EP4 Receptor Antagonist Polymorphs for Stable Drug Formulation
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Solution Overview
Problem
The existing crystalline forms of (S)-4-(1-(2-(4-fluorobenzyl)-4,7-dihydro-5H-thieno [2,3-c]pyran-3-carboxamido) ethyl) benzoic acid do not adequately address the stability and suitability for drug formulation, affecting solubility, stability, drug release rate, safety, and bioavailability.
Innovation Solution
Development of polymorphic forms I, II, III, IV, V, and VI, characterized by specific X-ray powder diffraction patterns and thermal analysis, including anhydrous and solvent-based crystal forms, with distinct peak profiles and thermal properties, suitable for pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the existing crystalline forms of the compound are used, then the compound can be obtained through conventional preparation methods, but the stability and suitability for drug formulation are insufficient, affecting solubility, stability, drug release rate, safety, and bioavailability
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization parameters (temperature, solvent composition, cooling rates, pH conditions) to obtain six distinct polymorphic forms (Forms I-VI) with different physical properties. Each polymorph exhibits different solubility, stability, and dissolution characteristics, allowing optimization for specific therapeutic applications. For example, Form I shows high stability with characteristic XRD peaks at 2θ values of 4.234±0.2°, 8.505±0.2°, and 11.177±0.2°, while other forms offer enhanced solubility or dissolution rates.
Solution Approach 2:
The patent utilizes phase transitions in the crystallization process to generate different polymorphic forms. By controlling the phase change from amorphous to crystalline states under varying conditions (temperature gradients, solvent evaporation, anti-solvent addition), the compound transforms into different crystal structures. This phase transition control enables the formation of stable polymorphs with optimized pharmacokinetic properties and formulation characteristics.
2Manufacturing precision
If different crystalline forms are obtained through various crystallization methods, then the physical and chemical properties can be optimized, but the complexity of obtaining and characterizing multiple polymorphic forms increases
Solution Approach 1:
The patent segments the crystallization process into multiple independent methods, each targeting specific polymorphic forms: (1) direct crystallization from solvent, (2) cooling crystallization, (3) anti-solvent precipitation, (4) evaporative crystallization, (5) pH-controlled crystallization, and (6) mechanical assistance crystallization. Each method is optimized for obtaining specific forms with desired properties, allowing systematic exploration of polymorphic space without requiring all methods to be performed simultaneously.
Solution Approach 2:
The patent employs intermediary substances and conditions to facilitate the formation of specific polymorphs. Solvents act as intermediaries to control crystal nucleation and growth; temperature gradients serve as intermediaries to direct phase transitions; pH modifiers act as intermediaries to stabilize specific crystal forms. These intermediaries simplify the crystallization process by providing controlled environments that favor the formation of target polymorphs with optimized properties.
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 polymorphic forms enhance stability and suitability for drug processing, improving solubility, stability, and bioavailability, making them more effective for treating diseases mediated by EP4 receptor activation.
Implementation Method 1
the X-ray powder diffraction pattern of the polymorphic Form I has characteristic peaks at 2θ values of 4.234±0.2°, 8.505±0.2°, 8.96±0.2°, 11.177±0.2°, 12.892±0.2°, 18.05±0.2°, 23.333±0.2°
Implementation Method 2
in the TGA pattern, the weight loss of the polymorphic Form I is about 0.1-1% from room temperature to 230° C., preferably 0.2-0.5%
Implementation Method 3
in the DSC pattern, the polymorphic Form I has an endothermic peak with a shoulder peak, the initial temperature of the endothermic peak is 251.55±3° C. (preferably ±2° C. or ±1° C.), and the shoulder peak temperature is 241.67±3° C. (preferably ±2° C. or ±1° C.)
Data Source
AI summary
Provided are a polymorph of an EP4 receptor antagonist, a preparation method therefor and a use thereof, relating in particular to a polymorph of an EP4 receptor antagonist(S)-4-(1-(2-(4-fluorobenzyl)-4, 7-dihydro-5H-thieno [2,3-c]pyran-3-carboxamido) ethyl) benzoic acid, a preparation method therefor and a use thereof. Compared with an amorphous form of a compound represented by formula I, the polymorph of the present invention has higher stability and better processing performance and is very suitable for being prepared into a medicine.