S1P Receptor Modulator Crystal Forms for Stability and Dissolution
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Solution Overview
Problem
There is a need for stable and well-defined crystalline forms of S1P receptor modulators that can effectively target sphingosine-1-phosphate receptors for therapeutic applications, as existing forms may lack consistency and stability, affecting their efficacy and bioavailability.
Innovation Solution
The development of specific crystalline forms of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, characterized by unique X-ray powder diffraction patterns and thermal properties, providing a stable and well-defined structure for pharmaceutical use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If amorphous forms or non-crystalline solid forms are used, then solubility and dissolution rate are improved, but physical stability and chemical stability deteriorate
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing specific crystalline forms with defined XRPD patterns, DSC thermograms, and TGA profiles. Different crystalline forms (Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8) are distinguished by their unique diffraction peaks and thermal properties, allowing selection of forms that balance dissolution rate and stability requirements
Solution Approach 2:
The patent utilizes phase transitions by describing the compound in various solid states including crystalline forms, amorphous forms, and solvates. The DSC thermograms show endothermic transitions at specific temperatures (e.g., 282°C for Form 1, 145°C and 280°C for Form 2) that characterize phase changes, enabling control over solubility and stability through selective crystallization conditions
2Reliability
If multiple crystalline forms are developed, then stability and solubility profiles are optimized, but manufacturing complexity increases
Solution Approach 1:
The patent systematically varies crystallization parameters including solvent type (THF, EtOAc, acetonitrile, toluene, ethanol, isopropanol, acetic acid), temperature conditions, and evaporation rates to produce distinct crystalline forms. Each form is characterized by unique XRPD peak patterns and DSC thermal transitions, providing a controlled approach to optimizing stability and solubility
Solution Approach 2:
The patent uses solvents as intermediary substances to mediate the formation of different crystalline forms. Specific solvents (THF, EtOAc, acetonitrile, toluene, ethanol, isopropanol, acetic acid) act as mediators that facilitate the formation of particular polymorphs or solvates, allowing control over the final solid form properties without direct manipulation of the active ingredient
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 crystalline forms exhibit enhanced stability and bioavailability, enabling effective modulation of S1P receptors for therapeutic indications such as multiple sclerosis, ulcerative colitis, and Crohn's disease, with controlled release and improved pharmacokinetic profiles.
Implementation Method 1
an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1
Implementation Method 2
an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 16.5° 2-Theta, 18.5° 2-Theta, 21.0° 2-Theta, 22.1° 2-Theta, 22.8° 2-Theta, 26.6° 2-Theta, 27.8° 2-Theta, and 28.9° 2-Theta
Implementation Method 3
a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in FIG. 2
Implementation Method 4
a DSC thermogram substantially similar to the one set forth in FIG. 2
Implementation Method 5
a DSC thermogram with an endotherm having an onset at about 282° C.
Data Source
AI summary
Described herein are crystalline forms of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a salt or solvate thereof.