more daily doses, wherein the subject receives a total of no more than 50 ppm of the N-nitroso-varenicline impurity per day as measured by the LC-ESI-HRMS Method.
91 . The method of claim 90 , wherein the dosage form comprises no more than about 5 ppm of the N-nitroso-varenicline impurity.
92 . The method of claim 90 , wherein the dosage form comprises no more than about 5 ppm of the dinitro nitrosamine impurity.
93 . The method of claim 90 , wherein the dosage form comprises no more than about 5 ppm of the diamino nitrosamine impurity.
94 . The method of claim 90 , wherein the dosage form comprises no more than about 0.15% (w/w) of n-methyl varenicline impurity.
95 . The method of claim 90 , wherein the acid-base treatment and layer separation comprises:
a) converting varenicline base into a varenicline salt with an organic or inorganic acid in an aqueous solution;
b) extracting the nitrosamine impurities with an organic solvent;
c) isolating substantially pure varenicline free base by adding a base to the aqueous solution and extracting the substantially pure varenicline free base with an organic solvent.
96 . The method of claim 95 , wherein the organic solvent is methylene dichloride.
97 . The method of claim 95 , wherein the base is sodium carbonate.
98 . The method of claim 95 , wherein the substantially pure varenicline base is combined with tartaric acid to form varenicline tartrate.