Crystalline form of ozanimod hydrochloride, and processes for preparation thereof
Inventors
Chen, Minhua • Zhang, Yanfeng • ZHAI, Xiaoting • YAN, Kaiqiang • YANG, Chaohui
Assignees
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Publication Number
US-11117876-B2
Publication Date
2021-09-14
Expiration Date
Abstract
The present disclosure is related to crystalline forms of ozanimod hydrochloride, as well as preparation method thereof. The crystalline form of ozanimod hydrochloride provided by the present disclosure can be used for treating autoimmune diseases, particularly multiple sclerosis and ulcerative colitis. The crystalline form of the present disclosure has advantages in at least one aspect of solubility, melting point, stability, dissolution, bioavailability and processability and provides a new and better choice for the preparation of drug product containing ozanimod, and has significant value for drug development.
Core Innovation
The invention relates to a crystalline form CS2 of ozanimod hydrochloride. The crystalline form is defined by an X-ray powder diffraction pattern measured using Cu-Kα radiation, showing characteristic peaks at specified 2theta values. The crystalline form CS2 is described as a distinct solid form of ozanimod hydrochloride.
The problem addressed is that prior art does not provide solid-form and crystallinity details for ozanimod hydrochloride. As a result, crystalline form CS2 is presented as needed to provide defined crystallinity information characterized by an XRPD peak profile. The disclosure ties the CS2 diffraction signature to preservation of crystallinity and purity under storage and processing-related conditions.
Crystalline form CS2 is further associated with improved physicochemical properties, including reported higher solubility, lower hygroscopicity, and good stability. The disclosed characterization includes that no XRPD/form change occurs after storage, purity is retained at greater than 99%, and crystallinity is maintained after grinding. Improved dissolution behavior is reported, including release from a capsule in pH 6.8 phosphate buffer at a specified time point.
The document also describes a process concept connected with CS2, including dissolution in a THF/water mixture followed by slow evaporation. Pharmaceutical compositions and therapeutic methods are described using the crystalline form CS2 of ozanimod hydrochloride, including use in autoimmune diseases with specific indications. Example characterization results are provided using analytical techniques including DSC, TGA, DVS, and particle size distribution.
Claims Coverage
The independent claim defines crystalline form CS2 of ozanimod hydrochloride by a specific XRPD signature with four characteristic peaks measured using Cu-Kα radiation. Dependent claims narrow or refine the diffraction characterization by using alternative peak sets, and other dependent claims move from characterization to preparation, pharmaceutical composition, and therapeutic use. Overall, at least five inventive features are covered.
XRPD-defined crystalline form CS2 identity
A crystalline form CS2 of ozanimod hydrochloride wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 19.7°±0.2°, 7.8°±0.2°, 14.4°±0.2° and 18.8°±0.2° using Cu-Kα radiation.
Alternative limited XRPD peak set for CS2
The crystalline form CS2 of ozanimod hydrochloride wherein the X-ray powder diffraction pattern has one or two characteristic peaks at 2theta values of 13.9°±0.2° and 12.7°±0.2° using Cu-Kα radiation.
THF-to-water controlled preparation concept
The process wherein the ether is tetrahydrofuran and the tetrahydrofuran-to-water volume ratio is 19:1.
Pharmaceutical composition with CS2 and acceptable carrier
A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS2 of ozanimod hydrochloride together with a pharmaceutically acceptable carrier, diluent, or excipient.
Treatment of ulcerative colitis with CS2
A method of treating ulcerative colitis by administering a therapeutically effective amount of the crystalline form CS2 of ozanimod hydrochloride to a subject in need.
The claim coverage anchors CS2 as an XRPD-defined crystalline form through a characteristic Cu-Kα diffraction profile, allows narrowing via alternative limited peak sets, and extends CS2 into a preparation concept, pharmaceutical compositions with acceptable carriers, and a therapeutic method for ulcerative colitis.
Stated Advantages
Improved physicochemical properties are reported, including higher solubility.
Lower hygroscopicity is reported.
Good stability is reported, including no XRPD/form change after storage.
Chemical purity retention greater than 99% is reported.
Crystallinity is reported to be maintained after grinding.
Improved dissolution is reported, including capsule dissolution with reported release at a specified time point.
Documented Applications
Ulcerative colitis treatment by administering a therapeutically effective amount of the crystalline form CS2 of ozanimod hydrochloride to a subject in need.
Multiple sclerosis use is described in the provided content as part of the pharmaceutical/formulation application context.
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