Quinoline-Substituted Crystal Form for Stable Low-Hygroscopic API
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Solution Overview
Problem
Existing compounds used as active pharmaceutical ingredients lack stable crystal forms with desirable properties such as thermal stability, storage stability, and low hygroscopicity, making them unsuitable for effective drug development and use.
Innovation Solution
Development of a type I crystal form of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide with specific X-ray diffraction peaks and thermal stability, along with a method for producing this crystal using solvents like ethanol and water or acetonitrile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If a compound is used as an active pharmaceutical ingredient, then its quality stability is required, but the compound may form different crystal polymorphs with different physical properties making it difficult to predict and control the stable crystal form
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent type (acetonitrile, ethanol, water, isopropanol), temperature ranges (room temperature to reflux), and pH levels to identify which parameters produce the desired stable crystal form with specific XRD characteristics and low hygroscopicity
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process from liquid solution to solid crystal phase, and by performing polymorph conversion studies where unstable crystal forms are transformed into the stable type I crystal form through controlled heating and cooling cycles
2Duration of action of stationary object
If a stable crystal form is formed for stable quality holding, then storage stability improves, but hygroscopicity may increase which is undesirable for pharmaceutical applications
Solution Approach 1:
The patent employs short-term controlled humidity exposure during the crystallization process to induce the stable crystal form, then quickly removes the compound from humid conditions through filtration and drying, using the humidity exposure only for the brief period needed to establish the desired crystal structure
Solution Approach 2:
The patent performs preliminary characterization of crystal forms under controlled humidity conditions to identify which crystal polymorph exhibits low hygroscopicity, then uses this information to optimize the crystallization process parameters to pre-form the stable, low-hygroscopicity type I crystal
3Reliability
If crystal forms are different from each other, then physical properties such as solubility and stability differ, but it is difficult to predict which crystal form will have excellent physical properties
Solution Approach 1:
The patent implements feedback by using powder X-ray diffraction (PXRD) analysis to characterize the crystal form obtained from each crystallization experiment, then using this feedback information to adjust subsequent crystallization conditions to achieve the desired type I crystal form with predictable and reliable physical properties
Solution Approach 2:
The patent replaces predictive mechanical/empirical methods with X-ray diffraction technology to identify and characterize crystal forms, using the diffraction patterns as fingerprints to reliably distinguish between different polymorphs and predict their physical 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 type I crystal exhibits enhanced thermal stability, storage stability, and low hygroscopicity, making it suitable for pharmaceutical applications and effective as an antitumor agent.
Implementation Method 1
peaks in a powder X-ray diffraction spectrum measured with CuKα characteristic X-ray at diffraction angles (2θ±0.2°) of 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°
Implementation Method 2
enhanced thermal stability
Implementation Method 3
low hygroscopicity
Data Source
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AI summary
An object is to provide a crystal of a compound having an EGFR inhibition ability or a salt thereof, the crystal being satisfactory in one or more of the following characteristics: stability (in terms of heat or purity) and/or low hygroscopicity. According to one aspect of the present invention, there is provided a crystal form of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]lindolizin-8-yl)acrylamide having a peak at a predetermined diffraction angle (2θ±0.2°) in its powder X-ray diffraction spectrum.