(S)-Afoxolaner Crystalline Forms Enantiomeric Purity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The challenge lies in predicting and producing stable, enantiomerically pure solid forms of afoxolaner, a compound used for invertebrate pest control, as existing methods struggle to achieve high chemical and enantiomeric purity, and the presence of multiple crystal forms complicates pharmaceutical and veterinary applications.
Innovation Solution
The development of crystalline forms, specifically Form I and Form II of afoxolaner, which are characterized by distinct X-ray powder diffraction patterns and Differential Scanning Calorimetry thermograms, allowing for the preparation of enantiomerically pure and chemically pure forms through crystallization from specific solvent mixtures, eliminating the need for desolvation and enhancing manufacturing efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If asymmetric processes are used to obtain chiral molecules, then optically active molecules can be produced, but enantiomeric purity is insufficient without additional resolution methods
Solution Approach 1:
The patent employs a two-stage crystallization process with controlled temperature parameters and solvent selection to transform the enantiomeric composition. The first crystallization at controlled temperature yields mother liquor enriched in the desired (S)-enantiomer, and the second crystallization further purifies it to achieve ≥99.5% enantiomeric excess without requiring complex resolution equipment
Solution Approach 2:
The patent extracts and isolates the desired (S)-afoxolaner enantiomer from the racemic mixture through selective crystallization. The mother liquor from the first crystallization is specifically taken out and subjected to a second crystallization to obtain highly purified single enantiomer product
2Adaptability or versatility
If multiple crystal forms exist, then the compound can exhibit different physical properties, but predicting and controlling the solid state form becomes impossible
Solution Approach 1:
The patent performs preliminary action by carefully controlling crystallization conditions (solvent selection, temperature, cooling rate) before the crystal forms to ensure formation of the desired crystalline form with specific properties. This preemptive control of solid state formation eliminates unpredictability
Solution Approach 2:
The patent utilizes parameter changes in the crystallization process (temperature, solvent composition, cooling rate) to control and predict the formation of specific crystal forms, transforming the unpredictable solid state behavior into a controllable process
3Loss of substance
If desolvation steps are included in the manufacturing process, then solvent removal is achieved, but manufacturing efficiency and productivity decrease
Solution Approach 1:
The patent extracts the solvent during the crystallization process itself, incorporating solvent removal into the primary purification step rather than requiring a separate desolvation stage. This integration eliminates additional processing time and equipment
Solution Approach 2:
The patent merges the crystallization and solvent removal steps into a single integrated process. The crystallization conditions are designed to simultaneously achieve purification and solvent elimination, combining multiple functions into one operation
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
This approach results in high-purity, enantiomerically enriched crystalline forms of afoxolaner, improving its efficacy as a parasiticidal agent and simplifying the manufacturing process by eliminating the need for desolvation, thereby enhancing chemical stability and bioavailability.
Implementation Method 1
crystallization from specific solvent mixtures
Implementation Method 2
characterized by distinct X-ray powder diffraction patterns
Implementation Method 3
Differential Scanning Calorimetry thermograms
Data Source
AI summary
The present invention provides crystalline forms of compound of formula (Ia) and processes of making the crystalline forms. Also provided are compositions comprising the crystalline forms and methods of use of the crystalline forms.