ABT-888 Crystalline Form 1 Stability via Solvent Crystallization
Solution Overview
Problem
There is a need for the identification of crystalline forms of ABT-888 and reproducible methods for their manufacture, as the crystallinity of ABT-888 affects its physical and mechanical properties such as stability, solubility, and ease of manufacture, which are crucial for its therapeutic applications.
Innovation Solution
Characterization and production of 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide Crystalline Form 1, specifically in the tetragonal crystal system with defined lattice parameters, and methods involving solvent dissolution, temperature control, and crystallization processes to isolate and stabilize this form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If co-crystallization with tartaric acid is used to form single crystal of ABT-888, then crystal formation is achieved, but the process complexity and manufacturing difficulty increase
Solution Approach 1:
The patent extracts and eliminates the tartaric acid co-crystallization step from the process. Instead of using co-crystallization with tartaric acid, the invention employs direct crystallization from organic solvents, removing the harmful factor of process complexity while maintaining crystal formation capability
Solution Approach 2:
The patent changes the crystallization parameters by using different solvent systems (ethyl acetate, isopropanol, ethanol) and temperature conditions instead of co-crystallization with tartaric acid. This parameter change simplifies the manufacturing process while achieving the desired crystalline form
2Stability of the object's composition
If crystalline forms of ABT-888 are identified and characterized, then stability and solubility are improved, but the characterization and identification process time increases
Solution Approach 1:
The patent performs preliminary characterization by identifying key PXRD peaks (2θ values of 9.9°, 11.0°, 11.8°) and DSC parameters (melting point 188.3°C) that define Crystalline Form 1. By establishing these preliminary characterization criteria, the patent enables rapid identification and confirmation of the crystalline form without requiring extensive additional analysis time
3Manufacturing precision
If reproducible crystallization methods are developed, then manufacturing precision is improved, but the process development complexity increases
Solution Approach 1:
The patent establishes reproducible crystallization by defining specific parameters: solvent type (ethyl acetate, isopropanol, or ethanol), temperature range (cooling to 0-5°C or 20-25°C), and pH adjustment (to pH 9-11 using sodium carbonate). These parameter specifications enable consistent reproduction of Crystalline Form 1 without requiring complex process development
Solution Approach 2:
The patent uses sodium carbonate as an intermediary to control pH during the crystallization process. By adjusting pH to specific ranges (pH 9-11) with sodium carbonate, the patent mediates the crystallization conditions to ensure reproducible formation of Crystalline Form 1 from the free base or salt forms
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 characterized Crystalline Form 1 of ABT-888 enhances its stability and solubility, facilitating its use in pharmaceutical compositions and methods for treating cancer, either alone or in combination with other anticancer drugs, by providing a therapeutically effective and reproducible formulation.
Implementation Method 1
providing a mixture comprising 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide and solvent, wherein the 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide is completely dissolved in the solvent
Implementation Method 2
causing 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide Crystalline Form 1 to exist in the mixture by lowering its temperature
Implementation Method 3
causing 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide Crystalline Form 1 to exist in the mixture by lowering its temperature
Implementation Method 4
when measured at about -100°C in the tetragonal crystal system and P43212 space group with radiation at 0.7107 Å
Implementation Method 5
when measured at about -100°C in the tetragonal crystal system and P43212 space group with radiation at 0.7107 Å
Implementation Method 6
isolating the 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide Crystalline Form 1
Data Source
AI summary
2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide Crystalline Form 1, ways to make it, compositions comprising it and made using it, and methods of treating patients having disease using it are disclosed.