Solid State Forms of N-((S)-2,3-Dihydroxy-Propyl) Isonicotinamide
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Solution Overview
Problem
There is a lack of publicly disclosed solid state forms of N-((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide, which hinders its development as a pharmaceutical drug substance, particularly in tablet form due to manufacturing, stability, and packaging challenges.
Innovation Solution
Stable crystalline solid state forms (A1, A2, B1, and B2) of the compound are developed, characterized by x-ray powder diffractometry, single crystal diffractometry, FT IR spectroscopy, FT Raman spectroscopy, differential scanning calorimetry, and thermogravimetric analysis, exhibiting high crystallinity, thermal stability, and varying solubility profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If no solid state form is provided, then the compound cannot be formulated into tablets, but manufacturing and stability challenges arise without a stable solid state form
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple crystalline forms (A1, A2, B1, B2) of the compound, each with distinct physical properties including solubility, dissolution rate, and stability characteristics. This allows selection of the optimal crystalline form for tablet manufacturing while ensuring stability requirements are met.
Solution Approach 2:
The patent develops pharmaceutical compositions that combine the active compound in specific crystalline forms with pharmaceutically acceptable carriers and excipients. This composite approach enables tablet formulation by integrating the active ingredient with materials that provide manufacturing ease, stability, and desired release characteristics.
2Reliability
If crystalline forms are developed to improve stability, then manufacturing and packaging become feasible, but solubility and dissolution kinetics may be compromised
Solution Approach 1:
The patent resolves this contradiction by identifying and characterizing multiple crystalline forms with different physical properties. Specifically, Form A1 exhibits high solubility and fast dissolution kinetics while maintaining stability, whereas other forms like B1 and B2 offer different stability profiles. This allows optimization based on therapeutic requirements.
Solution Approach 2:
The patent applies local quality by selecting specific crystalline forms for specific applications. For instance, Form A1 may be selected when rapid dissolution is critical, while other forms may be chosen when maximum stability is the priority. Each crystalline form has localized optimal properties for different therapeutic scenarios.
3Adaptability or versatility
If multiple solid state forms are developed with varying solubility profiles, then optimal formulation can be selected, but characterization and development complexity increases
Solution Approach 1:
The patent systematically characterizes multiple crystalline forms by varying physical and chemical parameters such as solvent systems, temperature, and pH during crystallization. Each form is fully characterized using techniques like XRD, DSC, and solubility measurements, creating a comprehensive database that guides formulation selection while managing development complexity through structured methodology.
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 developed solid state forms provide a stable and effective pharmaceutical dosage form for cancer treatment, offering improved solubility and dissolution kinetics, enabling their use in various cancer therapies and pharmaceutical compositions.
Implementation Method 1
characterized, e.g., by x-ray powder diffractometry
Implementation Method 2
x-ray powder diffractometry
Implementation Method 3
differential scanning calorimetry (DSC)
Implementation Method 4
thermogravimetric analysis (TGA)
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The invention relates to solid state forms of N-((S)-2,3-Dihydroxy- propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide or its pharmaceutically acceptable salts, processes for their preparation, e.g. formula (I) and medical uses thereof.