Acetate salt of buprenorphine and methods for preparing buprenorphine
Inventors
Huntley, C. Frederick • Kataisto, Erik Wayne • REISCH, Helge Alfred • Sharma, Archana
Assignees
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Publication Number
US-10874662-B2
Publication Date
2020-12-29
Expiration Date
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 invention relates to methods for preparing buprenorphine free base from an acetate salt of buprenorphine. The method provides buprenorphine free base by agitating an admixture that includes the acetate salt, a solution, and a basic material, followed by isolating the buprenorphine free base from the admixture.
The admixture agitation is carried out at a temperature of about 20° C. to about 90° C., and in some embodiments the solution includes an alcohol in water at about 30 wt% to about 70 wt%. The basic material can include ammonium hydroxide, and the isolating step can include slurry formation and filtering to obtain the buprenorphine free base.
The disclosure also addresses impurity control for buprenorphine free base and buprenorphine salts prepared using the disclosed preparation methods. In particular embodiments, the free base product is isolated without chromatography and includes specified low wt% levels of compounds of formula (12) and formula (13), and the description further recites crystalline forms, polymorphs, solvates, hydrates, and buprenorphine salts with disclosed impurity levels.
Claims Coverage
The document includes four independent inventive features centered on agitating or converting an acetate salt of buprenorphine to buprenorphine free base using a basic material, followed by isolation, with additional emphasis on solution composition and impurity control.
Agitating an acetate admixture to form buprenorphine free base
Agitating an admixture comprising an acetate salt of buprenorphine, a solution, and a basic material at a temperature of from about 20° C. to about 90° C. to provide buprenorphine free base.
Isolating buprenorphine free base from an acetate admixture
Isolating the buprenorphine free base from the admixture.
Using an alcohol-in-water solution with ammonium hydroxide during agitation
Agitating an admixture comprising an acetate salt of buprenorphine, a solution comprising from about 30 wt% to about 70 wt% of an alcohol in water, and ammonium hydroxide at a temperature of from about 20° C. to about 90° C., to provide buprenorphine free base.
Converting acetate salt to free base without chromatography and controlling impurity levels
Converting an acetate salt of buprenorphine to a buprenorphine free base product in the presence of a basic material, and isolating the buprenorphine free base product without chromatography, wherein the buprenorphine free base product comprises about 0.05 wt% to about 0.10 wt% of a compound of formula (12) and about 0.05 wt% or less of a compound of formula (13).
Across the independent claims, the inventive concept is producing buprenorphine free base from an acetate salt by basic-material conversion under agitated conditions, then isolating the free base, with embodiments specifying alcohol-in-water solution conditions and controlled impurity wt% levels, including isolation without chromatography.
Stated Advantages
Essentially impurity-free buprenorphine acetate salts, including anhydrates, solvates, hydrates, and crystalline forms.
Provides buprenorphine free base with specified low levels of compounds of formula (12) and (13).
Preparation of buprenorphine free base product is carried out without chromatography.
Documented Applications
Therapeutic indications for buprenorphine acetate hydrate products and pharmaceutical compositions, including treating pain, constipation, drug abuse/addictive disorder, vomiting, respiratory depression, and euphoria.
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