Substituted Urea Salt Crystalline Forms for Tyrosine Kinase Drug Stability
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Solution Overview
Problem
Current drug formulations face challenges with polymorphism, affecting drug quality, stability, bioavailability, and efficacy due to varying crystalline forms, solubility, and pharmacokinetic properties, particularly in treating diseases related to tyrosine kinase activity.
Innovation Solution
Development of acid addition salts, specifically hydrobromide, hydrochloride, and benzene sulfonate crystalline forms of the substituted urea derivative 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((4-(3-morpholinopropoxy)phenyl)ethynyl)phenyl)urea, which improve stability and bioavailability, and are used in pharmaceutical compositions to treat, remit, or prevent tyrosine kinase-related disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the substituted urea derivative is used in its original form, then the drug can be synthesized, but the stability and bioavailability are insufficient due to polymorphism and varying crystalline forms
Solution Approach 1:
The patent applies parameter changes by converting the substituted urea derivative into salt forms (hydrochloride, hydrobromide, sulfate, nitrate, phosphate) to alter its physical and chemical parameters. This transformation stabilizes the crystalline structure, eliminates polymorphism issues, and improves bioavailability while maintaining the drug's therapeutic activity against tyrosine kinase-related diseases
Solution Approach 2:
The patent creates composite material structures by forming salts between the substituted urea derivative and various acids. These composite salt forms provide defined crystalline structures with consistent physical properties, resolving the polymorphism problem and ensuring reliable stability and bioavailability across different formulations
2Reliability
If acid addition salts are developed to improve stability and bioavailability, then the pharmacokinetic properties are enhanced, but the device complexity increases due to multiple salt forms
Solution Approach 1:
The patent employs universality by developing a series of acid addition salts (hydrochloride, hydrobromide, sulfate, nitrate, phosphate) that all serve the same fundamental function of improving stability and bioavailability. Each salt form provides multi-functional benefits: enhancing pharmacokinetic properties, ensuring stable crystalline structures, and maintaining therapeutic efficacy, thereby managing complexity through functional equivalence
Data Source
AI summary
A salt of a substituted urea derivative of formula (I) and use thereof in the pharmaceutical field. Also, a pharmaceutical composition containing the salt or a combination thereof, and use of the salt or the pharmaceutical composition in the manufacture of a medicament for treating, remitting or preventing a disorder related to tyrosine kinase activity.