Crystalline forms of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
Inventors
Liu, Fei • Zhang, Cuixia • Jiang, Weiming • LAI, Chin-yu • Nguyen, Tan • Zhang, Haolong
Assignees
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Publication Number
US-10961203-B2
Publication Date
2021-03-30
Expiration Date
Abstract
Crystalline forms of free base 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and preparation methods thereof are provided; the pharmaceutical formulations containing the crystalline forms and their use in the treatment of diseases, particularly angiogenic eye diseases are also provided.
Core Innovation
The invention relates to crystalline forms of free base 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, including crystalline forms B–F. Each crystalline form is defined by an X-ray powder diffraction (XRPD) pattern with specific 2θ peak values and tolerances, and Form E and Form F are further characterized by melting temperature and DSC profiles.
The disclosed crystalline forms are characterized using XRPD together with thermal characterization and figure-referenced spectra/profiles. The document also reports preparation approaches based on solvent systems and crystallization/seeding, and identifies formulations associated with the crystalline forms.
An ophthalmic formulation is documented for treating or preventing eye diseases, particularly angiogenic eye diseases. The crystalline free base forms are presented in the context of pharmaceutical compositions with pharmaceutically acceptable carrier, and the document reports enhanced thermodynamic stability, including XRPD retention of the designated crystalline forms after storage/incubation and specific storage stability reporting for Form F.
Claims Coverage
The document contains two independent claims directed to crystalline free-base forms of the specified 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone. The inventive features across these claims are centered on XRPD-defined crystalline forms with explicit 2θ peak criteria; additional dependents further add thermal characterization and ophthalmic use through formulations.
Xrpd-defined crystalline free base with 2θ 6.4±0.2 and selected additional peaks
A crystalline form of free base 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone characterized by an XRPD pattern with a peak at 2θ value of 6.4±0.2, and at least one peak at 2θ value selected from 16.6±0.2, 17.4±0.2, 17.8±0.2, and 19.9±0.2.
Xrpd-defined crystalline free base with 2θ peaks at 11.2±0.2, 14.8±0.2, 16.4±0.2, 17.0±0.2, and 21.0±0.2
A crystalline form of free base 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone characterized by an XRPD pattern with peaks at 2θ values of 11.2±0.2, 14.8±0.2, 16.4±0.2, 17.0±0.2, and 21.0±0.2.
Overall, claim coverage is grounded in crystalline identity defined by XRPD peak sets with explicit 2θ values and tolerances for the specified free base. The dependent claims described in the provided material expand coverage by adding figure-referenced characterization, quantitative thermal properties, and ophthalmic formulation and administration for treating an eye disease in an individual using the ophthalmic formulation.
Stated Advantages
Enhanced thermodynamic stability.
Documented Applications
Ophthalmic use for treating or preventing eye diseases, particularly angiogenic eye diseases.
Treatment of an eye disease in an individual by administering an ophthalmic formulation, where the eye disease is selected from angiogenic eye diseases and other listed ocular conditions.
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