Method for producing a polymorphic form of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-n-cyclopropyl-4-methylbenzamide
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Solution Overview
Problem
There is a lack of efficient methods for selectively controlling the crystallization of polymorphic forms of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide, leading to issues such as instability, high hygroscopicity, and low solubility, which complicates pharmaceutical formulation and production.
Innovation Solution
A method involving the dissolution of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in a non-aqueous solvent, followed by controlled cooling and heating to produce a specific crystalline polymorph (Form B) with a unique X-ray powder diffraction pattern, ensuring thermodynamic stability and non-hygroscopicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If recrystallization is performed from various solvents, then the compound can be obtained in crystalline form, but a mixture of different polymorphic forms is produced including solvates and hydrates
Solution Approach 1:
The invention changes the solvent parameter from conventional aqueous or polar solvents to non-aqueous solvents with specific properties (low water content, specific boiling points). This parameter change in solvent selection enables selective crystallization of the desired polymorphic form while avoiding formation of solvates and hydrates, thereby resolving the contradiction between obtaining crystalline form and achieving polymorph selectivity
Solution Approach 2:
The invention introduces a specific non-aqueous solvent as an intermediary medium that mediates the crystallization process. This intermediary solvent facilitates the formation of the desired polymorphic form by providing a controlled environment that prevents unwanted solvate and hydrate formation, while still enabling crystalline precipitation
2Ease of manufacture
If unstable polymorphic forms are used, then they may exhibit better formulative ability and dispersability, but they convert to stable forms over time causing loss of revenue and inefficient production
Solution Approach 1:
The invention performs preliminary action by selecting specific non-aqueous solvents and crystallization conditions that directly produce the thermodynamically stable polymorphic form from the beginning. This preliminary control of crystallization parameters prevents the formation of unstable polymorphs that would otherwise require subsequent conversion, thereby maintaining both formulative ability and long-term stability
Solution Approach 2:
The invention changes the crystallization parameters including solvent type, temperature profile, and cooling rate to directly obtain the stable polymorphic form. These parameter changes ensure that the crystalline product possesses both the desired formulative properties and long-term stability, eliminating the need to use unstable forms that convert over time
3Quantity of substance
If hydrates and solvates are formed during recrystallization, then crystalline product is obtained, but the product requires disposal resulting in lost revenue and inefficient production
Solution Approach 1:
The invention converts the potential harm of solvent inclusion into a benefit by carefully selecting non-aqueous solvents with specific properties that promote crystallization of the anhydrous, solvent-free stable polymorphic form. This approach transforms what could be a problematic solvate formation into a controlled process that yields the desired pure crystalline product without unwanted solvates or hydrates
Solution Approach 2:
The invention changes the solvent parameters to non-aqueous solvents with controlled water content and specific physical properties. This parameter change in solvent selection ensures that crystallization proceeds to form the stable polymorphic form without incorporating solvent molecules into the crystal lattice, thereby maximizing product yield and eliminating disposal losses
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 method allows for the selective production of Form B, which is thermodynamically stable, non-hygroscopic, and has improved solubility, facilitating easier pharmaceutical formulation and handling, while reducing contamination and improving yields.
Implementation Method 1
crystallization of polymorphic forms of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide
Implementation Method 2
dissolving 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide in a non-aqueous solvent
Implementation Method 3
heating the resultant crystals to greater than 75°C for a period of greater than 1 minute to produce Form B
Implementation Method 4
X-ray powder diffraction pattern measured using Cu Kα radiation with peaks at 2θ = about 9.6, 10.1, 11.4, 13.1, 13.9, 14.8, 15.4, 15.8, 17.0, 17.4, 18.5, 18.8, 19.7, 19.9, 20.5, 21.0, 21.9, 22.9, 23.6, 24.6 and 25.7°
Data Source
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AI summary
This invention relates to a process for the preparation of Form B of 3-[5-amino-4-(3- cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide. Also disclosed herein is Form B of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methylbenzamide, or pharmaceutical compositions thereof, obtainable by the process described herein.