Ertapenem Sodium Crystalline Form E Preparation
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Solution Overview
Problem
Existing methods for preparing crystalline forms of ertapenem sodium face challenges such as high solution concentrations leading to degradation, poor purity, and environmental concerns due to excessive solvent use, as well as difficulties in filtration and stability issues.
Innovation Solution
A method involving an aqueous solution of ertapenem sodium at a concentration of 40-100 mg/ml, adjusted to a pH of 5.3-5.6, with incremental additions of methanol and 1-propanol to achieve a specific volume ratio, followed by cooling to precipitate the crystalline form E, which has major X-ray diffraction peaks at specific angles, resulting in high purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional concentration and nanofiltration are used to achieve high concentration (above 100 mg/ml) for crystallization, then the crystallization can proceed, but the product undergoes substantive degradation and polymerization, resulting in poor purity and chroma
Solution Approach 1:
The patent changes the concentration parameter from conventional high concentration (>100 mg/ml) to moderate concentration (40-100 mg/ml), and adjusts the pH parameter to 5.3-5.6, which prevents degradation and polymerization while enabling successful crystallization to obtain high purity product
Solution Approach 2:
The patent introduces organic solvents (acetone, ethyl acetate, or 1-propanol) as intermediary substances to facilitate crystallization at moderate concentrations without requiring aggressive concentration methods that cause degradation
2Quantity of substance
If large amount of solvent is used in the crystallization process, then the crystallization can proceed, but it is not conducive to environmental protection and increases process complexity
Solution Approach 1:
The patent optimizes the solvent volume ratio to 0.5-2 times the aqueous solution volume, significantly reducing solvent consumption compared to conventional methods while maintaining effective crystallization and reducing environmental impact
3Shape
If crystalline form D is prepared using water, methanol, and 1-propanol with cooling, then crystallization occurs, but the particles are small and filtration by suction is difficult
Solution Approach 1:
The patent adjusts the pH parameter to 5.3-5.6 and uses moderate concentration (40-100 mg/ml) instead of extreme conditions, which promotes formation of larger, more filterable crystals while maintaining crystallization efficiency
Solution Approach 2:
The patent performs preliminary pH adjustment and controlled solvent addition before crystallization, which prepares the system to form crystals of appropriate size and morphology that are easily filterable
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 crystalline form E of ertapenem sodium is stable, easily filtered and dried, with a purity exceeding 98.5%, reducing energy consumption and environmental impact, and facilitating industrial production.
Implementation Method 1
cooling to -10~-5℃ and standing; then adding dropwise methanol and 1-propanol, until the volume ratio of water：methanol：1-propanol is 1：0.8～3：0.8～3.5, and cooling to -30~-10℃ to precipitate crystal
Implementation Method 2
cooling to -30~-10℃ to precipitate crystal, to obtain the crystalline form E of ertapenem sodium
Implementation Method 3
adding dropwise methanol and 1-propanol to the solution obtained in step b), until the volume ratio of water：methanol：1-propanol is 1：0.5～2：0.25～1.5
Data Source
Figure 1
AI summary
Provided is a crystalline form E of ertapenem sodium. Further provided is a method for preparing a crystalline form E of ertapenem sodium, characterized by using an aqueous ertapenem sodium solution at a low concentration as a raw material. The crystalline form E can be easily filtered and dried, the properties in the drying process are stable, and the purity of the crystal is high and can be up to 98.5% or higher.