Dalteparin Sodium Preparation Process Impurity Control
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Solution Overview
Problem
Existing methods for producing Dalteparin sodium face challenges in controlling nitrite and boron impurities, which are stringent regulatory requirements, and often involve high reagent quantities and prolonged UV irradiation, affecting product quality and yield.
Innovation Solution
A process involving depolymerization of heparin sodium with sodium nitrite in the presence of an acid, followed by reduction with limited sodium borohydride, precipitation, UV irradiation at 254 nm for short durations, and lyophilization in alcohol to produce Dalteparin sodium within pharmacopoeial standards, reducing impurities and maintaining product quality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If higher quantities of sodium nitrite and sodium borohydride are used for depolymerization and reduction, then the depolymerization efficiency is improved, but the nitrite and boron impurity levels increase beyond pharmacopoeial limits
Solution Approach 1:
The patent optimizes the concentration parameters of reagents (sodium nitrite at 2.5-3.5% by weight, sodium borohydride at ≤2.0 mole equivalents) and process conditions (temperature range 5-35°C, pH 2-4 during depolymerization) to achieve efficient depolymerization while maintaining impurity levels within pharmacopoeial limits. This resolves the contradiction by finding the optimal parameter window that balances reaction efficiency with product purity.
2Object-generated harmful factors
If prolonged UV irradiation is used to control N—NO impurities, then the impurity levels are reduced, but heat generation increases affecting product quality
Solution Approach 1:
The patent employs periodic or controlled-duration UV irradiation (10 seconds to 8 minutes at 254 nm, 4-40 W power) instead of prolonged continuous irradiation. This periodic treatment effectively reduces N—NO impurities to below detection limits while limiting heat accumulation, thereby maintaining product quality and avoiding thermal degradation.
3Manufacturing precision
If chromatographic purification process is used to remove impurities, then the product purity is improved, but the process complexity and cost increase
Solution Approach 1:
The patent extracts and removes harmful impurities (nitrite, boron, N—NO compounds) through targeted chemical treatment and controlled precipitation steps before final product isolation. By removing impurities early in the process through extraction and controlled precipitation rather than relying on complex chromatographic purification, the method achieves pharmacopoeial purity levels with a simpler, more cost-effective process.
4Productivity
If large amounts of reagents are used for industrial scale production, then the production capacity is increased, but the impurity control becomes more difficult
Solution Approach 1:
The patent scales the process by maintaining optimized reagent concentrations (sodium nitrite 2.5-3.5% by weight, sodium borohydride ≤2.0 mole equivalents) and process parameters (temperature 5-35°C, controlled pH) even at industrial scale. This ensures that impurity control remains effective regardless of production volume, resolving the contradiction between production capacity and impurity control.
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 efficiently produces Dalteparin sodium with nitrite, N—NO, and boron impurities below pharmacopoeial limits, ensuring product quality and regulatory compliance, while minimizing reagent usage and avoiding heat generation during UV treatment.
Implementation Method 1
Dalteparin sodium is produced through controlled nitrous acid depolymerization of heparin sodium
Implementation Method 2
reducing the product obtained in step (a) with ≤2.0 mole equivalents of a reducing agent to obtain crude Dalteparin sodium
Implementation Method 3
dissolving the precipitate obtained in step (d) in water and subjecting to ultra-violet irradiation at 254 nm wavelength and 4 to 40 W power for a time period of 10 seconds to 8 minutes
Implementation Method 4
stirring the crude product obtained in step (c) in a solvent mixture to obtain precipitate of Dalteparin sodium
Implementation Method 5
lyophilizing the solution obtained in step (e) in presence of alcohol to obtain Dalteparin sodium in free powder form
Data Source
AI summary
The present invention provides an improved process for the preparation of Dalteparin sodium. The process is simple, commercially viable and industrially advantageous.