Abemaciclib Crystalline Forms for Thermal Stability
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Solution Overview
Problem
Current formulations of Abemaciclib (ABC) do not include solid-state methanol solvate, hydrate, or anhydrous forms, particularly a reversible water-solvated form, which are essential for stable pharmaceutical compositions.
Innovation Solution
Development of crystalline methanol solvate, hydrate, and anhydrous forms of Abemaciclib, including a process to prepare these forms, such as dissolving ABC in warm methanol, cooling to precipitate a methanol solvate, drying to obtain an anhydrous form, and exposing it to humidity to achieve a hydrate, enabling pharmaceutical compositions for treating breast cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional solid-state forms of ABC are used, then the basic pharmaceutical composition is available, but the thermal stability and water sorption properties are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the solid-state form of ABC through controlled solvation with methanol and water, creating distinct crystalline forms with different thermal and hygroscopic properties. The methanol solvate form exhibits improved thermal stability while the hydrate form demonstrates controlled water sorption characteristics, resolving the contradiction between thermal stability and water sorption properties.
Solution Approach 2:
The patent creates composite solid-state forms by incorporating solvent molecules (methanol or water) into the crystal lattice of ABC, forming solvates and hydrates. These composite structures combine the pharmacological activity of ABC with the stabilizing effects of the solvent molecules, improving overall pharmaceutical stability while maintaining therapeutic efficacy.
2Reliability
If new solid-state forms (methyl solvate, hydrate, anhydrous) are developed, then thermal stability and water sorption properties are improved, but the formulation complexity increases
Solution Approach 1:
The patent utilizes phase transitions during the formation of different solid-state forms. By controlling crystallization conditions (solvent selection, temperature, humidity), the patent directs the formation of specific phases (methanol solvate, hydrate, or anhydrous forms) with desired properties. This approach manages formulation complexity by providing clear protocols for obtaining each form rather than dealing with random polymorphic mixtures.
3Loss of substance
If anhydrous form is prepared by drying, then water content is reduced, but the reversible hydrate formation capability is lost
Solution Approach 1:
The patent applies dynamics by creating an anhydrous form that maintains the dynamic capability of reversible hydrate formation upon exposure to humidity. The anhydrous form is not a static, permanent state but a reversible intermediate that can transition to the hydrate form when environmental conditions change. This dynamic property allows the material to adapt to different storage and formulation conditions while maintaining controlled water content.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new forms provide stable and effective pharmaceutical compositions for treating breast cancer, with improved thermal stability and water sorption properties, enhancing the therapeutic efficacy of Abemaciclib.
Implementation Method 1
dissolving ABC in warm methanol, cooling to precipitate a methanol solvate
Implementation Method 2
drying to obtain an anhydrous form
Implementation Method 3
exposing it to humidity to achieve a hydrate
Data Source
AI summary
The invention relates to a crystalline methanol solvate or hydrate form of ABC, and an anhydrous form of ABC, that reversibly forms a hydrate of ABC. The invention is also directed to the preparation of the aforesaid solvate, hydrate, and anhydrous solid-state forms of ABC. Furthermore, the invention relates to pharmaceutical compositions comprising at least one of the aforesaid crystalline forms of ABC according to the invention, and the pharmaceutical use of at least one of the aforesaid crystalline forms of ABC according to the invention for treatment of a patient in need thereof.