Pralsetinib Solid Forms and Salts for Stable Oral Formulation
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Solution Overview
Problem
There is a need for identifying solid forms of pralsetinib suitable for the preparation of therapeutic compositions, including oral dosage forms, as therapeutic compounds often exist in various forms with different properties, and existing technologies have not effectively addressed this need.
Innovation Solution
The development of specific solid forms and salts of pralsetinib, including anhydrous and hydrated forms, characterized by XRPD, DSC, and DVS techniques, such as Solid Forms A, B, and C, and salts like benzenesulfonic acid, methanesulfonic acid, and hydrobromic acid salts, which are identified and produced through methods like slurry, evaporative crystallization, and antisolvent recrystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pralsetinib is used as a therapeutic compound, then RET signaling is attenuated and clinical responses are produced, but the compound exists in multiple solid forms with different properties that complicate pharmaceutical development
Solution Approach 1:
The patent systematically varies physical parameters (temperature, pressure, solvent composition, pH) during crystallization processes to generate and characterize multiple solid forms of pralsetinib. By controlling these parameters, the invention produces distinct polymorphic forms and salts with different physical properties suitable for pharmaceutical development
Solution Approach 2:
The patent divides the complex solid form landscape into distinct categories (anhydrous forms, hydrated forms, salts) and systematically characterizes each segment using specialized techniques (XRPD, DSC, DVS, TGA). This segmentation allows for targeted selection of optimal forms for pharmaceutical use
2Adaptability or versatility
If multiple salts and solid forms are generated, then pharmaceutical options increase, but characterization and selection processes become more complex
Solution Approach 1:
The patent employs a universal characterization framework that uses multiple analytical techniques (XRPD for structure, DSC for thermal properties, DVS for hygroscopicity, TGA for stability) to comprehensively evaluate all solid forms and salts. This multi-functional approach enables systematic comparison and selection of optimal pharmaceutical forms
Solution Approach 2:
The patent uses intermediary substances (counterions for salt formation, solvents for crystallization) to generate and differentiate solid forms. These intermediaries enable the creation of various pharmaceutical salts and polymorphic forms that can be systematically characterized and selected
3Measurement precision
If solid forms are characterized using multiple techniques, then identification accuracy improves, but analysis time and resource requirements increase
Solution Approach 1:
The patent performs preliminary characterization using rapid screening techniques (such as DVS for hygroscopicity assessment) to quickly identify promising solid forms before undertaking more time-consuming analyses. This preliminary action filters out unsuitable forms early, reducing overall characterization time while maintaining high accuracy
Data Source
AI summary
The compound cis)-N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4 methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide can be prepared as a free base in various crystalline solid forms, and in various salt forms each having one or more solid forms.