Aprocitentan Sodium Crystalline Forms for Stable Drug Manufacturing
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Solution Overview
Problem
Existing aprocitentan formulations lack physical and chemical stability, hygroscopicity, and reproducibility, which are crucial for effective pharmaceutical compositions.
Innovation Solution
Development of novel crystalline forms of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide with specific X-ray powder diffractogram peaks, allowing for improved stability, reduced hygroscopicity, and enhanced manufacturing reproducibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional aprocitentan formulations are used, then manufacturing simplicity is maintained, but physical and chemical stability deteriorates
Solution Approach 1:
The patent applies parameter changes by transitioning from conventional formulations to specifically defined crystalline forms (Forms 1-4) with distinct XRPD patterns. Each crystalline form has characteristic diffraction peaks at specific 2θ angles, representing changed physical parameters that directly improve stability while maintaining manufacturability through controlled crystallization processes
2Object-affected harmful factors
If conventional aprocitentan formulations are used, then formulation simplicity is maintained, but hygroscopicity worsens
Solution Approach 1:
The patent reduces hygroscopicity by changing the physical state from conventional formulations to specifically engineered crystalline forms. The ordered molecular arrangement in crystalline Forms 1-4, characterized by distinct XRPD patterns, reduces the compound's affinity for water molecules compared to amorphous or less-ordered states
3Manufacturing precision
If conventional aprocitentan formulations are used, then manufacturing process simplicity is maintained, but reproducibility deteriorates
Solution Approach 1:
The patent improves reproducibility by defining specific crystallization parameters for each crystalline form. The process controls variables such as solvent selection, temperature profiles, and precipitation conditions to reliably produce Forms 1-4 with their characteristic XRPD patterns, ensuring consistent quality across manufacturing batches
Solution Approach 2:
The patent applies preliminary action by pre-defining the target crystalline form characteristics (XRPD peak positions and intensities) before manufacturing. This allows the process to be designed and optimized to achieve the desired crystalline structure from the outset, rather than attempting to correct deficiencies after production
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 provide enhanced physical and chemical stability, better flow properties, and improved reproducibility in manufacturing, making them suitable for pharmaceutical compositions with improved efficacy.
Implementation Method 1
The XRPD shows peaks having a relative intensity, as compared to the most intense peak in the diffractogram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta
Implementation Method 2
X-ray powder diffractograms (XRPD) of COMPOUND in crystalline forms 1 to 4
Data Source
AI summary
The present invention concerns novel crystalline forms of aprocitentan sodium salt, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as endothelin receptor antagonists.