Crystalline compounds
Inventors
McKINNEY, Anthony Alexander • BYMASTER, Franklin • Piskorski, Walter • Fleitz, Fred J. • Yang, Yonglai • Engers, David A. • Smolenskaya, Valeriya • Kusukuntla, Venkat
Assignees
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Publication Number
US-9856217-B2
Publication Date
2018-01-02
Expiration Date
Abstract
The present invention relates to crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride and compositions comprising the same and methods of making and using the same.
Core Innovation
The invention provides crystalline polymorphs of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, including Crystalline Forms A to F. Crystalline Form A is defined by an XRPD-defined pattern and unit cell parameters in space group P212121, while Crystalline Forms B and C are likewise defined by their own unit cell parameters and XRPD, DSC, TGA, and DVS behavior.
Crystalline Form A is characterized by XRPD verification and by thermal analysis using DSC and TGA, together with dynamic vapor sorption and desorption behavior. The disclosure states that Crystalline Form A is kinetically stable while being metastable and can persist under conditions where conversion to another form occurs.
The disclosure also includes pharmaceutical compositions using crystalline forms A to F. The document provides composition-related language for CNS disorders and sustained release formulation concepts, while linking the crystalline form content to an unbalanced triple reuptake inhibitor context involving norepinephrine reuptake, dopamine reuptake, and serotonin reuptake.
Claims Coverage
The independent claims cover three process categories: making Crystalline Form A, making a pharmaceutical composition comprising Crystalline Form A, and making Crystalline Form A using an ethanol and heat dissolution route. Across these claims, Crystalline Form A is defined by an XRPD pattern comprising specified d-spacing values, and three inventive features are present.
Seeding to make Crystalline Form A with an XRPD d-spacing pattern
A process for making Crystalline Form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride by seeding a solution or slurry with Crystalline Form A, wherein the crystalline form exhibits an XRPD pattern comprising d-spacing values of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5.
Ethanol dissolving, concentrating, and seeding to make Crystalline Form A with an XRPD d-spacing pattern
A process for making Crystalline Form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride comprising dissolving the compound in ethanol with heating, optionally filtering, concentrating, seeding with Crystalline Form A before or after concentrating, and optionally filtering, wherein the crystalline form exhibits an XRPD pattern comprising d-spacing values of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5.
Forming a pharmaceutical composition by isolating Crystalline Form A and admixing with a diluent or carrier
A process for making a pharmaceutical composition comprising Crystalline Form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride by isolating Crystalline Form A and admixing the isolated crystalline form with a pharmaceutically acceptable diluent or carrier, wherein the crystalline form exhibits an XRPD pattern comprising d-spacing values of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5.
The core claimed subject matter is the production and use of Crystalline Form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, operationally distinguished by an XRPD pattern with specified d-spacing values. The claims cover seeding-based formation, an ethanol dissolution and concentration workflow with optional filtration, and preparation of a pharmaceutical composition by isolating Crystalline Form A and admixing it with a pharmaceutically acceptable diluent or carrier.
Stated Advantages
Crystalline Form A is described as kinetically stable despite metastability.
Crystalline Form A can persist under conditions where another crystalline form converts.
Produces and verifies pharmaceutical solid Crystalline Form A defined by XRPD d-spacing values.
Crystalline Form A is characterized with DSC/TGA thermal behavior and described as non-hygroscopic by DVS behavior.
Provides a crystalline form suitable for pharmaceutical composition by admixing with a pharmaceutically acceptable diluent or carrier.
Documented Applications
Pharmaceutical compositions for treating CNS disorders in the context of an unbalanced triple reuptake inhibitor involving norepinephrine reuptake, dopamine reuptake, and serotonin reuptake, including ADHD-related language in the disclosure.
Sustained release formulation concepts for pharmaceutical compositions using crystalline forms A to F.
Use of Crystalline Forms A to F as pharmaceutical solids.
Therapeutic application described as an unbalanced triple reuptake inhibitor targeting norepinephrine/dopamine/serotonin reuptake.
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