Stable Crystal Forms of Akt Inhibitor Compound I
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Solution Overview
Problem
There is a lack of stable crystal forms of Compound (I), which is essential for its use as a pharmaceutical product due to its inhibitory activity against Akt, Rsk, and S6K, and its potential in treating cancer.
Innovation Solution
The development of three crystal forms (type I, type II, and type III) of the free base of Compound (I), as well as crystals of its hydrochloride and maleate salts, which exhibit excellent solid-state stability and low hygroscopicity, making them suitable for pharmaceutical applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound (I) is used as a pharmaceutical active ingredient, then it provides excellent inhibitory activity against Akt, Rsk, and S6K, but it lacks stable crystal forms which compromises preservation stability and storage management
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing three distinct crystal forms (Type I, Type II, and Type III) of Compound (I), each with unique X-ray diffraction patterns and stability characteristics. This allows selection of the most stable crystal form for pharmaceutical applications, resolving the contradiction between maintaining pharmaceutical effectiveness and achieving stable composition.
Solution Approach 2:
The patent utilizes phase transitions by establishing specific crystallization conditions (solvent systems, temperatures, pH values) that enable controlled formation of stable crystal forms from the compound. This transforms the unstable amorphous compound into stable crystalline pharmaceutical products with predictable storage characteristics.
2Stability of the object's composition
If no stable crystal form is established, then the compound maintains its chemical structure, but it exhibits poor preservation stability and high hygroscopicity
Solution Approach 1:
The patent changes physical parameters by establishing specific crystal lattice structures through controlled crystallization. The three identified crystal forms exhibit different hygroscopicity and stability profiles, allowing selection of forms that maintain chemical stability while achieving reliable preservation during storage.
Solution Approach 2:
The patent uses solvent molecules as intermediaries during crystallization to mediate the formation of stable crystal lattices. Specific solvent systems (aqueous, organic, or mixed solvents at controlled pH and temperature) facilitate the transition from unstable monomeric compound to stable crystalline pharmaceutical form.
3Loss of substance
If the compound is stored without stable crystal forms, then it remains chemically intact, but it absorbs moisture readily which compromises quality and storage management
Solution Approach 1:
The patent changes the physical state parameters by establishing stable crystal forms with defined lattice structures. These crystalline forms exhibit reduced hygroscopicity compared to amorphous forms, thereby maintaining chemical integrity while resisting moisture absorption during storage.
Solution Approach 2:
The patent applies local quality by creating specific crystal packing arrangements where molecules are positioned in stable lattice configurations. This local structural organization reduces the surface area and energy sites available for moisture interaction, thereby reducing hygroscopicity while preserving chemical integrity.
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
These crystal forms provide enhanced stability and reduced moisture absorption, ensuring the compound's effectiveness and longevity as a pharmaceutical substance, particularly in treating tumors.
Implementation Method 1
which has peaks at, at least, 2 diffraction angles (2θ±0.2°) selected from the following (a), and at, at least, 2 diffraction angles (2θ±0.2°) selected from the following (b), in a powder X-ray diffraction spectrum (CuKα)
Implementation Method 2
wherein the peak temperature in thermogravimetry-differential thermal analysis (TG-DTA) has an endothermic peak of around 235°C
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
Provided is a type I crystal of a free base of 4-(4-(3-((2-(tert-butylamino)ethyl)amino)-6-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-1-yl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one, which has peaks at, at least, 2 diffraction angles (2θ±0.2°) selected from the following (a), and at, at least, 2 diffraction angles (2θ±0.2°) selected from the following (b), in a powder X-ray diffraction spectrum (CuKα): (a) 6.2°, 9.3°, 9.7°, 11.1°, 15.4° and 25.1°; and (b) 6.7°, 8.3°, 8.7°, 13.0°, 13.7°, 16.3°, 16.9°, 17.7°, 18.7°, 19.4°, 20.3°, 25.9° and 26.5°.