Ertapenem Sodium Stabilization via Formula II Conversion
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Solution Overview
Problem
Ertapenem sodium is unstable at temperatures above -20°C, leading to dimerization and hydrolysis, and existing processes for its preparation involve vigorous drying methods that result in degradation impurities, making it challenging to produce a stable pharmaceutical composition.
Innovation Solution
A process involving dissolving crude ertapenem sodium in water with a base, adjusting the pH to 5-6, treating with alkanols, and isolating pure ertapenem sodium to minimize degradation impurities, which avoids vigorous drying and stabilizes the compound, forming a more stable pharmaceutical composition comprising Formula II or its salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If ertapenem sodium is stored or processed at temperatures above -20°C, then processing and formulation become easier, but the compound undergoes dimerization and hydrolysis forming degradation impurities
Solution Approach 1:
The patent changes the chemical form of ertapenem from the unstable monosodium salt to the stable disodium salt, and further converts it to the more stable compound of Formula II (ertapenem carbapenemate). This parameter change in chemical structure fundamentally improves thermal stability, allowing processing at higher temperatures without degradation.
Solution Approach 2:
The patent converts the harmful tendency toward degradation at higher temperatures by transforming the compound into a more stable chemical form (Formula II). The instability issue is converted into an opportunity to develop a superior stable formulation that can be processed under conventional conditions.
2Productivity
If vigorous drying methods using nitrogen sweep or agitation are used, then drying efficiency increases, but degradation impurities increase due to instability
Solution Approach 1:
The patent changes the chemical form to compound of Formula II, which has superior stability. This allows the use of aggressive drying methods without causing degradation, as the transformed compound remains stable even under vigorous drying conditions.
Solution Approach 2:
The patent applies prior cushioning by pre-converting ertapenem to its more stable Formula II form before the drying process. This preparatory transformation cushions against the degrading effects that would otherwise occur during vigorous drying, preventing impurity formation before it can happen.
3Reliability
If ertapenem sodium is formulated with sodium carbonate or sodium bicarbonate, then stability improves and degradation impurities are minimized, but additional formulation steps are required
Solution Approach 1:
The patent merges the stabilization function into the molecular structure itself by creating compound of Formula II, which inherently contains the stabilizing characteristics. This eliminates the need for separate stabilization steps using carbonate or bicarbonate, as the stability is built into the compound's structure.
Solution Approach 2:
The compound of Formula II serves multiple functions: it maintains antibiotic activity, provides inherent stability without requiring additional stabilizing agents, and can be directly formulated for parenteral administration. This multi-functional compound simplifies the overall formulation process.
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
This process efficiently purifies ertapenem sodium, reducing degradation impurities and stabilizing the compound, resulting in a high-purity pharmaceutical composition suitable for parenteral administration with improved stability and reduced impurity formation.
Implementation Method 1
adjusting the pH of the solution obtained in step a) to about 5 to about 6
Implementation Method 2
treating the solution obtained in step b) with one or more alkanols
Data Source
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AI summary
The present invention relates to a process for preparing a carbapenem antibiotic composition, Formula (II). The present invention further relates to a carbapenem antibiotic composition substantially free of degradation impurities. The present invention further relates to a polymorphic form of ertapenem monosodium designated as Form D and its preparation.