Pralsetinib Solid Forms for Stable Oral Dosage Development
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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 chemical compounds can exist in various forms with different properties, and existing technologies have not adequately addressed this for RET inhibitor compounds like pralsetinib.
Innovation Solution
The development of specific solid forms and salts of pralsetinib, characterized by XRPD, DSC, and DVS techniques, including anhydrous and hydrated forms, and various polymorphs, such as Solid Forms A, B, and C, and salts like benzenesulfonic acid, methanesulfonic acid, and hydrobromic acid forms, which are produced through methods like slurry, evaporative crystallization, and antisolvent recrystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple solid forms and salts of pralsetinib are developed, then the stability and therapeutic efficacy of pharmaceutical compositions are improved, but the complexity of identifying and characterizing these forms increases
Solution Approach 1:
The patent segments the solid forms into distinct categories (anhydrous forms, hydrated forms, solvate forms) and characterizes each through specific techniques (XRPD, DSC, DVS, TGA). This segmentation allows systematic evaluation of each form's properties to identify the most suitable for pharmaceutical development.
Solution Approach 2:
The patent systematically varies physical and chemical parameters (temperature, humidity, solvent composition, pH) during the formation and characterization of solid forms. By changing these parameters, different polymorphic forms and salts are generated and evaluated for their stability and therapeutic properties.
2Adaptability or versatility
If multiple solid forms and salts are produced through various methods, then the versatility of pharmaceutical compositions is improved, but the manufacturing process complexity increases
Solution Approach 1:
The patent demonstrates that pralsetinib can be formulated into multiple solid forms (anhydrous, hydrated, solvate) and salt forms, each suitable for different pharmaceutical applications. This multi-functionality allows the same active ingredient to address various therapeutic needs while maintaining consistent efficacy.
Solution Approach 2:
The patent employs parameter changes in formulation processes (temperature, pH, solvent selection, drying conditions) to generate different solid forms and salts. By controlling these parameters, the manufacturing process can be optimized for each specific form while maintaining overall process manageability.
3Measurement precision
If solid forms are characterized using multiple techniques (XRPD, DSC, DVS, TGA), then the precision of form identification is improved, but the time and resources required for characterization increase
Solution Approach 1:
The patent assigns specific characterization techniques to specific form types: XRPD for crystalline structure identification, DSC for thermal properties, DVS for hygroscopicity, and TGA for thermal stability and composition. This segmented approach ensures precise identification while avoiding unnecessary techniques for each form.
Solution Approach 2:
The patent performs preliminary characterization steps (such as XRPD pattern analysis) that can predict or indicate the presence of specific forms before completing all detailed analyses. This preliminary action reduces the time required for comprehensive characterization by guiding which additional techniques are necessary.
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
These solid forms and salts of pralsetinib provide stable and effective pharmaceutical compositions with enhanced properties for treating RET-altered cancers, ensuring consistent therapeutic efficacy with reduced off-target toxicity.
Implementation Method 1
a X-ray powder diffraction (XRPD) pattern comprising characteristic diffraction peaks at 2-theta angles at approximately (±0.2 degrees) 5.0, 9.7, 12.7, 13.6, and 16.1
Implementation Method 2
a differential scanning calorimetry (DSC) thermogram with an endothermic event observed at about 205° C. (±0.2 degrees)
Implementation Method 3
a thermogravimetric analysis (TGA) having a mass loss associated with a broad endotherm with an onset of about 89° C. (e.g., 88.7° C.) and a melt onset at about 244° C. (e.g., 244.2° C.)
Implementation Method 4
a reversible mass change of about 10% by dynamic vapor sorption (DVS) between 2-95% relative humidity
Implementation Method 5
produced through methods like slurry, evaporative crystallization, and antisolvent recrystallization
Implementation Method 6
crystalline solid forms of the free base of pralsetinib... a first anhydrous solid form... a second anhydrous solid form... a hydrated solid form
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.