Deuterated Urea Polymorphs for Enhanced Drug Solubility
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Solution Overview
Problem
There is a lack of studies and developed polymorphs for the compound 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide, which affects its dissolution and clinical therapeutic effect in cancer treatment.
Innovation Solution
Development of various polymorphs, including p-toluenesulfonate salts and solvates, such as methanol and ethanol solvates, with specific X-ray powder diffraction and differential scanning calorimetry patterns, to enhance stability and solubility for pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymorphs of compound I are developed, then dissolution and absorption in vivo are improved, but manufacturing complexity increases
Solution Approach 1:
The patent develops multiple polymorphs of compound I by changing crystallization parameters such as temperature, solvent composition, and cooling rates. Different polymorphic forms (Form I, Form II, Form III) are obtained through controlled parameter changes during crystallization, each with distinct dissolution and absorption characteristics that improve reliability while managing manufacturing complexity through systematic parameter optimization.
2Reliability
If multiple polymorphs are developed, then therapeutic effect is improved, but loss of substance increases
Solution Approach 1:
The patent employs discarding and recovering principles by selectively discarding unwanted polymorphic forms during crystallization processes and recovering desired forms through controlled recrystallization. Impure or unwanted polymorphs are separated and discarded, while pure desired polymorphs are recovered through filtration and drying, thereby improving therapeutic effect reliability while minimizing substance loss through efficient recovery processes.
3Object-affected harmful factors
If polymorphs are developed, then clinical safety is improved, but measurement precision requirements increase
Solution Approach 1:
The patent replaces complex mechanical separation systems with thermal and chemical methods for polymorph separation and purification. Techniques such as differential scanning calorimetry, X-ray diffraction, and controlled crystallization from different solvents are used to identify and separate polymorphs based on their thermal and structural properties, thereby improving clinical safety while reducing the need for complex mechanical measurement and separation systems.
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 polymorphs are highly pure, stable, and suitable for inhibiting phosphokinase, reducing waste in manufacturing and improving health safety, making them beneficial for treating cancer and other diseases.
Implementation Method 1
polymorph I has 1 to 3 characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 13.182±0.2°, 21.472±0.2° and 22.833±0.2°
Implementation Method 2
polymorph I has a maximum peak of 231.5-237.7° C. in differential scanning calorimetry pattern
Data Source
AI summary
The invention relates to polymorphs of deuterated omega-diphenylurea or salts thereof. In particular, the invention provides polymorphs of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide or its salt, namely, polymorphs of the compound as shown in formula (I) or its salt. The polymorphs are suited for preparing the pharmaceutical composition used for inhibiting phosphokinase (such as raf kinases).