Crystalline forms of ozanimod and ozanimod hydrochloride, and processes for preparation thereof
Inventors
Chen, Minhua • Zhang, Yanfeng • ZHAI, Xiaoting • YAN, Kaiqiang • YANG, Chaohui • Zhang, Xiaoyu
Assignees
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Publication Number
US-11111223-B2
Publication Date
2021-09-07
Expiration Date
Abstract
The present disclosure is directed to novel crystalline forms of ozanimod and ozanimod hydrochloride, as well as preparation method thereof. Said crystalline forms of ozanimod and ozanimod hydrochloride can be used for treating autoimmune diseases, particularly used for preparing drugs for treating multiple sclerosis and ulcerative colitis. The crystalline forms of the present disclosure have one or more advantages in solubility, melting point, stability, dissolution, bioavailability and processability and provide new and better choices for the preparation of ozanimod drug product, and are very valuable for drug development.
Core Innovation
The invention relates to crystalline Form CS1, CS2, CS3, CS5, and CS6 of ozanimod, and to ozanimod hydrochloride, defined by characteristic X-ray powder diffraction patterns. Each crystalline form is characterized by XRPD characteristic peaks at specified 2theta values using CuKα radiation, and the document provides additional XRPD constraints that allow identification based on specified numbers of characteristic peaks in alternative peak sets.
The document describes preparation routes for the crystalline forms, including conversion from ozanimod hydrochloride to crystalline Form CS1 using sodium hydroxide solution-mediated conversion, thermal transformation between forms, and solvent-based suspension or other solvent-based routes to obtain crystalline forms such as CS3, CS5, CS6, and a crystalline hydrochloride form CS1. Solvent systems and named solvents are used in the preparation routes, and the obtained solids are isolated and dried to yield the targeted crystalline form.
The crystalline forms are characterized using DSC and TGA and are further evaluated with studies including Dynamic Vapor Sorption to assess hygroscopicity, humidity and temperature stability studies with XRPD and HPLC purity retention, particle size distribution and PLM morphology observations for process-related characteristics, and solubility assessments in simulated GI fluids including SGF and FeSSIF. The document connects these properties to performance outcomes described as improved solubility, melting behavior, solid-state stability, dissolution/bioavailability, and manufacturability in autoimmune disease treatments, including multiple sclerosis and ulcerative colitis.
Claims Coverage
The partial claims include five independent claims corresponding to crystalline forms CS1, CS2, CS3, CS5, and CS6 of ozanimod. Across these independent claims, the core inventive feature is an XRPD-defined crystalline form identified by characteristic peaks at specified 2theta values using CuKα radiation, with dependent claims refining the XRPD peak sets and extending coverage into pharmaceutical compositions, treatment methods for ulcerative colitis and multiple sclerosis, and preparation processes for certain forms.
X-ray powder diffraction-defined crystalline Form CS1
A crystalline Form CS1 of ozanimod, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 12.1°±0.2°, 10.4°±0.2° and 4.2°±0.2° using CuKα radiation.
X-ray powder diffraction-defined crystalline Form CS2
A crystalline Form CS2 of ozanimod, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 23.2°±0.2°, 18.5°±0.2° and 13.3°±0.2° using CuKα radiation.
X-ray powder diffraction-defined crystalline Form CS3
A crystalline Form CS3 of ozanimod, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 4.4°±0.2°, 13.0°±0.2°, 26.0°±0.2° and 11.0°±0.2° using CuKα radiation.
X-ray powder diffraction-defined crystalline Form CS5
A crystalline Form CS5 of ozanimod, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 4.3°±0.2°, 6.8°±0.2° and 16.4°±0.2° using CuKα radiation.
X-ray powder diffraction-defined crystalline Form CS6
A crystalline Form CS6 of ozanimod, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 4.4°±0.2°, 24.5°±0.2°, 26.5°±0.2° and 13.8°±0.2° using CuKα radiation.
Claim coverage centers on crystalline forms of ozanimod defined by XRPD characteristic peaks at specified 2theta positions using CuKα radiation. Dependent claims further refine the XRPD identification conditions and expand into pharmaceutical compositions and treatment methods, including ulcerative colitis and multiple sclerosis, and also include preparation processes for at least some forms.
Stated Advantages
Lower hygroscopicity as supported by Dynamic Vapor Sorption weight gain at 80% RH.
Solid-state stability under humidity/temperature conditions with XRPD and HPLC purity retention.
Improved solubility in simulated GI fluids including SGF and FeSSIF.
Improved melting behavior as characterized by DSC/TGA.
Better dissolution/bioavailability performance described for autoimmune disease treatments.
Improved manufacturability supported by particle size distribution and PLM morphology/processability observations.
Mechanical stability under grinding supporting solid handling robustness.
Documented Applications
Treatment of ulcerative colitis by administering a therapeutically effective amount of crystalline Form CS1, CS2, CS3, CS5, or CS6 of ozanimod.
Treatment of multiple sclerosis by administering a therapeutically effective amount of crystalline Form CS5 or CS6 of ozanimod.
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