Compound I Crystalline Forms for SYK Inhibitor Bioavailability
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Solution Overview
Problem
There is a need for polymorph forms of compounds that inhibit Spleen Tyrosine Kinase (Syk) activity with improved bioavailability and physical properties for treating diseases such as cancer and autoimmune diseases.
Innovation Solution
Development of crystalline forms of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine (Compound I) and its salts or co-crystals, characterized by specific X-ray powder diffractograms, to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional crystalline forms of Compound I are used, then Syk inhibition activity is achieved, but bioavailability and physical properties are insufficient
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple crystalline forms (Forms I-XIV) of Compound I, each with distinct physical properties such as melting point, density, and solubility. By changing the crystalline structure parameters, the patent achieves improved bioavailability while maintaining Syk inhibition activity, directly resolving the contradiction between reliability of inhibition and productivity of bioavailability.
2Reliability
If conventional crystalline forms of Compound I are used, then Syk inhibition activity is achieved, but physical properties such as solubility and stability are insufficient
Solution Approach 1:
The patent systematically varies crystalline structure parameters to generate multiple polymorphic forms with different physical properties. Each form (I-XIV) exhibits distinct melting points, solubility characteristics, and stability profiles, allowing optimization of physical properties while preserving the essential Syk inhibition function.
Solution Approach 2:
The patent creates composite crystalline structures through salt formation and co-crystallization, combining Compound I with various counterions and co-crystal partners. These composite crystalline forms exhibit enhanced physical properties including improved solubility, stability, and bioavailability while maintaining the core Syk inhibition activity of Compound I.
3Productivity
If multiple crystalline forms are developed, then bioavailability and physical properties are improved, but manufacturing complexity increases
Solution Approach 1:
The patent segments the crystalline forms into distinct categories (Forms I-XIV) with characteristic X-ray powder diffractogram patterns, allowing systematic identification and selection. This segmentation enables manufacturers to choose specific forms based on desired properties without needing to characterize all possible polymorphs, thereby managing manufacturing complexity while optimizing bioavailability.
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 crystalline forms and salts/co-crystals of Compound I demonstrate improved bioavailability and physical properties, effectively treating inflammatory disorders, autoimmune diseases, and cancers like lymphoma, multiple myeloma, and leukemia.
Implementation Method 1
Compound I Form I can be characterized by an X-ray powder diffractogram comprising the following peaks (±0.2°2θ) at 15.2, 18.0 and 20.0 °2θ, as determined on a diffractometer using Cu-Kα radiation.
Data Source
AI summary
Solid forms of the compound, 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine, and solid forms of salts or co-crystals of Compound I, were prepared and characterized:Also provided are processes of making the solid forms and methods of use thereof.