Compound 1 Crystalline Form II for Thermal Stability and Purity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing crystalline 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 (Compound 1) exhibit instability and degradation at high temperatures, limiting their effectiveness as a pharmaceutical agent for treating conditions like heavy menstrual bleeding, endometriosis, and prostate cancer.
Innovation Solution
Development of novel crystalline forms, particularly Form II, characterized by specific X-ray powder diffraction patterns and thermal stability, including an onset of degradation between 174° C. and 176° C., and an exothermic peak at 192° C., achieved through controlled crystallization in a DMF and acetone mixture at low temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms of Compound 1 are used, then the pharmaceutical agent can be prepared and administered, but the compound exhibits instability and degradation at high temperatures during processing and storage
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple crystalline forms (Form I, Form II, Form III) of Compound 1, each with distinct thermal stability properties. Form II specifically exhibits superior thermal stability with degradation onset at 174-176°C compared to other forms. This resolves the contradiction by changing the physical state parameter (crystalline form) of the compound to achieve enhanced thermal stability during pharmaceutical processing and storage.
Solution Approach 2:
The patent employs composite materials by formulating pharmaceutical compositions that contain Compound 1 in specific crystalline forms (particularly Form II) combined with pharmaceutically acceptable excipients and carriers. This composite approach maintains the thermal stability benefits of the specific crystalline form while enabling practical pharmaceutical application and administration.
2Manufacturing precision
If existing crystalline forms are used for pharmaceutical processing, then the compound can be manufactured, but purity is compromised due to degradation
Solution Approach 1:
The patent resolves the purity contradiction by changing the crystalline form parameter of Compound 1. Form II, with its higher thermal stability (degradation onset at 174-176°C), maintains chemical integrity during manufacturing processes such as tablet compression, capsule filling, and sterilization. This prevents degradation product formation and maintains high purity levels throughout the manufacturing lifecycle.
3Productivity
If standard crystallization methods are used, then Compound 1 can be produced, but the resulting crystalline forms exhibit lower thermal stability and earlier degradation
Solution Approach 1:
The patent achieves both productivity and reliability by optimizing crystallization parameters. Specific crystallization conditions (temperature, solvent system, cooling rate) are employed to preferentially form Form II, which exhibits superior thermal stability. This parameter optimization ensures high-yield crystallization while simultaneously producing the thermally stable polymorph, resolving the contradiction between manufacturing efficiency and product reliability.
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 II of Compound 1 demonstrates enhanced thermal stability and purity, facilitating its use in pharmaceutical compositions and treatments by maintaining its structural integrity during processing and administration.
Implementation Method 1
Form II of Compound 1 begins to melt at about 180° C.
Implementation Method 2
Form II of Compound 1 begins to degrade at about 175° C.
Implementation Method 3
Form II of Compound 1 shows an exothermic peak at about 192° C. by DSC
Data Source
AI summary
This disclosure relates to novel crystalline 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 them, and methods of treatment and uses comprising their administration.