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 invention relates to a buprenorphine free base composition that contains very low levels of specific impurity compounds. The composition comprises at least about 98 wt% buprenorphine free base and 0.10 wt% or less of a compound of formula (12) and 0.10 wt% or less of a compound of formula (13), with some embodiments also limiting the total amount of impurities to about 0.25 wt% or less.

The disclosure also relates to impurity control in relation to compounds of formulae (10)–(19), including combined levels at or below specified wt% limits, and is described in relation to meeting USP/FDA/EMA/ICH impurity thresholds. The disclosed impurity framework extends to conversion to specific pharmaceutically acceptable salts, including buprenorphine hydrochloride and a levulinic acid-salt of buprenorphine.

Crystalline characterization is described for buprenorphine acetate tetrahydrate, including X-ray powder diffraction with CuKα1 radiation and differential scanning calorimetry showing transition regions and peak temperatures with integral ratios. The resulting product forms are described in terms of crystalline form, impurity control, and essentially impurity-free material.

Claims Coverage

The independent claims are directed to buprenorphine free base compositions with very low wt% levels of specific impurity compounds of formula (12) and formula (13), and one independent claim additionally requires a total impurity limit. Across the independent claims, the inventive features focus on quantitative impurity limits and impurity characterization criteria, with dependent claims extending coverage to pharmaceutical compositions and transdermal/oral dosage forms using a pharmaceutically acceptable carrier.

Overall, the claim coverage centers on buprenorphine free base compositions defined by very low wt% levels of impurity compounds of formula (12) and formula (13), and one independent claim additionally requires a total impurity limit of about 0.25 wt% or less. Dependent claims further narrow specific impurity thresholds, add HPLC "not detected" conditions for the compound of formula (13), and include pharmaceutical compositions and administration/dosage form limitations such as oral administration and transdermal patch reservoir/matrix containment.

Stated Advantages

Documented Applications