High-Purity Cyclopeptide Crystallization via pH Control
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Solution Overview
Problem
The compound of formula I is difficult to crystallize and typically exists in an amorphous state, making it challenging to achieve stability and purity necessary for storage and use as a drug intermediate, particularly for antifungal applications.
Innovation Solution
Crystals of the compound of formula I are formed by dissolving it in water or a mixture of water-miscible lower alcohols, maintaining the solution at saturated solubility and controlling the pH within a specified range, followed by in-vacuo drying to control crystal water content, resulting in various stable crystal forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the compound of formula I is crystallized using conventional methods, then the crystal form can be obtained, but the crystallization is difficult and the compound typically exists in an amorphous state with poor stability
Solution Approach 1:
The patent applies parameter changes by controlling pH within a specified range (pH 2.0-5.0, preferably pH 3.0-4.0) and controlling the solvent system composition (water-miscible lower alcohol content of 10-50% v/v) to enable successful crystallization of compound of formula I, transforming it from an amorphous state to stable crystal forms with defined XRPD patterns
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process to form specific crystal forms (Crystal Form A, B, C, D, E, F, G) from the amorphous state, where each crystal form has distinct X-ray powder diffraction patterns and stability characteristics, allowing selection of the most stable form for storage and use
2Stability of the object's composition
If the compound is stored in amorphous state, then it can be easily handled, but it lacks stability and purity necessary for storage and use as drug intermediate
Solution Approach 1:
The patent applies parameter changes by optimizing crystallization conditions including pH control (pH 2.0-5.0), solvent system composition (water-miscible lower alcohol 10-50% v/v), and temperature control to achieve high-purity crystal forms with reduced impurities, meeting the purity requirements for drug intermediates
Solution Approach 2:
The patent applies extraction by using solvent systems comprising water and water-miscible lower alcohols to selectively crystallize the compound of formula I from reaction mixtures, separating it from impurities and achieving high purity crystal forms suitable for pharmaceutical use
3Productivity
If conventional crystallization methods are used, then the process is simple, but the yield and purity of the final product are insufficient
Solution Approach 1:
The patent applies parameter changes by optimizing multiple crystallization parameters including pH (2.0-5.0), solvent composition (water-miscible lower alcohol 10-50% v/v), and temperature to simultaneously achieve high yield and high purity crystal forms, resolving the contradiction between productivity and manufacturing precision
Solution Approach 2:
The patent applies universality by developing a multi-functional crystallization method that can produce multiple stable crystal forms (A-G) with different characteristics from the same compound, allowing selection based on specific requirements for stability, purity, and downstream processing needs
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
This method produces crystals with improved stability and high purity, suitable for storage and use, reducing impurities and simplifying the purification process for the compound, leading to enhanced yield and stability of the final product.
Implementation Method 1
crystals with different crystal forms can be prepared by using different solvent systems and drying methods
Implementation Method 2
The crystal of compound of formula I will lose crystal water during in-vacuo drying
Data Source
Figure 1~2
Figure 3
Figure 4~5
AI summary
A high purity cyclopeptide crystal has a structure shown by Formula I. R represents H or a cation forming a pharmaceutically acceptable salt. Also disclosed are a preparation method and a use of the high-purity cyclopeptide crystal.