Tafamidis Form 4 Crystallization for Polymorph Purity
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Solution Overview
Problem
Existing processes for preparing tafamidis are inefficient in producing crystalline Form 4 without contamination from other polymorphic forms, particularly Form 1, and there is a need for improved methods to produce stable salts of tafamidis with high purity.
Innovation Solution
A process involving the use of specific solvents and anti-solvents, such as C1-C4 amides, C2-C3 sulfoxides, and C5-C6 pyrrolidones, combined with C1-C8 alcohols, C3-C10 ketones, and C1-C3 nitriles, to isolate crystalline Form 4 of tafamidis, and reacting tafamidis with inorganic or organic bases to form stable salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing processes are used to prepare tafamidis, then production can be achieved, but the crystalline form obtained is contaminated with other polymorphic forms particularly Form 1 and the process is inefficient
Solution Approach 1:
The patent applies parameter changes by carefully controlling crystallization conditions including solvent selection (amides, sulfoxides, pyrrolidones), temperature profiles, pH levels, and addition rates of anti-solvents to selectively obtain crystalline Form 4 while preventing formation of other polymorphic forms, thereby achieving both high purity and efficient production
Solution Approach 2:
The patent uses specific solvents and anti-solvents as intermediaries to mediate the crystallization process. These solvent systems act as mediators that facilitate selective nucleation and growth of crystalline Form 4, enabling controlled polymorph selection and preventing contamination from other forms
2Productivity
If existing processes are used to prepare tafamidis, then production can be achieved, but the process is inefficient and time-consuming
Solution Approach 1:
The patent applies preliminary action by pre-selecting and optimizing the solvent system composition, pre-determining the crystallization temperature profile, and pre-establishing pH conditions before initiating crystallization. This preparation ensures that crystalline Form 4 forms selectively and rapidly, reducing both process time and improving productivity
3Ease of manufacture
If tafamidis is prepared without specific solvent systems, then production is simpler, but the crystalline form obtained is contaminated with other polymorphic forms
Solution Approach 1:
The patent modifies key parameters including selecting specific solvent classes (amides, sulfoxides, pyrrolidones), controlling temperature ranges, adjusting pH levels, and managing anti-solvent addition rates. These parameter changes enable selective formation of crystalline Form 4 while maintaining relatively simple manufacturing procedures
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 achieves crystalline Form 4 of tafamidis that is substantially free of Form 1 and other polymorphic forms, with high purity and stability, and produces salts with enhanced properties.
Implementation Method 1
providing a solution of tafamidis in a solvent selected from the group consisting of C1-C4 amides, C2-C3 sulfoxides, C5-C6 pyrrolidones, and mixtures thereof
Implementation Method 2
combining the solution of step (a) with an anti-solvent selected from the group consisting of C1-C8 alcohols, C3-C10 ketones, C1-C3 nitriles, water and mixtures thereof
Implementation Method 3
obtaining crystalline Form 4 of tafamidis from the solution of step (a) by (i) combining the solution of step (a) with an anti-solvent
Implementation Method 4
reacting tafamidis with an inorganic or organic base to form a reaction mixture comprising the tafamidis salt
Data Source
AI summary
The present invention relates to process for preparation of crystalline Form 4 of tafamidis. The present invention also relates to salts of tafamidis and process of preparation of salts of tafamidis. The present invention also relates to process for preparation of an amorphous solid dispersion of tafamidis or salt thereof.