Crystalline Forms of Compound I for Oral Solubility and Dissolution
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Solution Overview
Problem
There is a need for specific polymorph forms of the compound (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 2,6< ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (Compound (I)) that balance properties such as stability, solubility, and bioavailability for effective oral administration in pharmaceutical compositions.
Innovation Solution
The development of crystalline forms of Compound (I), characterized as Forms A through J, which are characterized by specific X-ray diffraction patterns, infrared spectra, and thermal analysis, providing a balance of desired properties for pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If amorphous or hydrate forms of the compound are used, then the compound can be obtained, but the compound shows poor water solubility and insufficient dissolution rate
Solution Approach 1:
The patent applies parameter changes by transforming the compound from amorphous or hydrate forms to specific crystalline forms (Form A, Form B, Form C) with defined crystal structures. This phase transition fundamentally alters the solubility and dissolution rate parameters, achieving both improved water solubility and sufficient dissolution rate simultaneously.
Solution Approach 2:
The invention utilizes phase transitions by converting the compound from amorphous or hydrate states to specific crystalline forms. The patent explicitly describes obtaining crystalline forms through controlled crystallization processes, where the phase transition to specific crystal structures enables both enhanced solubility and dissolution rate that cannot be achieved in amorphous or hydrate forms.
2Manufacturing precision
If conventional crystallization methods are used, then crystals can be obtained, but the crystal form and properties cannot be adequately controlled
Solution Approach 1:
The patent employs intermediaries (specific solvents and additives) to control crystal formation. By using particular solvent systems and crystallization conditions as intermediaries, the process achieves precise control over crystal form and properties while maintaining reasonable manufacturing complexity.
Solution Approach 2:
The invention controls crystal form by systematically adjusting crystallization parameters such as solvent type, temperature, pH, and addition rate. These parameter changes enable precise control over which crystalline form (A, B, or C) is obtained, achieving high manufacturing precision without excessive process complexity.
3Reliability
If the compound is administered to achieve therapeutic effect, then anti-cancer activity is achieved, but gastrointestinal side effects occur
Solution Approach 1:
The patent applies parameter changes by transitioning from amorphous or hydrate forms to specific crystalline forms, which fundamentally alters the dissolution rate parameter. This controlled change in dissolution kinetics maintains effective drug concentration for anti-cancer activity while reducing peak concentrations that cause gastrointestinal side effects.
Solution Approach 2:
The invention implements periodic action through controlled dissolution profiles of the crystalline forms. The crystalline structure enables sustained release patterns where the drug dissolves at controlled rates, maintaining therapeutic levels over time while avoiding sudden high concentrations that trigger gastrointestinal adverse reactions.
Data Source
Figure 1A
Figure 1B
Figure 1C
AI summary
Disclosed are crystalline forms of Compound (I). Compound (I) is useful as an anti-thromboembolic agent in the treatment of cardiovascular diseases.