Pharmaceutical Composition Formulation for Nitrosamine Impurity Control
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Solution Overview
Problem
Existing pharmaceutical compositions contain nitrosamine impurities that exceed acceptable levels, posing a risk of genotoxicity and carcinogenicity, and current methods fail to maintain these compositions within safe limits during storage.
Innovation Solution
The compositions are formulated with a solvent system containing no more than 20% water and controlled nitrite and nitrate levels, using non-aqueous solvents and specific excipients to minimize nitrosamine formation, ensuring stability and compliance with acceptable intake limits.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional pharmaceutical compositions are formulated with standard solvent systems containing higher water content, then the compositions exhibit good solubility and stability, but nitrosamine impurities form and exceed acceptable levels during storage
Solution Approach 1:
The patent changes the water content parameter in the solvent system from conventional high levels to no more than 20%, and controls nitrite and nitrate levels to no more than 2 ppm each. This parameter modification prevents nitrosamine formation while maintaining composition stability during storage.
Solution Approach 2:
The patent creates an inert environment by using non-aqueous solvents and严格控制 nitrite/nitrate levels, eliminating the conditions necessary for nitrosamine formation. This inert formulation approach prevents genotoxic impurity generation without requiring additional packaging or storage conditions.
2Reliability
If nitrite and nitrate levels are controlled to reduce nitrosamine formation, then nitrosamine impurities remain within acceptable levels, but the composition may become less stable or require more complex formulation
Solution Approach 1:
The patent modifies multiple parameters simultaneously: water content to ≤20%, nitrite levels to ≤2 ppm, and nitrate levels to ≤2 ppm. This multi-parameter optimization maintains composition stability while preventing nitrosamine formation, demonstrating that parameter changes can achieve both safety and stability goals.
3Productivity
If standard manufacturing processes are used without controlling nitrite and nitrate, then the manufacturing process is simple and efficient, but nitrosamine impurities are generated during manufacture and storage
Solution Approach 1:
The patent implements preliminary control measures during manufacturing by specifying that nitrite and nitrate levels be controlled to no more than 2 ppm each in the final composition. This preliminary action prevents nitrosamine formation during both manufacture and storage, eliminating the need for post-manufacturing remediation while maintaining manufacturing efficiency.
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 solution results in storage-stable pharmaceutical compositions with nitrosamine impurities within acceptable levels, meeting regulatory standards and maintaining composition integrity over extended periods.
Implementation Method 1
nitrosamine impurities are generated when secondary, tertiary, or quaternary amine groups react with nitrous acid (nitrosating agent)
Data Source
AI summary
The present invention relates to storage-stable pharmaceutical compositions comprising a drug substance containing amine, and at least one excipient, wherein the nitrosamine impurities in the said compositions are within acceptable levels. The nitrite content of the storage-stable pharmaceutical compositions is not more than about 2 ppm. Further, the present invention also provides a process for the manufacture of the said compositions.