Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof
Inventors
Smolenskaya, Valeriya N. • Al Shareffi, Kadum A. • Perez, Julio • Shah, Syed M. • Boyd, Thomas A.
Assignees
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Publication Number
US-9102680-B2
Publication Date
2015-08-11
Expiration Date
Abstract
The present invention provides a new forms of (R)—N-methylnaltrexone, and compositions thereof, useful as a peripheral mu opioid receptor antagonist.
Core Innovation
The document describes (R)-N-methylnaltrexone bromide as Compound 1 and characterizes it as a peripheral bc-opioid receptor antagonist. It discloses multiple solid forms of Compound 1, including polymorphs, solvates/hydrates, and amorphous forms, defined by X-ray powder diffraction (XRPD) characteristics.
Crystal Form A is described as a neat form, while Crystal Form B is described as a mixed hydrate/methanolate. Crystal Form D is defined by an XRPD pattern comprising specified peaks at about 7.66, 8.42, 14.79, and 21.06 degrees 2-theta, and Crystal Form C is described as an n-propanolate solvate with XRPD peak sets and monoclinic unit-cell parameters at 150±1 K.
The document also includes characterization by XRPD, DSC, and TG, and discusses preparation and polymorph screening for Forms A through D, including characterization of Form A/Form C mixtures with preferred orientation XRPD behavior. The document further describes pharmaceutical compositions and use context relating to opioid-induced gastrointestinal dysfunction/constipation and other peripheral effects, and states an amorphous water-solubility advantage for parenteral delivery.
Claims Coverage
The provided independent claims define three main areas: specific XRPD-based definitions of Form D and Form C of Compound 1, and a pharmaceutical composition comprising a specified Form A/Form C mixture characterized by an XRPD peak set. Each independent claim is anchored to the (R) configuration with respect to the nitrogen for the covered compound.
Form D of Compound 1 defined by a specified XRPD peak set
A form of Compound 1 in the (R) configuration with respect to the nitrogen, wherein the compound has an X-ray powder diffraction pattern comprising all of the peaks at about 7.66, 8.42, 14.79, and 21.06 degrees 2-theta.
Form C of Compound 1 defined by a single-crystal calculated XRPD pattern at 150±1.0 K
A form of Compound 1 in the (R) configuration with respect to the nitrogen, wherein the compound has an X-ray powder diffraction pattern, calculated from single crystal data collected at a temperature of 150±1.0 K, comprising all of the peaks at about 10.8, 12.8, 14.8, 15.9, 16.25, 18.5, 19.15, 22, 23.6, 24.25, 25.7, 27.5, 28.1, 28.9, 31.5 and 31.75 degrees 2-theta.
A composition comprising a mixture of Form A and Form C defined by a specified XRPD peak set
A composition comprising a mixture of Form A of Compound 1 and Form C of Compound 1 in the (R) configuration with respect to the nitrogen, wherein the composition has an X-ray powder diffraction pattern comprising all of the peaks at about 10.58, 11.56, 13.88, 15.42, 20.82, 21.86, 22.74, 23.2, 24.74, and 26.96 degrees 2-theta.
Overall claim coverage centers on defining specific solid-state forms (Form D and Form C) and a mixed Form A/Form C composition by XRPD peak sets, with Form C further tied to an XRPD pattern calculated from single-crystal data at 150±1.0 K. Dependent claim refinements in the provided text further add peak constraints, figure-based similarity references, unit-cell parameter constraints for Form C, and formulation or administration contexts for the mixture composition.
Stated Advantages
Amorphous Form 1 has enhanced water solubility for parenteral delivery.
Documented Applications
Treatment and/or reduction of opioid-induced gastrointestinal dysfunction/constipation and other peripheral effects associated with opioid administration.
Reducing a side effect of opioid therapy by administering a pharmaceutical composition comprising a mixture of Form A and Form C of Compound 1 to a subject receiving opioid treatment.
Reducing the effect of endogenous opioid activity in a subject by administering the pharmaceutical composition comprising a mixture of Form A and Form C of Compound 1.
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