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Publication Number
US-11807629-B2
Publication Date
2023-11-07
Expiration Date
Abstract
The present invention relates to crystalline forms of the compound represented by Structural Formula I, and compositions comprising crystalline forms of the compound represented by Structural Formula I described herein. The crystalline forms of the compound of Structural Formula I and compositions comprising the crystalline forms of the compound of Structural Formula I provided herein, in particular, single crystalline Form A, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders associated with CRM1 activity, including cancer. Also described herein are methods for preparing the compound of Structural Formula I and its single crystalline forms.
Core Innovation
The invention relates to crystalline forms of a compound represented by Structural Formula I, also identified as KG8, and to polymorph and crystalline forms of selinexor. The crystalline form is characterized by X-ray powder diffraction using at least three X-ray powder diffraction peaks at 2 angles selected from 4.4, 19.9, 21.3 and 22.0.
The disclosure defines crystalline Forms A, B, C, and D using corresponding XRPD peak sets, with Form A described as the thermodynamically most stable crystalline form. Form D is described as an acetonitrile solvate and as an intermediate used in a conversion approach to prepare Form A.
The document also describes solvent system and crystallization concepts for selinexor forms AD, including cooling-based approaches, seeding, anti-solvents, vapor diffusion, solvent exchange to acetonitrile, and Form D-to-Form A conversion concepts. It further includes polymorphism studies identifying stability and solvate behavior using XRPD, DSC, and TGA peak-based identification, together with particle size characterization using d(0.9) particle size distribution measurements.
Claims Coverage
The claim coverage includes one independent claim directed to a crystalline form of a compound represented by Structural Formula I, defined by at least three specified XRPD peaks at selected 2 angles. The dependent claims refine the XRPD peak constraints and add characterization by a DSC endothermic peak and by substantially matching a disclosed XRPD pattern figure.
Crystalline form defined by at least three specified XRPD peaks
A crystalline form of a compound represented by Structural Formula I, characterized by at least three X-ray powder diffraction peaks at 2 angles selected from 4.4, 19.9, 21.3 and 22.0.
Crystalline form with an expanded XRPD peak set at specified 2 angles
A crystalline form characterized by X-ray powder diffraction peaks at 2 angles including 4.4, 20.3, 21.3, 22.0, 23.5 and 25.0.
Crystalline form defined by a DSC endothermic peak at 179C
The crystalline form is characterized by a differential scanning calorimetry thermogram showing an endothermic peak at 179C.
Crystalline form defined by an XRPD pattern substantially matching FIG. 1A
The crystalline form is defined by an X-ray powder diffraction pattern that substantially matches the pattern shown in FIG. 1A.
Crystalline form with an extensive specified XRPD peak set
The crystalline form is characterized by specific X-ray powder diffraction peak positions at 2 angles including 4.4, 12.4, 13.1, 14.5, 14.7, 15.8, 16.9, 17.5, 18.2, 19.9, 20.3, 21.3, 22.0, 23.1, 23.5, 23.7, 23.9, 25.0, 25.3, 25.6, 27.0, 27.3, 28.3, 28.5, 31.4, 34.8, 37.2, and corresponding additional specified peaks as part of the crystalline-form signature.
Across the independent claim and dependent refinements, the inventive coverage is directed to crystalline forms of a compound represented by Structural Formula I that are defined primarily by XRPD peak positions at specified 2 angles, with additional refinements including an expanded exact peak list, a DSC thermogram endothermic peak at 179C, and substantially matching an XRPD pattern in FIG. 1A.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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