Meglumine Salt of 6-Fluoro-3-Hydroxy-2-Pyrazine Carboxamide for Injectable Formulation
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Solution Overview
Problem
Current therapeutic agents for influenza, such as Oseltamivir, Zanamivir, Peramivir, Laninamivir, and Amantadine, face challenges like difficulty in administration for certain patients, low solubility of Compound A, and resistance issues, necessitating a more effective and easily administrable antiviral agent.
Innovation Solution
The development of a meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (Compound A) in amorphous, crystalline, or milled crystalline forms, with a lyophilization process that includes controlled temperature steps and additives to enhance solubility and stability, resulting in a superior injectable preparation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If Compound A is prepared as a sodium salt to improve water solubility, then solubility is improved, but the lyophilized preparation forms a poorly soluble mass substance that takes a long time to dissolve
Solution Approach 1:
The patent changes the cation parameter from sodium to meglumine, which fundamentally alters the solubility characteristics. The meglumine salt maintains high water solubility while preventing the formation of poorly soluble mass substances during lyophilization, thereby resolving the contradiction between solubility improvement and dissolution time
Solution Approach 2:
Meglumine acts as an intermediary substance that mediates between the drug compound and water. It forms a salt that maintains solubility benefits while avoiding the aggregation problems that occur with sodium salts during lyophilization, thus serving as a bridging compound that resolves the solubility-dissolution time contradiction
2Ease of operation
If Compound A is administered orally, then it can be given to patients, but it cannot be administered to patients having difficulty in oral administration
Solution Approach 1:
The patent changes the dosage form parameter from oral solid to injectable solution/lyophilized preparation. This fundamental parameter change enables administration to patients who cannot take oral medications, including those with swallowing difficulties, unconscious patients, and children, thereby expanding patient applicability while maintaining ease of administration through simple injection
3Quantity of substance
If an amorphous state is used to improve water solubility, then solubility is improved, but the lyophilized cake changes into a poorly soluble mass substance
Solution Approach 1:
The patent changes the chemical composition parameter by selecting meglumine as the counterion, which alters the molecular interactions in the amorphous state. This prevents the spontaneous crystallization and aggregation that occurs with sodium salts, maintaining both high solubility and solubility stability in the amorphous lyophilized preparation
Solution Approach 2:
The patent employs the amorphous state as a temporary, disposable formulation approach. The amorphous meglumine salt is designed to remain stable during storage but rapidly dissolve upon contact with water for injection, providing a short-lived but highly effective soluble state that eliminates the need for long-term solubility stability during storage
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 meglumine salt of Compound A achieves high solubility and rapid dissolution, making it suitable for injectable use, particularly for patients with difficulty in oral administration, and demonstrates improved stability and appearance compared to previous sodium salt preparations.
Implementation Method 1
the solubility of Salt A in water is high, the dissolution rate of amorphous Salt A in water, the dissolution rate of a crystal of Salt A in water, and the dissolution rate of a milled crystal of Salt A in water are significantly high
Implementation Method 2
a method for preparing a lyophilized preparation
Data Source
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AI summary
A preparation replete with a meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide has superior solubility, and is useful as a preparation for injection.