Polymorphic Crystallization of Pyrazine PGI2 Agonist
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Solution Overview
Problem
The challenge is to obtain a crystal form of Compound B with excellent physicochemical stability, as existing methods do not specify the crystal form obtained and the current form-III crystal is thermodynamically unstable.
Innovation Solution
The development of form-I and form-II crystals of Compound B, which are characterized by specific diffraction peaks, absorption peaks, and thermal stability, providing a more stable alternative to the previously obtained form-III crystal.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If form-III crystal of Compound B is used as active ingredient, then it can be obtained through existing synthesis methods, but it exhibits poor thermodynamic stability and transforms under storage conditions
Solution Approach 1:
The patent applies parameter changes by modifying crystallization conditions including solvent selection (acetonitrile, ethanol, isopropyl alcohol), temperature profiles (cooling rates from 0.1 to 10°C per minute), and pH adjustment to transform the unstable form-III crystal into stable form-I and form-II crystals with distinct diffraction patterns and improved thermodynamic stability
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process from solution phase to solid crystal phase under specific conditions, enabling the transformation from unstable form-III to stable polymorphic forms (form-I and form-II) through controlled cooling and solvent evaporation processes
2Reliability
If strict evaluation and examination of polymorphism is performed, then physicochemical stability can be ensured, but the development process becomes time-consuming and complex
Solution Approach 1:
The patent applies preliminary action by pre-establishing the stable crystal forms (form-I and form-II) with well-characterized diffraction patterns and stability profiles before pharmaceutical development, eliminating the need for extensive polymorphism evaluation during later stages and reducing overall development time
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 and form-II crystals demonstrate enhanced thermodynamic stability, maintaining their chemical integrity under various storage conditions, and are suitable for use as active ingredients in pharmaceutical compositions.
Implementation Method 1
A form-I crystal of Compound B... A form-II crystal of Compound B
Implementation Method 2
which shows diffraction peaks at diffraction angles (2θ) of 6.4°, 8.1°, 9.5°, 10.9°, 13.2°, 15.7°, 17.0°, 19.5°, 20.3°, 21.0°, and 22.8° in a powder X-ray diffraction spectrum
Implementation Method 3
The form-I and form-II crystals demonstrate enhanced thermodynamic stability, maintaining their chemical integrity under various storage conditions
Data Source
AI summary
A main object of the present invention is to provide a novel crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (hereinafter referred to as “Compound B”). A form-I crystal of Compound B, which shows peaks at diffraction angles (2θ) of 6.4°, 8.1°, 9.5°, 10.9°, 13.2°, 15.7°, 17.0°, 19.5°, 20.3°, 21.0°, and 22.8° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å). A form-II crystal of Compound B, which shows peaks at diffraction angles (2θ) of 9.6°, 11.4°, 11.7°, 16.3°, 17.5°, 18.5°, 18.7°, 19.9°, 20.1°, 21.0°, and 24.6° in a powder X-ray diffraction spectrum obtained using a Cu-Kα radiation (λ=1.54 Å).