Acetate salt of buprenorphine and methods for preparing buprenorphine
Inventors
Huntley, C. Frederick M. • Kataisto, Erik Wayne • REISCH, Helge Alfred • Sharma, Archana
Assignees
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Publication Number
US-10278967-B2
Publication Date
2019-05-07
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 a crystalline form of the acetate salt of buprenorphine comprising a hydrate, wherein the hydrate is a tetrahydrate. The solid form is characterized by X-ray powder diffraction, thermal analysis, and crystallographic identity parameters, including monoclinic symmetry, space group information, and unit cell parameters.
The disclosure also specifies impurity specifications for buprenorphine free base obtained from multiple methods starting from an acetate salt of buprenorphine, including buprenorphine acetate tetrahydrate. The buprenorphine free base contains impurities represented by formulae (11)–(15) and additional impurities represented by formulae (16)–(19) at specified limits, together with combined impurity limits for impurities represented by formulae (10)–(15).
Further characterization includes essentially pure or impurity-reduced buprenorphine acetate salt products and impurity retention under long-term and accelerated conditions. The document links the defined buprenorphine acetate tetrahydrate crystalline form and derived low-impurity salts with pharmaceutical use in compositions and treatment of pain.
Claims Coverage
The provided claim coverage centers on two main inventive features: a crystalline tetrahydrate form of buprenorphine acetate and a low-impurity buprenorphine free base with specified impurity limits. Dependent claims further refine the crystalline form by XRPD, DSC transition regions, monoclinic symmetry, and unit-cell parameters, and extend to pharmaceutical composition and treatment of pain.
Acetate salt of buprenorphine tetrahydrate crystalline form
A crystalline form of the acetate salt of buprenorphine comprising a hydrate, wherein the hydrate is a tetrahydrate.
X-ray powder diffraction identity
A crystalline form characterized by an X-ray powder diffraction pattern using CuKα radiation, with peaks at 2θ angles substantially equivalent to 16.21 and 18.70 and at least one additional peak at a 2θ angle substantially equivalent to 8.77, 10.31, or 18.47.
DSC transition region with defined heating-rate condition
The crystalline form has a first transition region with at least one peak position in the range of about 50°C to about 140°C as measured by a heat flow differential scanning calorimeter at a heating rate of about 10°C per minute.
Monoclinic crystal system
The crystalline form is characterized as being a monoclinic crystal.
Unit-cell parameters
The crystalline form has unit cell parameters specified as a=10.5±0.5 Å, b=10.9±0.5 Å, and c=14.4±0.5 Å.
Low-impurity buprenorphine free base
Buprenorphine free base obtained from multiple methods starting from an acetate salt of buprenorphine, with specified limits for impurities represented by formulae (11)–(15), additional impurities represented by formulae (16)–(19), and combined impurity limits for impurities represented by formulae (10)–(15).
Treating pain by administering the crystalline form
A method of treating pain in an animal by administering an effective amount of the crystalline form of the acetate salt of buprenorphine comprising a hydrate, wherein the hydrate is a tetrahydrate.
The claim coverage is directed to a tetrahydrate crystalline form of buprenorphine acetate, with additional features defining the solid-state identity by XRPD peak positions, DSC-based transition regions under a specified heating rate, and crystallographic parameters including monoclinic symmetry and unit-cell dimensions. It also covers a low-impurity buprenorphine free base with specified impurity limits and includes treatment of pain by administering the crystalline tetrahydrate.
Stated Advantages
Impurity reduction and essentially pure buprenorphine acetate salt products are emphasized in the document.
Reports high stability/purity, including impurity retention under long-term and accelerated conditions.
Reports photostability of the crystalline form.
Describes highly pure buprenorphine acetate in relation to impurity limits for the acetate salt form.
Documented Applications
Pharmaceutical use for treating pain by administering an effective amount of the crystalline tetrahydrate.
Treating pain in an animal by administering an effective amount of the crystalline form.
Pharmaceutical composition comprising the crystalline form and a pharmaceutically acceptable carrier.
The document also lists additional conditions associated with buprenorphine acetate hydrate/crystalline tetrahydrate: constipation, drug abuse/addictive disorder, vomiting, respiratory depression, and euphoria.
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