Polymorph Form A Crystallization Control
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Solution Overview
Problem
There is a need for an efficient method to selectively control the crystallization of polymorphic forms of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide, as existing methods fail to produce the desirable Form A, leading to inefficient production processes and contamination by residual solvents.
Innovation Solution
A method involving dissolving 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in a non-aqueous solvent at temperatures above 40°C, optionally seeding with Form A crystals, and cooling to form crystals of polymorph Form A, while maintaining temperatures below 100°C to avoid hydrate or other impurity formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If recrystallization is performed from various solvents, then the compound can be purified, but mixtures of different polymorphic forms are obtained instead of the desired Form A
Solution Approach 1:
The patent applies parameter changes by carefully controlling crystallization conditions including temperature ranges (cooling from dissolution temperature to final crystallization temperature), solvent composition ratios, pH values, and addition rates of antisolvents. These parameter optimizations enable selective formation of Form A polymorph while avoiding mixtures or unwanted polymorphic forms.
Solution Approach 2:
The patent employs preliminary action through seeding with Form A crystals before the main crystallization process. This pre-introduction of the desired polymorphic form provides a template that guides the crystallization process to produce Form A, preventing the formation of other polymorphic forms or solvates.
2Productivity
If other polymorphic forms are obtained during recrystallisation, then they can be disposed of, but revenue is lost and production efficiency decreases
Solution Approach 1:
By optimizing crystallization parameters including temperature profiles, solvent selection and ratios, pH control, and antisolvent addition rates, the method achieves high selectivity for Form A production. This eliminates the need to dispose of unwanted polymorphic forms, thereby improving productivity and preventing product loss.
3Quantity of substance
If temperatures above 100°C are used during crystallization, then dissolution is achieved, but hydrate or other impurity formation occurs
Solution Approach 1:
The patent employs parameter changes by using alternative dissolution approaches that do not require temperatures above 100°C. This includes optimizing solvent selection (using solvents with appropriate boiling points and solubility characteristics), adjusting pH to enhance solubility, and controlling addition rates to achieve complete dissolution at lower temperatures, thereby preventing hydrate formation while maintaining dissolution completeness.
4Ease of operation
If the compound is non-hygroscopic and free-flowing, then handling and processing is improved, but achieving this polymorphic form requires precise crystallization control
Solution Approach 1:
The patent achieves the desired handling properties by precisely controlling crystallization parameters including temperature profiles, solvent composition, pH values, and antisolvent addition rates. These parameter optimizations selectively produce Form A, which inherently exhibits non-hygroscopic and free-flowing characteristics, thereby improving ease of operation through proper manufacturing control.
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
This method allows for improved control of particle properties, increased yields of specific polymorphs, and reduced contamination, producing a non-hygroscopic, free-flowing powder suitable for pharmaceutical formulations with high purity and reduced residual solvent levels.
Implementation Method 1
dissolving 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in a non-aqueous solvent or mixture of non-aqueous solvents to obtain a solution
Implementation Method 2
cooling the solution, thereby forming crystals of polymorph Form A
Implementation Method 3
cooling the solution
Implementation Method 4
optionally seeding the solution with Form A crystals
Data Source
AI summary
This invention relates to a process for the preparation of Form A of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide. Also disclosed herein is Form A of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide, or pharmaceutical compositions thereof, obtainable by the process described herein.