Polymorph C and D Stability in Pyrimidinylamino-Pyrazole Kinase Inhibitors
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Solution Overview
Problem
The pharmaceutical industry faces challenges in manufacturing consistency due to the unpredictable behavior of polymorphs of drug substances, which affect bioavailability, shelf life, and physical-chemical properties, requiring the development of new polymorph forms and methods for their preparation.
Innovation Solution
The development of crystalline polymorphs C and D of a pyrimidinylamino-pyrazole kinase inhibitor, characterized by specific X-ray powder diffraction patterns and thermal stability, along with processes for their preparation, including heating and cooling in specific solvents, to achieve stable and therapeutically effective forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If multiple polymorph forms of a drug substance are present, then the drug can exhibit different physicochemical properties, but manufacturing consistency becomes difficult to achieve
Solution Approach 1:
The patent applies parameter changes by modifying crystallization conditions including temperature ranges (e.g., cooling from 40°C to 25°C), solvent compositions (e.g., acetonitrile/water ratios), and pH levels to selectively produce specific polymorph forms. This allows control over which polymorph is formed during manufacturing, ensuring consistency while leveraging the beneficial physicochemical properties of each form.
Solution Approach 2:
The patent employs preliminary action by pre-characterizing multiple polymorph forms and establishing their formation conditions before production. This includes determining XRPD patterns, stability profiles, and solubility characteristics of each polymorph in advance, allowing the manufacturer to select and control the formation of the desired polymorph form during manufacturing processes.
2Reliability
If different crystal phases are used, then bioavailability and shelf life can be optimized, but identifying and controlling polymorph interconversions becomes complex
Solution Approach 1:
The patent implements feedback mechanisms by using analytical techniques such as XRPD and DSC to monitor and identify polymorph forms during development and manufacturing. This feedback allows for real-time detection of polymorph formation and interconversion, enabling control strategies to maintain the desired polymorph form and ensure product reliability.
Solution Approach 2:
The patent utilizes phase transitions by studying the conditions under which different polymorph forms interconvert, including temperature-dependent transitions and solvent-induced transformations. By understanding these phase transition behaviors, the patent establishes storage and processing conditions that prevent unwanted polymorph interconversions, ensuring shelf life and bioavailability are maintained.
3Measurement precision
If comprehensive polymorph screening is performed, then all crystal phases can be identified, but the time and resources required increase significantly
Solution Approach 1:
The patent applies segmentation by dividing the polymorph screening process into focused segments based on specific formulation parameters and processing conditions. Instead of exhaustive screening of all possible conditions, the patent segments the study to examine polymorph formation under representative manufacturing and storage conditions, reducing time and resources while maintaining identification accuracy for clinically relevant forms.
Data Source
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AI summary
The present disclosure relates to crystalline polymorph and amorphous forms 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile or solvates, tautomers, and pharmaceutically acceptable salts or cocrystals thereof, and processes for their preparation.