Azabicyclic Compound Analogues for ICH Impurity Reference Standards
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Solution Overview
Problem
Existing technologies do not provide a suitable analogue for quality control of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (compound 1) to ensure compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards, particularly for impurities such as analogues, residual solvents, and residual metals.
Innovation Solution
Development of novel analogues 1 to 9 and their salts as reference standards for quality control of compound 1, ensuring the pharmaceutical composition meets ICH standards by controlling the total content of these analogues to 1.0% or less, with individual contents of 0.30% or less for analogue 1 and 0.10% or less for others.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing technologies are used for quality control of compound 1, then production can proceed without novel reference standards, but quality control cannot meet ICH standards for impurity detection
Solution Approach 1:
The patent applies preliminary action by synthesizing and identifying novel analogues (analogue 1-9) before they become problematic impurities in large-scale production. This allows the establishment of reference standards in advance, enabling proper quality control methods to be developed and validated before manufacturing begins, thus ensuring ICH compliance from the outset.
Solution Approach 2:
The patent creates reference standards by synthesizing copies of potential impurity analogues (analogue 1-9) that mirror the structure of compound 1. These copied molecular structures serve as authentic reference materials for detection methods, allowing quality control systems to identify and quantify these specific impurities without requiring the actual impurities to be present during method development.
2Productivity
If compound 1 is produced in large amounts without novel analogues, then production volume increases, but quality cannot be confirmed to meet ICH standards
Solution Approach 1:
The patent implements feedback by establishing detection methods using the novel analogues (analogue 1-9) as reference standards. These methods provide quantitative feedback on impurity levels during production, allowing real-time monitoring and adjustment of manufacturing processes to maintain impurity content below ICH thresholds while maximizing production volume.
Solution Approach 2:
The patent applies parameter changes by setting specific quantitative thresholds for impurity content (e.g., total analogue content ≤1.0%, individual analogue content ≤0.10%) that must be maintained during production. These parameter specifications enable scalable manufacturing while ensuring consistent quality, as production processes can be optimized to meet these defined parameters.
3Measurement precision
If detection methods are developed without reference standards, then method development can begin immediately, but accurate detection and quantification of analogues cannot be achieved
Solution Approach 1:
The patent applies segmentation by dividing the complex task of quality control into manageable components: nine distinct analogues (analogue 1-9) are identified and synthesized as separate reference standards, each with specific detection requirements. This segmentation allows detection methods to be developed and validated for each analogue individually, simplifying the overall measurement system while maintaining high accuracy.
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
Ensures the production of highly pure compound 1 with suitable quality as a medicament by using these analogues as reference standards, confirming the presence and stability of impurities through methods like HPLC, thereby maintaining compliance with ICH standards.
Implementation Method 1
Analogues... can generally be detected by high-performance liquid chromatography
Data Source
AI summary
Provided is a novel compound serving as an analogue to be removed from API or a preparation. Further provided is a reference standard of an analogue for use in the quality control of a medicament. Analogue 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3′-di(propan-2-yl)-1′H-[1,4′-bipyrazolo[3,4-b]pyridin]-1′-yl}benzamide. Analogue 2: 3-ethyl-4-fluorobenzamide. Analogue 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide. Analogue 4: 3-ethyl-4-{14-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-13,23,33-tri(propan-2-yl)-31H-[11,24:21,34-terpyrazolo[3,4-b]pyridin]-31-yl}benzamide. Analogue 5: 4,4′-(1H,1′H-[4,4′-biimidazole]-1,1′-diylbis{[3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide). Analogue 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl }-3-ethylbenzonitrile. Analogue 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl }-3-ethylbenzamide. Analogue 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide. Analogue 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide.