Lyophilized Copanlisib Formulation pH Stability
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Solution Overview
Problem
Copanlisib exhibits pH-dependent solubility and stability issues, making it challenging to formulate a stable, lyophilized form suitable for parenteral administration, particularly due to low solubility at physiological pH and increased instability at acidic or alkaline conditions, which complicates the development of a formulation that maintains chemical and physical integrity during storage and reconstitution.
Innovation Solution
A manufacturing process involving a copanlisib-containing aqueous bulk solution with a pH-adjusting agent, such as citric acid, and a bulking agent like mannitol, adjusted to a pH of 4-5, which enhances solubility and stability, allowing for lyophilization in one or two containers and maintaining the amorphous state during long-term storage and reconstitution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If copanlisib is formulated at low pH to increase solubility, then solubility is improved, but chemical stability deteriorates
Solution Approach 1:
The patent applies pH-adjusting agents to modify the pH of the bulk solution to a specific range (pH 4-5) where copanlisib exhibits optimal balance between solubility and stability. This parameter change enables the formulation to maintain both adequate solubility for therapeutic dose and chemical stability during storage and reconstitution.
Solution Approach 2:
The patent introduces pH-adjusting agents as intermediary substances that mediate between the conflicting requirements of solubility and stability. These agents modify the chemical environment to allow copanlisib to maintain both properties simultaneously, preventing degradation while ensuring adequate dissolution.
2Stability of the object's composition
If copanlisib is formulated at high pH to improve stability, then chemical stability is improved, but solubility deteriorates
Solution Approach 1:
The patent identifies and utilizes the optimal pH range (pH 4-5) where copanlisib exhibits maximum stability while maintaining acceptable solubility. This parameter optimization resolves the contradiction by finding the sweet spot where both properties are satisfied simultaneously.
3Stability of the object's composition
If copanlisib is formulated as crystalline form, then manufacturing stability is improved, but reconstitution solubility deteriorates
Solution Approach 1:
The patent utilizes the amorphous phase of copanlisib in the lyophilized formulation, which provides rapid dissolution upon reconstitution. The amorphous state acts as a metastable phase that transitions quickly to dissolved state in aqueous solution, ensuring fast and complete reconstitution without requiring crystalline structure.
4Quantity of substance
If copanlisib is formulated in amorphous form, then reconstitution solubility is improved, but storage stability deteriorates
Solution Approach 1:
The patent accepts the metastable amorphous form as a temporary state during storage, utilizing its rapid dissolution property for reconstitution. The amorphous form is maintained through controlled storage conditions and lyophilization, serving its purpose during the therapeutic window even though it is thermodynamically unstable.
Solution Approach 2:
The patent employs lyophilization technology as a protective measure that preserves the amorphous form during storage. The lyophilized state acts as a cushioning mechanism that prevents premature crystallization or degradation, maintaining the formulation in a stable physical state until reconstitution is required.
5Stability of the object's composition
If copanlisib is formulated in crystalline form, then storage stability is improved, but reconstitution speed deteriorates
Solution Approach 1:
The patent leverages the phase transition characteristics of copanlisib, utilizing the amorphous phase for rapid dissolution during reconstitution. The amorphous state provides a metastable form that quickly transitions to dissolved state in aqueous solution, achieving fast reconstitution speed while maintaining storage stability through lyophilization.
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 process results in a stable, lyophilized copanlisib formulation with increased solubility upon reconstitution, preventing physical and chemical instability, and allowing for a therapeutic dose in a single container, ensuring effective and safe parenteral administration.
Implementation Method 1
a copanlisib-containing aqueous bulk solution with a pH-adjusting agent, such as citric acid, and a bulking agent like mannitol, adjusted to a pH of 4-5
Implementation Method 2
allowing for lyophilization in one or two containers and maintaining the amorphous state during long-term storage and reconstitution
Implementation Method 3
maintaining the amorphous state during long-term storage and reconstitution
Data Source
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AI summary
The present invention relates to : a method of preparing a stable, copanlisib-containing aqueous bulk solution suitable for lyophilisation and for therapeutic applications; a stable, copanlisib-containing bulk solution, of increased solubility which is directly suitable for lyophilisation; a method of lyophilizing such a copanlisib-containing aqueous bulk solution; a stable, lyophilized, copanlisib-containing solid, in particular powder or cake, particularly containing a therapeutic dose of copanlisib in one or two containers, particularly one sealed container; a method of reconstituting such lyophilisates; and a stable, reconstituted, copanlisib-containing solution of increased solubility, suitable for further dilution and for therapeutic applications.