HPβCD Aqueous Production for Low β-CD Pharmaceutical Purity
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Solution Overview
Problem
Existing methods for producing hydroxypropyl-beta-cyclodextrin (HPβCD) face challenges in achieving a low average degree of molar substitution (MS) of 0.71 while minimizing residual β-cyclodextrin (β-CD) content and avoiding the use of toxic organic solvents, particularly for pharmaceutical applications requiring high safety and purity.
Innovation Solution
A novel process involving hydroxypropylation in an aqueous medium with controlled parameters, including temperature, propylene oxide ratio, and addition rate, followed by solvent-free purification, to produce HPβCD with an MS of 0.71 and β-CD content below 0.3%, eliminating the need for organic solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the average degree of molar substitution (MS) is reduced to 0.71 or lower to improve safety for pharmaceutical applications, then the residual β-cyclodextrin content increases, but this compromises purification quality and regulatory compliance
Solution Approach 1:
The patent applies parameter changes by precisely controlling the molar substitution degree (MS) within the range of 0.50-0.71 through optimized hydroxypropylation conditions, including controlled propylene oxide addition rates and reaction parameters. This allows achieving the desired safety profile while maintaining purification quality through subsequent advanced purification steps that can effectively remove residual β-cyclodextrin even at these low MS values
2Manufacturing precision
If conventional purification methods using organic solvents are employed to reduce residual β-cyclodextrin content, then purification effectiveness improves, but toxic residues remain in the final product
Solution Approach 1:
The patent converts the limitation of avoiding organic solvents into a benefit by implementing an alternative purification sequence using aqueous-based methods including ultrafiltration, dialysis, and chromatography. These methods, while requiring multiple steps, effectively remove residual β-cyclodextrin and reaction byproducts without introducing toxic organic solvent residues, ultimately producing a safer pharmaceutical-grade product
Solution Approach 2:
The purification process is segmented into multiple distinct stages: initial filtration, ultrafiltration with specific molecular weight cutoffs, dialysis against buffered solutions, and chromatographic purification. This segmentation allows each step to target specific impurities progressively, achieving high purification effectiveness without relying on organic solvents
3Manufacturing precision
If multiple purification steps are implemented to reduce residual β-cyclodextrin and reaction byproducts, then product purity improves, but production complexity and time increase
Solution Approach 1:
The patent employs ultrafiltration membranes with specific molecular weight cutoffs that serve multiple functions simultaneously: they remove residual β-cyclodextrin, clarify the solution, and concentrate the HPβCD product in a single operation. This multi-functionality reduces the overall number of purification steps needed while maintaining high product purity, thereby simplifying the production process
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 yields HPβCD with improved safety and efficacy for pharmaceutical use, enhancing the solubilization and stabilization of active agents, particularly pharmaceutically active proteins, while meeting regulatory standards for purity and safety.
Implementation Method 1
the HPβCD is obtained by reacting a β-cyclodextrin with propylene oxide in a basic medium
Implementation Method 2
This purification is carried out by means of one or more treatments such as filtration, decoloration, demineralization, washing with ethanol, extraction with acetone, dialysis
Implementation Method 3
filtration, decoloration, demineralization, washing with ethanol, extraction with acetone, dialysis
Data Source
AI summary
The present invention relates to a novel hydroxypropyl-β-cyclodextrin (HPβCD) and also to a novel process that is of use for producing same. The invention also relates to the use of this HPβCD as an excipient. The invention also relates to an HPβCD for use thereof as a medicament, and more particularly for the treatment or prevention of diseases or conditions related to cholesterol overload and/or storage and/or accumulation in the tissues, and also the consequences thereof, such as certain central nervous system or cardiovascular system ailments.