Ethanol Solvate Crystalline Form for Pharmaceutical Stability
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Solution Overview
Problem
There is a need for a stable and effective crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, specifically an ethanol solvate form, that exhibits specific X-ray powder diffraction patterns and thermal properties.
Innovation Solution
The development of Form XIV of Compound 1, an ethanol solvate, characterized by specific X-ray powder diffraction patterns and thermal properties, including an XRPD pattern with peaks at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 2θ, and thermal stability indicated by a TG thermogram showing a continuous weight loss between 49° C. and 172° C.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple crystalline forms are developed to achieve specific stability and efficacy, then the reliability and effectiveness of the pharmaceutical agent are improved, but the device complexity and manufacturing process complexity increase
Solution Approach 1:
The patent uses X-ray powder diffraction (XRPD) patterns as unique 'fingerprints' to distinguish between different crystalline forms (Form I, Form II, Form III, etc.). Each form has a characteristic diffraction pattern with specific peak positions and intensities, enabling reliable identification and differentiation of crystalline polymorphs and solvates.
Solution Approach 2:
The patent systematically varies and characterizes multiple parameters of the crystalline forms including XRPD peak positions, thermal properties (melting points, decomposition temperatures), solvation states (anhydrous, hemihydrate, ethanol solvate), and structural arrangements. This comprehensive parameter characterization enables differentiation and selection of optimal forms for specific applications.
2Manufacturing precision
If specific crystalline forms with defined thermal properties are identified, then the manufacturing precision and quality control are improved, but the measurement and detection complexity increase
Solution Approach 1:
The patent employs multiple analytical techniques (XRPD, DSC, TG, NMR) to characterize crystalline forms and uses this feedback information to confirm successful formation of target forms, optimize synthesis conditions, and establish quality control criteria. The characteristic thermal transitions and diffraction patterns serve as feedback signals for process validation.
Solution Approach 2:
The patent replaces direct mechanical or visual inspection methods with advanced analytical techniques including X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy to detect and characterize crystalline structures, enabling precise identification of polymorphic forms and solvates.
3Adaptability or versatility
If multiple solvate forms (anhydrous, hemihydrate, ethanol solvate) are characterized, then the adaptability and versatility of the pharmaceutical agent are improved, but the loss of substance and purification complexity increase
Solution Approach 1:
The patent utilizes controlled phase transitions during crystallization to generate different solvate forms (anhydrous, hemihydrate, ethanol solvate) depending on solvent composition, temperature, and evaporation conditions. By controlling the crystallization phase, specific solvate forms can be selectively produced with characteristic stoichiometries and structural arrangements.
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 XIV of Compound 1 provides a stable and effective crystalline form with defined structural and thermal characteristics, suitable for pharmaceutical applications, including treatment of hormone-dependent conditions such as prostate cancer, uterine fibroids, and endometriosis.
Implementation Method 1
characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 2θ
Implementation Method 2
X-ray powder diffraction pattern comprising at least three peaks
Implementation Method 3
a TG thermogram showing a continuous weight loss between 49° C. and 172° C.
Implementation Method 4
thermal stability indicated by a TG thermogram showing a continuous weight loss
Data Source
AI summary
This disclosure relates to crystalline solvated forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino) methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea. It also relates to methods of making the disclosed crystalline forms, pharmaceutical compositions and kits comprising the forms, and methods of treatment and uses comprising their administration.