Carbapenem Antibiotic Stabilization via Simplified Crystallization
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Solution Overview
Problem
The instability of carbapenem antibiotics at elevated temperatures poses challenges in commercial manufacturing, as they undergo dimerization and hydrolysis, requiring complex and costly processes to maintain stability and quality, such as multiple steps and lyophilization.
Innovation Solution
A simplified process involving dissolving a carbonate source and a base in a diluent to form a solution at controlled temperatures, reducing the number of manufacturing steps and eliminating the need for multiple titrations, allowing for the production of a stable carbapenem formulation suitable for use as a ready-to-use injection, and an alternative crystallization process using an organic anti-solvent to achieve high-quality, low-cost products without lyophilization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Temperature
If carbapenem is stored at elevated temperatures, then storage convenience is improved, but stability deteriorates due to dimerization and hydrolysis
Solution Approach 1:
A stabilizing agent is introduced as an intermediary substance that mediates between the carbapenem and the environmental conditions. The stabilizing agent prevents dimerization and hydrolysis reactions by interfering with the degradation pathways, allowing the carbapenem to remain stable at higher storage temperatures without direct thermal exposure.
Solution Approach 2:
The patent modifies the chemical environment by adjusting pH levels, adding stabilizing agents, or changing the formulation composition. These parameter changes create a protective chemical milieu that prevents degradation reactions, enabling the carbapenem to maintain stability at temperatures above −20° C. while preserving its therapeutic efficacy.
2Stability of the object's composition
If complex manufacturing processes with multiple steps and lyophilization are used, then stability is improved, but device complexity and manufacturing cost increase
Solution Approach 1:
The invention extracts and eliminates the lyophilization step from the manufacturing process by incorporating stabilizing agents directly into the formulation. This allows the carbapenem to be processed and stored in a simpler, non-lyophilized form while maintaining stability, thereby removing complex equipment and process steps from the manufacturing workflow.
Solution Approach 2:
Stabilizing agents are incorporated into the carbapenem formulation during the early stages of manufacturing, before the product requires storage or distribution. This preliminary stabilization action prevents degradation throughout the product lifecycle, eliminating the need for subsequent complex stabilization steps or specialized storage infrastructure.
3Manufacturing precision
If multiple titrations and water charging steps are performed, then manufacturing precision is improved, but productivity decreases
Solution Approach 1:
A single buffering system or stabilizing agent is designed to perform multiple functions simultaneously: maintaining pH, preventing dimerization, and inhibiting hydrolysis. This multi-functional approach replaces the need for multiple separate titration steps, achieving the same precision goals in a single operational step that enhances manufacturing throughput.
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 carbapenem product with high purity (>94% by HPLC) that can be stored at room temperature, reducing costs and simplifying the manufacturing process while maintaining high quality and stability, with the crystallization method achieving yields comparable to lyophilization and higher purity than traditional methods.
Implementation Method 1
dissolving a carbonate source and a base in a diluent to form a first solution
Implementation Method 2
mixing the compound of formula (I) with the first solution to form a solution
Implementation Method 3
crystallization process using an organic anti-solvent to achieve high-quality, low-cost products
Data Source
AI summary
The present invention relates to a process for the preparation of carbapenem antibiotic compounds, which are useful for intravenous and intramuscular administration.