Crystalline Forms of P2Y12 Antagonist via Heterogeneous Solvent Crystallization
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Solution Overview
Problem
Existing methods have struggled to effectively crystallize 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (COMPOUND·HCl) in a mono-phase solvent system, leading to challenges in achieving desired purity, stability, and reproducibility in pharmaceutical compositions.
Innovation Solution
The development of novel crystalline forms of COMPOUND·HCl, characterized by specific X-ray powder diffraction peaks, which are obtained through controlled crystallization processes in heterogeneous solvent systems, leading to improved properties such as higher purity, stability, and reproducibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If crystallization is attempted in a mono-phase solvent system, then the process is simple, but the desired purity, stability, and reproducibility cannot be achieved
Solution Approach 1:
The patent changes the fundamental parameter of the solvent system from mono-phase to heterogeneous (two-phase) system. This parameter change enables the crystallization process to achieve the desired purity, stability, and reproducibility that were unattainable in simple mono-phase systems, while the heterogeneous nature of the system is managed through controlled phase separation.
2Ease of operation
If conventional crystallization methods are used, then the process is straightforward, but the crystalline forms do not exhibit the desired enhanced properties
Solution Approach 1:
The patent introduces a heterogeneous solvent system as an intermediary medium that facilitates the crystallization process. This two-phase system acts as a mediator between the compound and the crystallization environment, enabling the formation of crystalline forms with enhanced purity, stability, and reproducibility while maintaining operational feasibility through controlled phase separation.
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 novel crystalline forms of COMPOUND·HCl exhibit enhanced purity, stability, and reproducibility, making them particularly suitable for pharmaceutical compositions and improving their efficacy as P2Y12 receptor antagonists in treating various receptor-mediated diseases and disorders.
Implementation Method 1
The development of novel crystalline forms of COMPOUND·HCl, characterized by specific X-ray powder diffraction peaks, which are obtained through controlled crystallization processes in heterogeneous solvent systems
Implementation Method 2
the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ
Implementation Method 3
the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ
Data Source
AI summary
The invention relates to crystalline forms of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms and their use as a medicament, especially as a P2Y12 receptor antagonist.