Benserazide Hydrochloride Crystallization Process
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Solution Overview
Problem
Current methods for preparing benserazide hydrochloride in crystalline form I are inefficient and include the use of toxic solvents like DMF, which are not suitable for industrial-scale production and do not meet regulatory requirements for residual solvents.
Innovation Solution
A new process for preparing benserazide hydrochloride in crystalline form I that does not use methanol and/or DMF as crystallization solvents, allowing for the elimination of methanol from the final product and resulting in high yields with lower impurity levels, particularly non-toxic solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If DMF is used as crystallization solvent, then crystalline form I can be obtained, but toxic residual solvent remains in the product
Solution Approach 1:
The patent extracts and removes the harmful DMF solvent from the crystallization process by replacing it with alternative solvents (water, ethanol, isopropanol, acetone, or their mixtures), thereby eliminating toxic residual solvent from the final product while maintaining the ability to produce crystalline form I
Solution Approach 2:
The patent introduces intermediary solvents (water, ethanol, isopropanol, acetone) that serve as safe alternatives to DMF for crystallization, allowing the formation of crystalline form I without the use of toxic solvents. These intermediary substances enable the same crystallization outcome without the harmful effects
2Manufacturing precision
If traditional preparation methods are used, then crystalline form I can be obtained, but the process is inefficient and produces high impurity levels
Solution Approach 1:
The patent changes the crystallization parameters by using alternative solvents and optimized conditions (temperature, time, solvent ratios) to achieve both high purity and high efficiency in producing crystalline form I, eliminating the need for time-consuming washing steps and reducing impurity levels
3Manufacturing precision
If DMF is used in the process, then crystalline form I can be prepared, but regulatory requirements for residual solvents are not met
Solution Approach 1:
The patent extracts DMF from the process entirely and replaces it with regulatory-compliant solvents (water, ethanol, isopropanol, acetone), ensuring that the final product meets ICH guidelines for residual solvents while maintaining crystalline form I quality
Solution Approach 2:
The patent uses safe, easily removable solvents (water, ethanol, isopropanol, acetone) that can be completely eliminated from the final product, unlike DMF which leaves persistent toxic residues. These disposable solvents leave no harmful trace in the final pharmaceutical product
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 new process achieves high purity and low residual solvent levels, making it suitable for industrial production and compliant with regulatory standards, while avoiding the use of toxic solvents like DMF.
Implementation Method 1
WO 2015/197909 describes additional crystalline forms of benserazide hydrochloride of formula (I), e.g. crystalline form VI, obtained by recrystallization from an aqueous solution of ethanol (90%) and 1-propanol
Data Source
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AI summary
The present invention relates to the preparation of a crystalline form of a DOPA decarboxylase inhibitor.