Crystalline Macrolide Forms for Anti-inflammatory Use
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Solution Overview
Problem
Conventional macrolide compounds with anti-inflammatory properties also exhibit strong antibacterial activity, limiting their use in chronic inflammatory processes not caused by pathogens due to the risk of developing resistant strains, and existing forms are unstable and difficult to handle.
Innovation Solution
Stable crystalline forms of the macrolide derivative (9S)-3-descladinosyl-3'-desmethyl-3'-acetyl-9-deoxo-9-dehydro-erythromicin A, referred to as crystalline Form I and Form II, are obtained through specific reaction conditions and solvents, providing improved stability and ease of handling, characterized by distinct X-ray diffraction patterns and differential scanning calorimetry curves, and can be converted between forms for enhanced pharmaceutical suitability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional macrolide compounds are used for anti-inflammatory treatment, then anti-inflammatory activity is achieved, but antibacterial activity causes development of resistant strains
Solution Approach 1:
The patent extracts and removes the antibacterial property from the macrolide compound while retaining the anti-inflammatory activity. This is achieved through specific chemical modification of the erythromycin structure (removal of cladinose sugar, demethylation, and dehydrogenation) to create a derivative that selectively maintains anti-inflammatory effects without antibacterial effects, thus eliminating the harmful development of bacterial resistance.
2Ease of manufacture
If amorphous form of the compound is used, then the compound can be produced, but stability and handling difficulty arise
Solution Approach 1:
The patent utilizes phase transition from amorphous to crystalline form to improve the compound's properties. By inducing crystallization through specific solvents and conditions, the compound transitions from an unstable amorphous state to a stable crystalline state, thereby improving stability, purity, and handling characteristics while maintaining manufacturability.
3Productivity
If amorphous form of the compound is used, then the compound can be isolated, but purity and stability problems occur
Solution Approach 1:
The patent employs crystallization (phase transition) as a purification mechanism. The transition from amorphous to crystalline form selectively incorporates the pure compound into the crystal lattice while excluding impurities, thereby achieving both efficient isolation and high purity simultaneously.
Solution Approach 2:
The patent uses specific solvents as intermediaries to facilitate the crystallization process. These solvents mediate the transition from amorphous to crystalline form and assist in excluding impurities from the crystal structure, thereby improving both isolation efficiency and purity.
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 stable crystalline forms exhibit improved solubility, stability, and manufacturability, making them suitable for broader therapeutic use without antibiotic activity, addressing the limitations of amorphous forms and enabling effective treatment of inflammatory diseases.
Implementation Method 1
The crystallinity of the polymorphic forms was confirmed by measuring X-ray diffraction of a powder sample.
Implementation Method 2
Crystalline Form I is further characterized by providing a differential scanning calorimetry curve to have an onset of melting which is comprised in the range 163-174 °C
Data Source
Figure 1~2
Figure 3~4
AI summary
The present invention relates to macrolide compounds endowed with antiinflammatory activity and more particularly relates to new stable crystalline forms of a macrolide derivative with antiinflammatory activity, processes for the preparation of such forms, pharmaceutical compositions containing them as active ingredient and the use of said crystalline Forms for the treatment of inflammatory diseases.