Tafamidis Form Alpha Crystalline Process Scalability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for producing tafamidis polymorphic forms, particularly crystalline form 1 and form 4, and their meglumine salt are not scalable and lack robust industrialization, limiting their large-scale production and pharmaceutical formulation suitability.
Innovation Solution
A new crystalline form of tafamidis, designated as form alpha, characterized by specific XRPD peaks, is developed, along with a process involving solvent and anti-solvent treatment, enabling scalable production and conversion into other forms or salts, including the meglumine salt, suitable for pharmaceutical use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current methods for producing tafamidis polymorphic forms are used, then the desired crystalline forms can be obtained, but the production process is not scalable and lacks robust industrialization
Solution Approach 1:
The patent applies parameter changes by modifying the solvent system (using ethyl acetate and heptane instead of previous solvent combinations) and processing conditions (temperature, addition rate) to enable scalable production of tafamidis crystalline forms while maintaining product quality and process robustness
Solution Approach 2:
The patent uses an intermediary approach by introducing a specific solvent system that mediates between the solubility requirements for large-scale production and the crystallization requirements for obtaining pure polymorphic forms, enabling both scalability and process robustness
2Stability of the object's composition
If amorphous tafamidis is obtained by concentration in vacuo, then the compound can be isolated, but it converts into crystalline form 4 upon storage and lacks stability
Solution Approach 1:
The patent applies preliminary action by directly producing the stable crystalline form alpha through controlled crystallization from solvent systems, eliminating the need for storage and preventing subsequent polymorphic conversion that would occur with amorphous forms
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process from liquid solvent to solid crystalline form alpha, ensuring the product is obtained directly in the stable crystalline state rather than requiring conversion from an amorphous phase during storage
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
Form alpha is chemically and physically stable, allowing for the production of other tafamidis forms and salts in a pure crystalline form, maintaining stability over various storage conditions, and facilitating large-scale production and pharmaceutical formulation.
Implementation Method 1
dissolving tafamidis in a solvent
Implementation Method 2
adding the solution to an anti-solvent to precipitate form alpha
Implementation Method 3
drying under reduced pressure at a temperature from 40° C. to 60° C. for a period from 12 to 48 hours
Data Source
AI summary
A crystalline form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid and a method for its preparation are described. The crystalline form is further suitable as intermediate compound to prepare Form 1, Form 4 and Form M with improved stability and purity.