Anagrelide Hydrochloride Monohydrate Form II Crystallization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for producing anagrelide hydrochloride monohydrate are limited by the use of unsuitable solvents, instability, and uncertainty about the crystalline form, which affects its pharmaceutical properties and scalability.
Innovation Solution
Identification and stabilization of a new crystalline polymorph, form II of anagrelide hydrochloride monohydrate, characterized by a distinct XRPD pattern, which is more stable and soluble than form I, obtained through solvent-mediated polymorphic transition or reaction with hydrochloric acid in alcohols, avoiding high temperatures and hazardous solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional methods using acetonitrile/ether HCl or methanol/HCl are used to produce anagrelide hydrochloride monohydrate, then the salt can be formed, but the process uses hazardous solvents or less pharmaceutically acceptable solvents
Solution Approach 1:
The patent removes hazardous solvents (ether, acetonitrile, methanol) from the pharmaceutical manufacturing process and replaces them with safer alternatives (ethanol, water, isopropanol), thereby extracting the harmful elements while maintaining the salt formation capability
Solution Approach 2:
The patent changes the solvent system parameters from conventional organic solvents to pharmaceutically acceptable alcohols and water, modifying the chemical environment to achieve both safety and pharmaceutical compliance in the salt formation process
2Productivity
If reflux temperature is used for salt preparation as in prior art, then the reaction proceeds, but energy is wasted and decomposition risk increases
Solution Approach 1:
The patent performs salt formation at ambient or moderate temperatures without requiring reflux conditions, preparing the product under milder conditions that prevent decomposition and reduce energy consumption while maintaining reaction efficiency
Solution Approach 2:
The patent achieves complete salt formation without excessive heating, using moderate conditions that are sufficient for the reaction to proceed to completion, thereby avoiding energy waste associated with prolonged reflux
3Ease of manufacture
If conventional crystallization methods are used, then anagrelide hydrochloride monohydrate is obtained, but the crystalline form is uncertain and physical properties are not optimized
Solution Approach 1:
The patent modifies crystallization parameters by using specific pharmaceutically acceptable solvents and controlled temperature conditions to obtain a defined crystalline form with optimized physical properties, achieving both manufacturing simplicity and precision
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
Form II exhibits enhanced thermodynamic stability, improved solubility, and resistance to aqueous hydrolysis, making it a superior form for pharmaceutical compositions, particularly in formulations for treating essential thrombocythaemia.
Implementation Method 1
The present invention is based on the discovery of polymorphism and the identification of a specific useful polymorphic form of anagrelide hydrochloride monohydrate
Implementation Method 2
crystalline anagrelide hydrochloride monohydrate form I can generally be characterized by an XRPD pattern as shown in Figure 1
Implementation Method 3
characterized by an X-ray powder diffraction (XRPD) pattern comprising signals at diffraction angles
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present invention relates to crystalline form II of anagrelide hydrochloride monohydrate, processes for making it, and pharmaceutical compositions comprising it.