PDE3/PDE4 Dual-Inhibitor Crystalline Forms for Solubility and Stability
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Solution Overview
Problem
Existing PDE3/PDE4 inhibitors, such as RPL554 and RPL565, exhibit poor solubility, high plasma clearance, and insufficient anti-inflammatory effects, necessitating the development of a compound with improved PDE3/4 inhibitory activity and enhanced physicochemical properties for effective bronchodilation and anti-inflammatory treatment of chronic obstructive pulmonary disease (COPD).
Innovation Solution
The development of crystalline forms of a PDE3/PDE4 dual inhibitor with specific X-ray diffraction patterns and thermal properties, including crystalline forms A, B, C, and their respective pharmaceutically acceptable salts, which are prepared through precipitation in solvents like methanol, ethanol, water, and acetonitrile, to enhance stability, solubility, and pharmaceutical properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing PDE3/PDE4 inhibitors (RPL554, RPL565) are used, then bronchodilation effect is achieved, but solubility is poor and plasma clearance is high
Solution Approach 1:
The patent changes the physical and chemical parameters of the compound by developing multiple crystalline forms (Forms A, B, C) with different crystal structures. This transforms the physical state and improves solubility and stability parameters while maintaining the PDE3/PDE4 inhibitory activity for bronchodilation.
Solution Approach 2:
The patent creates composite crystalline structures through the formation of different crystalline forms and their respective salts (sulfate, p-toluenesulfonate, methanesulfonate, maleate). These composite structures combine the active ingredient with counterions or solvents in specific crystalline arrangements to optimize both bronchodilation efficacy and solubility.
2Reliability
If existing PDE3/PDE4 inhibitors are used, then bronchodilation is achieved, but anti-inflammatory effect is insufficient
Solution Approach 1:
The patent modifies the pharmacological parameters of the compound through the development of new crystalline forms that may alter the compound's interaction with biological targets. This could enhance the anti-inflammatory effect while preserving bronchodilation activity.
Solution Approach 2:
The patent uses salts and crystalline forms as intermediary structures that may facilitate the compound's interaction with inflammatory mediators and PDE enzymes, thereby enhancing the anti-inflammatory effect while maintaining bronchodilation.
3Stability of the object's composition
If crystalline forms are developed to improve stability and solubility, then pharmaceutical properties are enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent segments the manufacturing process into distinct steps for preparing different crystalline forms (A, B, C) and their respective salts. Each crystalline form can be prepared through separate precipitation or crystallization processes, allowing for optimized manufacturing of each form while maintaining overall system stability.
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 crystalline forms provide improved stability, solubility, and pharmaceutical properties, facilitating a fixed dose regimen for simplified administration and enhanced therapeutic efficacy in treating COPD by dual targeting bronchodilation and anti-inflammation.
Implementation Method 1
crystalline forms of a PDE3/PDE4 dual inhibitor with specific X-ray diffraction patterns and thermal properties, including crystalline forms A, B, C, and their respective pharmaceutically acceptable salts, which are prepared through precipitation in solvents like methanol, ethanol, water, and acetonitrile
Implementation Method 2
crystalline form A of the compound of formula (I) having diffraction peaks in an X-ray powder diffraction pattern using Cu Kα radiation at the following 20 angles: 4.14±0.2°, 6.98±0.2°, 8.20±0.2° and 11.50±0.2°
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
Provided are a crystal of a tricyclic compound as shown in formula (I) or a pharmaceutically acceptable salt thereof and a preparation method therefor, and the use thereof in preparing a drug for treating PDE3- and/or PDE4-related diseases.