PLK1 Inhibitor Crystal Salts for Stability and Oral Bioavailability
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Solution Overview
Problem
Current PLK1 kinase inhibitors, such as volasertib and onvansertib, face challenges with high adverse events, low bioavailability, and narrow safety margins, necessitating the development of compounds with high selectivity and better safety for clinical use.
Innovation Solution
Development of specific crystal forms and pharmaceutically acceptable salts of a PLK1 kinase inhibitor, including maleate, fumarate, and succinate forms, characterized by distinct X-ray diffraction peaks, and preparation methods involving solvent and anti-solvent crystallization techniques.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous drug products are used, then ease of manufacture is improved, but product stability deteriorates due to poor crystallization, agglomeration, and flowability
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the drug from amorphous to crystalline form. Specifically, it develops three distinct crystal forms (Crystal Form A, B, and C) with different X-ray diffraction patterns, thereby changing the structural parameters of the compound to achieve both manufacturability and stability.
Solution Approach 2:
The patent creates composite material systems by forming salts of the PLK1 inhibitor with different counterions (sulfate, maleate, fumarate, succinate, tartrate, citrate, aspartate, glutamate, hippurate, benzenesulfonate, tosylate, methanesulfonate, and camphorsulfonate). Each salt form exhibits distinct crystalline properties that balance manufacturing ease with product stability.
2Reliability
If volasertib is used as injection, then anti-tumor effect is improved, but adverse events increase due to higher-grade toxicity
Solution Approach 1:
The patent changes the chemical parameters of the PLK1 inhibitor by developing multiple salt forms with different solubility and pharmacokinetic properties. This allows optimization of the drug's safety profile while maintaining anti-tumor efficacy, potentially enabling oral administration routes with reduced toxicity.
Solution Approach 2:
The patent applies local quality by creating salt forms with specific local properties (solubility, stability, bioavailability) tailored for different administration routes and therapeutic needs, allowing selective optimization of efficacy versus toxicity for different clinical scenarios.
3Ease of operation
If onvansertib is used as oral preparation, then ease of administration is improved, but bioavailability decreases and safety margin narrows
Solution Approach 1:
The patent changes the physicochemical parameters of the oral PLK1 inhibitor by developing multiple salt forms with enhanced solubility and stability characteristics. This improves oral bioavailability while maintaining ease of administration, and allows for optimized dosing that expands the safety margin.
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 crystal forms and salts exhibit improved stability and bioavailability, enhancing the safety and efficacy of PLK1 kinase inhibitors for clinical applications, particularly in treating tumors and other dysregulated kinase activity-related diseases.
Implementation Method 1
having, in an X-ray powder diffraction pattern using Cu-Kα radiation, characteristic diffraction peaks at the following 2θ angles: 4.807±0.2°, 8.532±0.2°, 11.645±0.2°, 15.160±0.2°, 18.347±0.2°, and 25.514±0.2°
Implementation Method 2
The pharmaceutical form (e.g., crystal form or salt) of a compound often affects the chemical stability of the drug. Differences in crystallization conditions and storage conditions may lead to changes in the crystal form structure of the compound
Data Source
Figure 1-1~1-3
Figure 2-1~2-3
Figure 3-1~3-3
AI summary
Provided are a salt form and a crystal form of a PLK1 kinase inhibitor, and a preparation method therefor and the use thereof. Specifically, provided are a salt form and a crystal form of a compound of formula I, a preparation method therefor, and the use thereof in the preparation of a drug for diseases caused by and/or related to PLK1 kinase activity disorders.