Eravacycline Bis-HCl Crystal Forms for Stable Drug Formulation
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Solution Overview
Problem
There is a need for thermodynamically stable crystalline forms of eravacycline HCl salt with improved physical properties, such as solubility and chemical stability, suitable for pharmaceutical compositions, and capable of being produced in high yield and purity.
Innovation Solution
The development of crystalline forms of eravacycline HCl salt, specifically Form A, Form B, Form I, and Form J, characterized by distinct x-ray powder diffraction peaks, which can be identified through XRPD analysis, and further characterized by DSC and TGA, with potential solvates and co-solvates, enabling high-purity and high-yield production for pharmaceutical use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline forms of eravacycline HCl salt are developed for pharmaceutical use, then stability and solubility are improved, but manufacturing complexity increases due to the need to produce multiple crystalline forms with distinct properties
Solution Approach 1:
The patent segments the single compound eravacycline HCl salt into multiple distinct crystalline forms (Form A, Form B, Form I, Form J), each with unique XRPD patterns and physical properties. This segmentation allows optimization of different formulations for specific pharmaceutical applications while maintaining the core active ingredient identity.
Solution Approach 2:
The patent applies parameter changes by modifying the crystalline structure parameters of eravacycline HCl salt to create different polymorphic forms. Each form has distinct XRPD peak patterns, density, solubility, and stability characteristics, enabling selection of optimal forms for different pharmaceutical needs without changing the chemical composition.
2Ease of operation
If multiple crystalline forms are produced for pharmaceutical compositions, then solubility and flow properties are enhanced, but production yield and purity requirements become more stringent
Solution Approach 1:
The patent replaces mechanical purification methods with characterization-based identification. Each crystalline form is defined by its unique XRPD pattern, allowing non-destructive identification and quality control through diffraction analysis rather than complex mechanical separation and purification processes.
Solution Approach 2:
The patent creates replicated crystalline structures with consistent, reproducible properties. Each crystalline form serves as a standardized copy with defined characteristics, enabling consistent manufacturing quality across different production batches through controlled crystallization protocols.
3Measurement precision
If crystalline forms with distinct XRPD patterns are developed, then identification and quality control are improved, but the number of characterization parameters increases
Solution Approach 1:
The patent uses XRPD peak patterns as a 'fingerprint' or signature for each crystalline form, analogous to color identification. Each form (A, B, I, J) has a distinctive pattern of diffraction peaks at specific 2θ angles, providing rapid visual identification and quality control without complex additional characterization.
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 exhibit enhanced stability, solubility, and flow properties, facilitating the formulation of pharmaceutical compositions with improved efficacy and manufacturability.
Implementation Method 1
crystalline Form I is characterized by at least three x-ray powder diffraction peaks at 2θ angles selected from 7.22°, 7.80°, 10.41°, and 11.11°
Implementation Method 2
x-ray powder diffraction peaks at 2θ angles
Implementation Method 3
further characterized by DSC and TGA
Implementation Method 4
further characterized by DSC and TGA
Data Source
AI summary
The invention relates to crystalline forms of the bis-HCl salt of a compound represented by Structural Formula 1, and pharmaceutical compositions comprising crystalline forms of the bis-HCL salt of a compound represented by Structural Formula 1 described herein. The crystalline forms of the bis-HCl salt of a compound of Structural Formula 1 and compositions comprising the crystalline forms of the compound of Structural Formula 1 provided herein, in particular, crystalline Form I, crystalline Form J, crystalline Form A, and crystalline Form B, or mixtures thereof, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders. Also described herein are methods for preparing the crystalline forms (e.g., Forms I, J, B and A) of the bis-HCl salt of a compound represented by Structural Formula 1.