Neflamapimod Co-crystals Enhance Solubility and Stability
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Solution Overview
Problem
Neflamapimod, a p38-specific inhibitor, is poorly water soluble and lacks readily ionizable functional groups, posing challenges for formulations and bioavailability when administered, necessitating the development of potent and effective pharmaceutical compositions.
Innovation Solution
The formation of novel co-crystals comprising neflamapimod with specific coformers such as gentisic acid, glutaric acid, or zinc chloride, which enhance solubility, bioavailability, and stability, and modulate the morphology and hygroscopicity of neflamapimod, thereby improving its pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If neflamapimod is administered in its free form, then the compound maintains its chemical stability, but it exhibits poor water solubility and limited bioavailability
Solution Approach 1:
The patent changes the physical state parameters of neflamapimod by forming co-crystals with specific coformers (e.g., gentisic acid, glutaric acid, zinc chloride). This transforms the free base form into a new crystalline structure with modified solubility characteristics while preserving chemical stability. The co-crystal formation alters the lattice energy and intermolecular interactions, enabling improved water solubility without compromising the compound's chemical integrity.
Solution Approach 2:
The invention creates composite crystalline structures by combining neflamapimod with coformer molecules in defined stoichiometric ratios. These co-crystals represent composite materials where the active pharmaceutical ingredient is integrated with auxiliary molecules that enhance desirable properties. The composite structure allows the system to achieve both chemical stability and improved solubility/bioavailability simultaneously.
2Quantity of substance
If neflamapimod is formulated as a co-crystal, then solubility and bioavailability are improved, but the formulation complexity increases
Solution Approach 1:
The patent systematically varies parameters such as coformer identity, stoichiometric ratio, and crystal structure to optimize solubility and bioavailability. By controlling these parameters, the invention achieves improved pharmacokinetic properties while maintaining manageable formulation complexity through structured approaches to co-crystal design and characterization.
3Stability of the object's composition
If neflamapimod is used in its original form, then the compound maintains its structural integrity, but it exhibits high hygroscopicity and form diversity
Solution Approach 1:
The invention modifies the physical parameters of neflamapimod through co-crystal formation, creating a new crystalline phase with reduced hygroscopicity. The co-crystal structure alters the surface properties and moisture absorption characteristics while preserving the structural integrity and pharmacological activity of the active ingredient.
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 co-crystals exhibit increased solubility, bioavailability, and stability, leading to enhanced therapeutic efficacy and improved dosing response, while reducing hygroscopicity and form diversity, thus addressing the limitations of neflamapimod's poor water solubility and formulation challenges.
Implementation Method 1
The formation of novel co-crystals comprising neflamapimod with specific coformers such as gentisic acid, glutaric acid, or zinc chloride, which enhance solubility, bioavailability, and stability
Implementation Method 2
co-crystals comprising neflamapimod and at least one coformer... exhibit desirable characteristics... the solubility of the co-crystal is increased as compared with a free VX-745
Implementation Method 3
These co-crystals can be used as inhibitors of one or more protein kinases and exhibit desirable characteristics for the same... the morphology of the co-crystal is modulated as compared with a free VX-745
Data Source
AI summary
Provided herein are co-crystal forms comprising 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745):and compositions thereof, useful as inhibitors of one or more protein kinases and which exhibit desirable characteristics for the same.