Crystalline Forms of PI3K Inhibitor for Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The pharmaceutical field lacks stable and reproducible crystalline forms of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile, which are essential for effective inhibition of PI3K activity in treating autoimmune diseases and cancer, due to unpredictability in polymorphism and properties of solid forms.
Innovation Solution
Development of specific crystalline forms, such as Form I, Form IV, Form V, and solvates like monoacetone solvate and water and i-propanol solvate, which exhibit good crystallinity, stability, and non-hygroscopicity, along with methods for their reproducible preparation and use in pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If polymorphism of the compound is considered, then multiple crystalline forms can be obtained, but the stability and reproducibility of the solid forms become unpredictable
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent types (acetone, ethanol, water, i-propanol), temperatures (room temperature to reflux), and pH levels to obtain different stable crystalline forms (Forms I, IV, V, VI, VIII) with defined properties
Solution Approach 2:
The patent uses solvates as intermediary structures where solvent molecules are incorporated into the crystal lattice, creating stable intermediate forms that bridge different polymorphic states. Examples include monoacetone solvate (Form VI) and water and i-propanol solvate (Form VIII)
2Adaptability or versatility
If different solid forms of the compound are developed, then biopharmaceutical properties such as solubility and bioavailability can be optimized, but the complexity of characterization and differentiation increases
Solution Approach 1:
The patent employs X-ray powder diffraction (XRPD) patterns as a fingerprinting system for each crystalline form, where specific diffraction peaks at defined 2θ angles serve as unique identifiers for differentiation and quality control
Solution Approach 2:
The patent replaces complex structural characterization with simplified analytical methods including DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), and XRPD to efficiently distinguish between different solid forms based on their physical properties
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 crystalline forms and solvates provide effective PI3K inhibition, ensuring stability and bioavailability, making them suitable for treating autoimmune diseases and cancer, particularly hematological malignancies, with improved pharmaceutical properties.
Implementation Method 1
the solvates of compound of Formula A and the crystalline forms thereof, which are acetone solvate, and water and i-propanol solvate of compound of Formula A
Implementation Method 2
The phenomenon that a compound could exist in two or more crystal structures is known as polymorphism. Many compounds may exist as various polymorph crystals
Data Source
AI summary
The present invention belongs to the pharmaceutical field, and provides crystalline forms, solvates and the crystalline forms thereof of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile of the formula shown below, and the pharmaceutical compositions comprising the same as well as the methods of preparing the same and the use thereof.