SHR1258 Dimaleate Form I Crystallization Stability
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Solution Overview
Problem
Current tyrosine kinase inhibitors, such as SHR1258 dimaleate, face challenges with chemical stability due to polymorph structure changes under different storage and crystallization conditions, leading to poor product stability, small particle size, easy agglomeration, and filtration issues.
Innovation Solution
A stable crystal form I of SHR1258 dimaleate is developed through a recrystallization process using polar organic solvents like isopropyl alcohol or ethanol, with specific conditions to achieve high purity and stability, including gradual cooling and vacuum drying, which results in a crystal form with distinct X-ray diffraction and DSC patterns.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If recrystallization is performed under various conditions, then different polymorph structures are obtained, but chemical stability deteriorates
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions (solvent type, temperature, pH, concentration) to identify the specific parameter combination that produces the most stable polymorph form. This resolves the contradiction by finding the optimal point in the parameter space where both adaptability in process design and stability in product composition are achieved.
Solution Approach 2:
The patent utilizes phase transitions during recrystallization to transform the compound from less stable polymorph forms or amorphous states into the stable Form I crystal structure. By controlling the phase transition conditions, the patent ensures that the compound adopts the thermodynamically stable polymorph form with superior chemical stability while maintaining flexibility in the recrystallization process.
2Ease of manufacture
If amorphous drug product is used, then processing is easier, but product stability deteriorates
Solution Approach 1:
The patent employs controlled phase transition from amorphous or liquid state to crystalline Form I during the recrystallization process. This transformation maintains the ease of manufacture benefits (as the compound can be processed in amorphous form during synthesis) while ensuring final product stability through conversion to the stable crystal form before packaging and storage.
Solution Approach 2:
The patent applies preliminary action by performing recrystallization to Form I crystal as a final purification and stabilization step before product formulation. This ensures that the stable crystalline form is established prior to manufacturing operations, combining the processing flexibility of amorphous intermediates with the stability of the final crystalline product.
3Manufacturing precision
If recrystallization is performed multiple times to improve purity, then polymorph purity improves, but productivity deteriorates
Solution Approach 1:
The patent optimizes crystallization parameters (solvent selection, cooling rate, supersaturation level, pH control) to achieve high polymorph purity in a single or minimal recrystallization steps. By carefully tuning these parameters, the process maximizes the yield of pure Form I crystal while minimizing the need for repeated recrystallization cycles, thus maintaining high productivity.
Solution Approach 2:
The patent uses carefully selected solvents and additives as intermediaries that facilitate the selective formation of Form I crystal with high purity in a single recrystallization step. These intermediary substances promote the preferential nucleation and growth of the stable polymorph form, reducing the need for multiple purification cycles and improving overall production efficiency.
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 form I crystal of SHR1258 dimaleate exhibits improved chemical stability under high temperature, humidity, grinding, pressure, and heating conditions, meeting pharmaceutical requirements and ensuring stable industrial production and storage.
Implementation Method 1
A stable crystal form I of SHR1258 dimaleate is developed through a recrystallization process using polar organic solvents like isopropyl alcohol or ethanol
Implementation Method 2
The X-ray diffraction pattern is shown in figure 1 which use Cu-Kα radiation to obtain the X-ray diffraction patterns represented by 2θ angels and interplannar crystal spacing (d value)
Implementation Method 3
DSC patterns of the present form I crystal of SHR1258 dimaleate show distinct fusion absorption peak at 130°C
Data Source
Figure 1
Figure 1
Figure 2
AI summary
Provided are crystalline Form I of (R,E)-N-(4-(3-chloro-4-(pyridin-2-yl -methoxy)-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl)-3-(1-methylpyrr olidin-2-yl) propenamide dimaleate (called SHR1258 dimaleate for short), preparation methods thereof and pharmaceutical composition containing the same. Said crystalline Form I of SHR1258 dimaleate has good crystal stability and chemical stability, and can be used in preparation of medicaments for treating diseases relevant to EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase.