Polymorphic Bis-Mesylate Salt Forms for Syk Inhibitor Stability
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Solution Overview
Problem
Variations in crystal structure of pharmaceutical drugs, such as the mono-mesylate salt of the compound of Formula I, affect bioavailability, manufacturability, and stability in solid oral dosage forms, leading to inconsistent pharmacodynamic responses and challenges in handling and shelf life.
Innovation Solution
Development of additional polymorphic forms of the bis-mesylate salt of the compound of Formula I, including Forms I, II, VI, XIII, XIV, XV, XVI, XVIII, and XIX, which offer improved dissolution, thermal stability, and processability, characterized by specific X-ray diffraction patterns and methods for their preparation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If additional polymorphic forms are developed to improve dissolution and stability, then bioavailability and shelf life are enhanced, but the complexity of the pharmaceutical formulation increases
Solution Approach 1:
The patent applies parameter changes by developing multiple polymorphic forms (Forms I, II, VI, XIII, XIV, XV, XVI, XVIII, and XIX) with different crystal structures, each having distinct dissolution rates, thermal stability, and bioavailability characteristics. This allows selection of optimal polymorphic forms for specific formulation requirements, resolving the contradiction between stability and formulation complexity.
2Manufacturing precision
If polymorphic forms with improved dissolution are selected, then bioavailability is enhanced, but manufacturing precision requirements increase
Solution Approach 1:
The patent applies local quality by characterizing each polymorphic form with specific X-ray diffraction patterns and assigning them to different formulation applications based on their unique properties. For example, certain forms are selected for applications requiring rapid dissolution while others are chosen for thermal stability, allowing optimized manufacturing for each specific product indication.
3Duration of action of stationary object
If the crystal structure is modified to improve thermal stability, then shelf life is extended, but the pharmacodynamic response may vary
Solution Approach 1:
The patent applies dynamics by establishing a systematic framework for selecting and characterizing polymorphic forms based on their specific properties. The methodology allows dynamic selection of the most appropriate polymorphic form for each formulation purpose, balancing thermal stability requirements with pharmacodynamic consistency through rigorous characterization and controlled conversion processes.
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 polymorphic forms provide consistent bioavailability, enhanced stability, and improved manufacturability, addressing the variations in pharmacodynamic responses and stability issues associated with the mono-mesylate salt, thereby optimizing the pharmaceutical composition for treating conditions like cancer and autoimmune diseases.
Implementation Method 1
characterized by specific X-ray diffraction patterns
Data Source
AI summary
Polymorphs of a bis-mesylate salt of a compound of Formula IA:are provided. Also provided are process for making the polymorphs and methods of use thereof.