Rivaroxaban Crystallization Purity and Waste Reduction
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Solution Overview
Problem
Existing processes for preparing Rivaroxaban's crystal Modification I suffer from lack of reproducibility, contamination with other polymorphic and solvated forms, and high chemical waste, resulting in impure products unsuitable for pharmaceutical use.
Innovation Solution
A process involving a solution of Rivaroxaban in a solvent medium of water and acetone at reflux, followed by carbon treatment and cooling to induce crystallization, effectively producing highly pure crystal Modification I with high chemical and enantiomeric purity, free from other solid state forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing processes for preparing Rivaroxaban are used, then the product can be obtained, but the purity is insufficient and contaminated with other polymorphic and solvated forms
Solution Approach 1:
The patent applies parameter changes by carefully controlling crystallization conditions including temperature gradients, solvent composition ratios, pH levels, and cooling rates to selectively obtain crystal Modification I while preventing formation of other polymorphic forms and solvates. This resolves the contradiction by adjusting process parameters to achieve high purity product.
Solution Approach 2:
The patent utilizes phase transitions during controlled crystallization from solution, where the substance transitions from dissolved state to solid crystal form. By controlling the phase transition conditions (temperature, solvent removal rate), the process selectively forms crystal Modification I with high purity, eliminating contamination issues.
2Manufacturing precision
If column chromatographic purifications are used to improve purity, then the product purity increases, but the process complexity and chemical waste increase
Solution Approach 1:
The patent extracts and removes impurities and other polymorphic forms during the crystallization process itself, eliminating the need for subsequent column chromatographic purification steps. This is achieved through selective crystallization conditions that separate the desired crystal Modification I from contaminants in a single operation, reducing both process complexity and chemical waste.
Solution Approach 2:
The crystallization process is designed to be self-purifying, where the controlled phase transition automatically separates pure crystal Modification I from impurities without requiring additional purification equipment or complex multi-step procedures. The process serves its own purification function, eliminating the need for separate chromatographic steps.
3Manufacturing precision
If existing crystallization methods are used, then crystal Modification I can be obtained, but the reproducibility is poor
Solution Approach 1:
The patent applies preliminary action by pre-establishing optimal crystallization conditions including specific solvent compositions, temperature profiles, and pH ranges before the actual crystallization process. These pre-determined parameters ensure that when the crystallization is performed, it consistently yields crystal Modification I with high reproducibility, eliminating variability in results.
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 consistently yields Rivaroxaban with greater than 99.95% chemical purity and 99.999% enantiomeric purity, avoiding column chromatographic purifications and reducing chemical waste, making it suitable for pharmaceutical formulations.
Implementation Method 1
providing a solution of Rivaroxaban in a solvent medium comprising water and acetone at reflux
Implementation Method 2
subjecting the solution to carbon treatment
Implementation Method 3
cooling the solution to below about room temperature to cause crystallization
Data Source
AI summary
Provided herein are improved, commercially viable and consistently reproducible processes for the preparation of highly pure crystal Modification I of Rivaroxaban, which is free from other polymorphs and undesired solvated forms. Provided also herein is a highly pure and stable crystal Modification I of Rivaroxaban essentially free of other solid state forms.