Crystals
Inventors
Mcguirk, Paul Robert • Zamboni, Robert • BEVILL, Melanie • Parent, Stephan
Assignees
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Publication Number
US-11725018-B2
Publication Date
2023-08-15
Expiration Date
Abstract
Provided are crystals of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, compositions comprising the same, and methods of making and using such crystals.
Core Innovation
The subject matter relates to crystalline solids of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, including hydrate and non-solvate, non-hydrate solid forms, as well as crystalline Form 5 (Form N) and Form 6 (Form B). The document characterizes these solid forms by X-ray powder diffraction (XRPD) fingerprints using Cu Kα radiation, with selected 2-theta (°) values or d-spacing (Å) values, and includes optional XRPD deviation tolerance of ±0.2°.
The disclosure describes ethyl acetate solvate Form A and reports single-crystal X-ray diffraction structures for solvated forms, including hemi-ethyl acetate solvate and hemi-sodium hemi-acetonitrile solvate. It also evaluates hygroscopicity, conversion under RH stressing and slurrying, water content behavior from DVS isotherms and Karl Fischer analysis, and thermal behavior by TGA and DSC.
The document further extends to preparation-related conditions involving mixing the compound with water or an organic solvent, with solvent/water activity considered in relation to the hydrate and crystalline forms. Broader context is provided for pharmaceutical compositions, kits, treatment methods, and an aquaporin inhibitor candidate for acute IV use.
Claims Coverage
Three inventive features are represented across the input items: a hydrate defined by XRPD fingerprint criteria, a process for making a hydrate by mixing with water, and a process for making a non-solvate non-hydrate crystalline form by mixing with an organic solvent. The central inventive feature is XRPD identification using at least five selected 2-theta (°) values or at least five selected d-spacing (Å) values measured using Cu Kα radiation.
Hydrate exhibiting specified XRPD pattern
A hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate wherein the hydrate exhibits at least one of an XRPD pattern comprising at least five specified 2-theta (°) values measured using an incident beam of Cu Kα radiation, or an XRPD pattern comprising at least five specified d-spacing (Å) values.
Process of making a hydrate by mixing with water
A process for making a hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate wherein the process comprises mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and water.
Non-solvate non-hydrate crystalline form by mixing with an organic solvent
A process for making a non-solvate non-hydrate crystalline form of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate wherein the non-solvate non-hydrate crystalline form exhibits at least one of an XRPD pattern comprising at least five specified 2-theta (°) values measured using an incident beam of Cu Kα radiation, or an XRPD pattern comprising at least five specified d-spacing (Å) values, and wherein the process comprises mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and an organic solvent.
The claim scope is directed to XRPD-defined solid forms of the specified compound and to processes for producing them by mixing with water or with an organic solvent.
Stated Advantages
Addresses limitations of existing solid forms or salts for enabling appropriate solid-form selection, including issues related to solubility and stability.
Provides solid forms suitable for use considerations associated with acute IV administration.
The forms show differing hygroscopicity and stability behavior.
Documented Applications
Aquaporin inhibitor candidate for acute IV use.
Pharmaceutical compositions, kits, and treatment methods in relation to the crystalline forms and their characterization.
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