Selumetinib Sulfate Crystal Forms With Direct Sulfate Crystallization
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Solution Overview
Problem
Existing methods for preparing selumetinib sulfate are complex and inefficient, requiring multiple steps and neutralization processes, which can lead to operational complexity and impurity residues, affecting the stability and solubility of the final product.
Innovation Solution
The development of seven distinct crystal forms (A, B, C, D, E, F, and G) of selumetinib sulfate, characterized by specific X-ray powder diffraction peaks, and novel preparation methods using sulfuric acid to remove the vinyl protecting group, allowing direct crystallization without neutralization, reducing the number of steps and impurities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the prior art method is used to prepare selumetinib sulfate, then the preparation process can be completed, but the process becomes extremely complicated requiring multiple steps including removal of vinyl protecting group, neutralization, and crystallization
Solution Approach 1:
The patent extracts and eliminates the neutralization step from the preparation process. By using sulfuric acid to remove the vinyl protecting group directly to form selumetinib sulfate, the complex multi-step process (removal of protecting group, neutralization, crystallization) is simplified into a more direct one-step crystallization process, reducing operational complexity and impurity residues
Solution Approach 2:
The patent changes the chemical parameter by using sulfuric acid as the reagent to remove the vinyl protecting group, which directly forms the sulfate salt without requiring subsequent neutralization. This parameter change in the reagent type and reaction mechanism simplifies the overall process by eliminating the need for separate neutralization and extraction steps
2Reliability
If the prior art method is used, then selumetinib sulfate can be prepared, but impurity residues affect the stability and solubility of the final product
Solution Approach 1:
The patent converts the potentially harmful effect of using strong acid (sulfuric acid) to remove the vinyl protecting group into a beneficial outcome. The sulfuric acid directly forms the sulfate salt, and the crystallization process selectively precipitates the pure selumetinib sulfate while leaving impurities in the solution, thereby improving product stability and reducing harmful impurity residues
3Adaptability or versatility
If multiple crystal forms are developed, then the pharmaceutical properties can be optimized, but the characterization and preparation complexity increases
Solution Approach 1:
The patent segments the crystallization process into different conditions (varying temperatures, solvent ratios, pH levels) to obtain different crystal forms (A, B, C, D, E, F, G). Each crystal form is characterized by specific X-ray powder diffraction peaks, allowing systematic optimization of pharmaceutical properties such as solubility, stability, and bioavailability for different therapeutic applications
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 new crystal forms and methods provide stable, easily stored selumetinib sulfate preparations with improved yield and reduced production costs, enhancing the pharmaceutical industry's efficiency and effectiveness.
Implementation Method 1
adding sulfuric acid into butanone and water... adding sulfuric acid into tetrahydrofuran and water... removing the vinyl protecting group with hydrochloric acid... neutralizing the reactant mixture to pH7... adding sulfuric acid into the mixture to form selumetinib sulfate
Implementation Method 2
increasing a temperature of the solution to enhance dissolution, then decreasing the temperature of the solution to facilitate crystallization and thereby obtaining the crystal form A of selumetinib sulfate... increasing the temperature of the solution to enhance dissolution, then lowering the temperature of the solution to facilitate crystallization
Implementation Method 3
characterized by having characteristic peaks at 2θ=6.62°±0.20°, 9.64°±0.20°, 12.34°±0.20°, 13.19°±0.20°, 18.00°±0.20°, 21.17°±0.20°, 22.14°±0.20°, 24.85°±0.20° and 26.53°±0.20° in an X-ray powder diffraction (XRPD) pattern
Data Source
AI summary
The present invention relates to crystal forms of A, B, C, D, E, F and G of selumetinib sulfate and the preparation method thereof. The crystal forms A, B and F of selumetinib sulfate are obtained by adding 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (SEL-3) into an organic solvent; further, crystal form A of selumetinib sulfate can be as a raw material to prepare crystal forms C, D and E of selumetinib sulfate, and crystal form C of selumetinib sulfate can be as a raw material to prepare crystal form G of selumetinib sulfate.