Letermovir Potassium Salt Crystallization Process
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Solution Overview
Problem
There is a need for a stable crystalline salt of letermovir that can be prepared in a reproducible and scalable process and remains stable over a long period of time, particularly for the treatment and prevention of cytomegalovirus (CMV) infections.
Innovation Solution
A crystalline potassium salt of letermovir is developed, which can be easily prepared from a solution of letermovir in a mixture of a dialkyl ether and an alcohol with the addition of potassium hydroxide, exhibiting high yields, good solubility, and storage stability, especially at physiological pH, without toxic solvent residuals.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If a stable crystalline salt of letermovir is prepared, then storage stability is improved, but the preparation process becomes more complex
Solution Approach 1:
The patent changes the chemical parameters by selecting specific solvent systems (dialkyl ether and alcohol mixtures) and controlling pH conditions to achieve crystallization of the potassium salt. By optimizing these parameters, the process achieves both stability and reproducibility without excessive complexity.
Solution Approach 2:
The patent utilizes phase transition from solution to crystalline solid through controlled evaporation and cooling processes. This phase change enables the formation of stable crystalline salts with reproducible structures, achieving storage stability while maintaining a relatively simple preparation process.
2Manufacturing precision
If high purity and solubility are achieved, then pharmaceutical effectiveness is improved, but the production process becomes less scalable
Solution Approach 1:
The patent segments the preparation process into distinct stages: dissolution in specific solvent mixtures, controlled evaporation, and crystallization. This segmentation allows each step to be optimized for both purity and scalability, with the dialkyl ether and alcohol solvent system enabling efficient separation and purification that scales well.
Solution Approach 2:
The patent uses dialkyl ether and alcohol as intermediary solvent systems that facilitate both high purity production and scalable manufacturing. These solvents serve as mediators between the reactants and the final crystalline product, enabling efficient purification and crystallization that can be scaled to industrial production levels.
3Object-affected harmful factors
If toxic solvent residuals are eliminated, then safety is improved, but the preparation process becomes more difficult
Solution Approach 1:
The patent converts the potential harm of solvent residues into a benefit by selecting dialkyl ether and alcohol as solvent systems that are either non-toxic or easily removable. The crystallization process itself serves to eliminate residual solvents, transforming a potential contamination issue into a purification advantage that enhances safety while maintaining manufacturing ease.
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 crystalline potassium salt of letermovir demonstrates high purity and solubility, allowing for effective pharmaceutical compositions for treating and preventing CMV infections, with a reproducible and scalable production process that maintains stability over time.
Implementation Method 1
can be easily prepared from a solution of letermovir in a mixture of a dialkyl ether and an alcohol with the addition of potassium hydroxide
Implementation Method 2
exhibit good storage stability in an aqueous medium, in particular at physiological pH. In particular, concentration levels of above 100 mg/mL in an aqueous medium can be achieved by dissolving said crystalline potassium salt of letermovir
Data Source
AI summary
The present invention relates to potassium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid and solvates thereof. The invention further relates to methods of preparation of said potassium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-4H-quinazolin-4-yl]acetic acid or solvates thereof as well as pharmaceutical compositions comprising said salt.