Acetate salt of buprenorphine and methods for preparing buprenorphine

Inventors

Huntley, C. Frederick M. • Kataisto, Erik Wayne • REISCH, Helge Alfred • Sharma, Archana

Assignees

Noramco LLC

Abstract

The present disclosure provides acetate salts of buprenorphine, and its anhydrates, solvates, hydrates, and crystalline forms thereof, where the acetate salts of buprenorphine are essentially free of impurities. The disclosure further provides method of preparing the acetate salts, buprenorphine free base prepared from the acetate salts, other salts prepared from the free base, and pharmaceutical compositions thereof essentially free of impurities.

Core Innovation

The document discloses methods for preparing buprenorphine free base from an acetate salt of buprenorphine by treating the acetate salt at a pressure from about 50 Torr to about 250 Torr, inclusive, and at a temperature at least about 30°C for a period of time sufficient to form buprenorphine free base. It further includes embodiments at about 100 Torr to about 200 Torr, at least about 50°C for at least about 10 hours, and slurrying and filtering at a temperature of at least about 50°C.

The disclosure further addresses impurity control in the resulting buprenorphine free base, including low residual acetic acid and very low levels of impurity compounds represented by formulae (10)–(15). Each impurity compound is described as being at or below 0.10 wt%, with further embodiments at or below 0.05 wt%, and the combined total impurity level from formulae (10)–(15) is also limited. An isolated buprenorphine free base product contains about 0.08 wt% or less of a compound of formula (12).

The document also discloses methods for preparing buprenorphine acetate salts from buprenorphine free base by contacting with acetic acid and forming the acetate salt through precipitation using an anti-solvent and optionally seed crystals, followed by isolation. It further characterizes buprenorphine acetate crystalline forms, including polymorphs, hydrates, anhydrous forms, and solvates, and emphasizes an acetate tetrahydrate crystalline form with defined X-ray powder diffraction, DSC transition regions, unit cell and space group parameters, and high stability.

Claims Coverage

The claims coverage centers on independent claims for preparing buprenorphine free base from an acetate salt by treating the acetate salt under defined pressure and temperature conditions for a sufficient time, with dependent claims adding narrower pressure/time/temperature regimes, hot slurrying and filtration, and impurity constraints. It also includes claim coverage for impurity-limited product features, with seven inventive features in total.

Across the independent and dependent claims, the inventive coverage focuses on converting a buprenorphine acetate salt to buprenorphine free base by treating the acetate salt at a defined pressure and temperature for a sufficient time, with further refinements that narrow the pressure and temperature/time regimes and impose impurity limits for residual acetic acid and a compound of formula (12).

Stated Advantages

Documented Applications