Crystalline Form I Monohydrate Stability via Hydration
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Solution Overview
Problem
There is a need for more stable forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile that maintain high solubility, as existing forms are prone to degradation and have variable stability.
Innovation Solution
The development of crystalline Form I, a monohydrate with a specific x-ray diffraction pattern, which is more stable and has a higher transition temperature, achieved through treatment of anhydrous Form V with heated water or at room temperature, converting other polymorphs into Form I using water.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms are used, then the compound can be supplied for pharmaceutical use, but the forms are prone to degradation and have variable stability
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing different polymorphic forms (Form I through Form VI) of the compound, each with distinct crystal structures, stability profiles, and physical properties. Form I is specifically identified as the most stable polymorph with defined XRD patterns and transition temperatures, resolving the stability issue by selecting and controlling for this specific crystalline parameter configuration
Solution Approach 2:
The patent employs composite material principles by creating a monohydrate form (Form I) that incorporates water molecules into the crystal lattice structure. This composite approach, where the compound forms a stable hydrate complex, enhances the overall stability and reliability of the pharmaceutical material compared to anhydrous forms
2Stability of the object's composition
If more stable crystalline forms are developed, then degradation resistance improves, but maintaining high solubility becomes challenging
Solution Approach 1:
The patent resolves this contradiction by systematically evaluating multiple polymorphic forms with different physical parameters. Form I is identified as having the optimal balance, exhibiting both high stability (transition temperature 109-115°C) and maintained solubility characteristics, demonstrating that parameter optimization can achieve both stability and solubility requirements simultaneously
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
Form I exhibits enhanced stability, retaining purity and physical integrity under various environmental conditions, including high humidity, temperature, and light exposure, with a transition temperature range of 109°C to 115°C, making it more desirable for pharmaceutical applications.
Implementation Method 1
One method of preparing 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate (Form I) comprises the step of treating anhydrous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, known herein as Form V, with heated water
Implementation Method 2
One method of preparing 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate (Form I) comprises the step of treating anhydrous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, known herein as Form V, with heated water
Implementation Method 3
The polymorph is a monohydrate (Form I) having an x-ray diffraction pattern wherein all of the 2θ angles (°) of significant peaks are either at about: 9.19, 11.48, 14.32, 19.16, 19.45, 20.46, 21.29, 22.33, 23.96, 24.95, 25.29, 25.84, 26.55, 27.61, and 29.51
Data Source
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AI summary
This invention is directed to a crystalline 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3- quinolinecarbonitrile monohydrate having an x-ray diffraction pattern wherein 20 angles (°) of significant peaks are at about: 9.19, 11.48, 14.32, 19.16, 19.45, 20.46, 21.29, 22.33, 23.96, 24.95, 25.29, 25.84, 26.55, 27.61, and 29.51, and a transition temperature of about 109ºC to about 115ºC.