Varenicline standards and impurity controls

Abstract

The subject invention provides a varenicline composition that comprises varenicline, or a pharmaceutically acceptable salt thereof, and an amount of a compound selected from one or more of several mononitro, monoamine mixed aminonitro, diamino or dinitro intermediates, and the concentration of said compound is greater than 0 ppm and not greater than about 500 ppm, not greater than about 100 ppm or not greater than about 10 ppm. Methods for synthesizing and using such varenicline compositions are also provided.

Description

Background technique

[0001] Efforts are made to prepare high grade pharmaceutical products with the least amount of impurities present. The control of impurities requires the study of various options for the reaction conditions and testing protocols necessary to ensure that the drug product administered to the public is pure.

[0002] Guidance given by regulatory agencies, including the U.S. Food and Drug Administration (FDA), states that for a drug substance at a dose of 2 g / day or less, if an impurity in the drug substance, if present, is present at 0.1% (i.e. 1000ppm) or higher should be identified. (Note that ppm is parts per million, so 1% = 10,000 ppm; 0.1% = 1000 ppm; 0.01% = 100 ppm; 0.001% = 10 ppm). For example, the FDA has indicated that for a drug substance dosed at 2 g / day, it is generally considered unnecessary to identify impurities at apparent levels below 0.1% (Federal Register, 65 (140), 45085-45090, 45086 and 45089 (20 July 2000). However, FDA also notes...

Examples

Embodiment

[0088] Part A: Example Clearance Experiments

[0089] Experimental Determination of Fold Clearance: Synthesis of Varenicline

[0090] Compound 8 was slurried in toluene and added to an aqueous solution of NaOH (3.1 equiv). The biphasic mixture was heated to 37-40°C, whereupon two clear yellowish layers resulted. At this point, 50 ppm of compound 3 (R=H) was spiked into the reaction mixture. The conversion of compound 8 to varenicline (9) was then carried out, including treating the biphasic toluene / water phase with Darco KB-B and recovering the compound 9 / toluene solution. The compound 9 / toluene solution was azeotroped with MeOH. The resulting compound 9 / methanol solution was added to the L-(+)-tartaric acid / MeOH solution to form salt 10. After the granules were formed, Salt 10 was filtered and dried.

[0091] The isolated material was analyzed for residual compound 3 (R=H). When a temperature of 37-40°C was reached, 50 ppm of Blend 3 was introduced into the reaction mix...

Background technique

[0001] Efforts are made to prepare high grade pharmaceutical products with the least amount of impurities present. The control of impurities requires the study of various options for the reaction conditions and testing protocols necessary to ensure that the drug product administered to the public is pure.

[0002] Guidance given by regulatory agencies, including the U.S. Food and Drug Administration (FDA), states that for a drug substance at a dose of 2 g / day or less, if an impurity in the drug substance, if present, is present at 0.1% (i.e. 1000ppm) or higher should be identified. (Note that ppm is parts per million, so 1% = 10,000 ppm; 0.1% = 1000 ppm; 0.01% = 100 ppm; 0.001% = 10 ppm). For example, the FDA has indicated that for a drug substance dosed at 2 g / day, it is generally considered unnecessary to identify impurities at apparent levels below 0.1% (Federal Register, 65 (140), 45085-45090, 45086 and 45089 (20 July 2000). However, FDA also notes...

Examples

Embodiment

[0088] Part A: Example Clearance Experiments

[0089] Experimental Determination of Fold Clearance: Synthesis of Varenicline

[0090] Compound 8 was slurried in toluene and added to an aqueous solution of NaOH (3.1 equiv). The biphasic mixture was heated to 37-40°C, whereupon two clear yellowish layers resulted. At this point, 50 ppm of compound 3 (R=H) was spiked into the reaction mixture. The conversion of compound 8 to varenicline (9) was then carried out, including treating the biphasic toluene / water phase with Darco KB-B and recovering the compound 9 / toluene solution. The compound 9 / toluene solution was azeotroped with MeOH. The resulting compound 9 / methanol solution was added to the L-(+)-tartaric acid / MeOH solution to form salt 10. After the granules were formed, Salt 10 was filtered and dried.

[0091] The isolated material was analyzed for residual compound 3 (R=H). When a temperature of 37-40°C was reached, 50 ppm of Blend 3 was introduced into the reaction mix...

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