Rocuronium Bromide Purification via Ethyl Acetate Crystallization
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Solution Overview
Problem
Current methods for producing rocuronium bromide often result in products with excessive residual solvents and impurities, exceeding the purity and solvent content limits set by European pharmacopoeia and ICH guidelines, which can be harmful and affect the stability and shelf life of the pharmaceutical.
Innovation Solution
A process involving the combination of 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α-ol-17β-acetate with allyl bromide and an inorganic base, followed by isolation, dissolution in a polar aprotic solvent, addition of a decolorizing agent, filtration, and stirring with an anti-solvent to obtain a suspension, and subsequent drying at controlled temperatures to achieve rocuronium bromide with high purity and reduced solvent content.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional purification methods (chromatography and crystallization from dichloromethane and ether) are used, then rocuronium bromide can be obtained, but the product contains excessive residual solvents (dichloromethane and ethyl ether) exceeding ICH guidelines
Solution Approach 1:
The patent changes the solvent system parameters by replacing dichloromethane with ethyl acetate and adjusting the crystallization conditions (temperature, anti-solvent addition rate) to obtain pure rocuronium bromide with residual solvents within ICH limits. Specifically, the process uses ethyl acetate as the primary solvent and controls crystallization at 20-25°C with controlled addition of diethyl ether as anti-solvent, achieving purity >98% with residual solvents <0.2%
Solution Approach 2:
The patent introduces an intermediate purification step using activated carbon treatment before crystallization. The activated carbon acts as an intermediary that adsorbs colored impurities and residual solvents from the reaction mixture, allowing the subsequent crystallization to produce high-purity product with acceptable residual solvent levels
2Object-affected harmful factors
If multiple purification steps are added to reduce residual solvents, then solvent content decreases, but process complexity and manufacturing cost increase
Solution Approach 1:
The patent combines the purification and crystallization steps into a single integrated process. The activated carbon treatment is performed in the same reaction vessel, followed by direct crystallization from the treated solution. This merging of steps achieves effective purification while avoiding the need for separate purification equipment and operations, maintaining process simplicity
3Reliability
If conventional crystallization from dichloromethane and ether is used, then rocuronium bromide crystallizes, but the product requires additional drying at elevated temperatures which may affect stability
Solution Approach 1:
The patent changes the crystallization solvent system to ethyl acetate/diethyl ether, which provides better solubility characteristics. This allows crystallization to occur more completely at lower temperatures (20-25°C), reducing the need for high-temperature drying and minimizing thermal degradation of the sensitive rocuronium bromide molecule
Data Source
AI summary
The invention encompasses substantially pure rocuronium bromide.