Crystalline forms and methods of producing crystalline forms of a compound
Inventors
Lian, Brian • Masamune, Hiroko • Barker, Geoffrey
Assignees
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Publication Number
US-12227533-B2
Publication Date
2025-02-18
Expiration Date
Abstract
Disclosed herein are methods of crystallizing the compound of Formula I, as well as crystalline forms thereof. Crystalline forms of Formula I disclosed include the TBME solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, THF solvate crystalline form, EtOAc solvate crystalline form, acetone solvate crystalline form and crystalline Form C.
Core Innovation
The invention relates to crystalline forms of a compound of Formula I, including solvates, and an unsolvated crystalline Form C. Crystals are obtained by dissolving an amorphous form of a compound of Formula I in a first solvent to create a first solution, adding a second solvent to create a second mixture, and isolating a crystalline form from the second mixture.
The invention further provides crystallization by seeding, in which a compound of Formula I is dissolved in a first solvent to create a first solution, a seeding crystalline form of the compound of Formula I or a solvate thereof is added to create a seeded mixture, and a produced crystalline form is isolated from the seeded mixture. The seeding crystalline form includes particular solvate crystalline forms and crystalline Form C, to yield targeted crystalline outcomes including Form C.
The described crystalline form Form C is characterized by XRPD-defined characteristic 2θ peaks and a DSC melting point of about 122°C. Form C is reported to exhibit very low residual solvent, non-hygroscopic behavior with water uptake <0.2% by DVS, no hydrate formation, and stability over humidity and temperature without polymorphic transition.
The document links these crystalline forms and compositions to therapeutic use, including adrenoleukodystrophy and lipid disorders such as hypercholesterolemia, NAFLD/NASH, and GSD. It also states that pharmaceutical compositions containing the crystalline forms are suitable for oral and intravenous administration.
Claims Coverage
The partial document identifies two independent claims: a crystallization process using an amorphous form with a first and second solvent, and a seeding-based crystallization process using a specified seeding crystalline form. Across the claim sets, the main inventive features include controlled formation of crystalline forms, including solvates, and producing a crystalline form defined by XRPD characteristic peaks and a melting point.
Two-solvent crystallization from amorphous form
Dissolving an amorphous form of a compound of Formula I in a first solvent to create a first solution; adding a second solvent to the first solution to create a second mixture; and isolating a crystalline form of a compound of Formula I from the second mixture.
First and second solvent selection for crystalline formation
The process includes selecting the first solvent and selecting the second solvent from specified lists of solvents or solvent mixtures that include TBME, toluene, ethanol, THF, EtOAc, acetone, heptane, and other named solvents, optionally as mixtures.
Seeded crystallization using a seeding crystalline form
Dissolving a compound of Formula I in a first solvent to create a first solution; adding a seeding crystalline form of the compound of Formula I, or a solvate thereof, to the first solution to create a seeded mixture; and isolating a produced crystalline form of the compound of Formula I, or a solvate thereof, from the seeded mixture.
Seeding with specified solvate crystalline forms or crystalline Form C
The seeding crystalline form is chosen from specified solvate crystalline forms or crystalline Form C, including mixtures thereof.
XRPD-defined crystalline identity with characteristic 2θ peaks
The produced crystalline form has an X-ray powder diffraction pattern containing at least one characteristic peak at specified 2θ values within ±0.5° and, in related refinements, at least three characteristic peaks selected from listed 2θ angles.
Target melting point for produced crystalline form
The produced crystalline form has a melting point of about 122°C.
Isolation by filtration of the mixture
Isolating the produced crystalline form is performed by filtering the second mixture or the seeded mixture.
Overall, the claim coverage centers on producing crystalline forms of a Formula I compound either by two-solvent crystallization from an amorphous form or by seeding with specified solvate crystalline forms and crystalline Form C. The resulting crystalline solids are characterized by XRPD characteristic 2θ peaks and by a melting point of about 122°C, with isolation specified as filtration.
Stated Advantages
Very low residual solvent for Form C.
Non-hygroscopic behavior, with water uptake <0.2% by DVS.
No hydrate formation.
Stability over humidity and temperature without polymorphic transition.
Documented Applications
Therapeutic use for adrenoleukodystrophy.
Therapeutic use for lipid disorders including hypercholesterolemia, NAFLD/NASH, and GSD.
Pharmaceutical compositions suitable for oral administration.
Pharmaceutical compositions suitable for intravenous administration.
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