TETA.4HCl Form B Crystallization for Ambient Stability
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Solution Overview
Problem
Existing forms of triethylenetetramine tetrahydrochloride (TETA.4HCl) are unstable at room temperature and sensitive to humidity, making them challenging to formulate into stable oral treatments for conditions like Wilson's disease, which requires storage under special conditions.
Innovation Solution
A new crystalline form of TETA.4HCl, known as Form B, is produced by carefully controlling the crystallization conditions, particularly temperature and rate of anti-solvent addition, resulting in improved stability and handling properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional crystallization methods are used to produce TETA.4HCl, then the compound can be obtained, but it exhibits poor stability at room temperature and high sensitivity to humidity
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization temperature (maintaining 0-15°C throughout the process) and the rate of anti-solvent addition (0.5-2 mL/min) to obtain a specific crystalline form (Form B) with improved stability properties. This controlled parameter approach produces crystals that are stable at room temperature and less sensitive to humidity compared to conventionally produced TETA.4HCl
Solution Approach 2:
The patent utilizes phase transitions during the crystallization process, where TETA.4HCl transitions from dissolved state to crystalline solid form under controlled conditions. The slow addition of anti-solvent at low temperature induces controlled phase transition that forms a stable crystalline structure (Form B) with improved storage properties and reduced hygroscopicity
2Reliability
If TETA.2HCl is used for treating Wilson's disease, then copper chelating properties are achieved, but the treatment requires storage under reduced temperature conditions
Solution Approach 1:
The patent changes the physical parameters of the compound by producing a new crystalline form (Form B) through controlled low-temperature crystallization. This structural modification enables the compound to maintain stability at room temperature, eliminating the need for refrigerated storage while preserving the copper chelating activity required for Wilson's disease treatment
3Ease of manufacture
If anti-solvent crystallisation is carried out at room temperature, then TETA.4HCl can be produced, but it results in a crystalline form with poor handling properties and stability
Solution Approach 1:
The patent modifies the crystallization temperature parameter from room temperature to low temperature (0-15°C) and controls the anti-solvent addition rate. This parameter change transforms the product quality from unstable Form A to stable Form B, while the process remains manufacturable through automated controlled addition systems
Solution Approach 2:
The patent applies preliminary action by pre-cooling the reaction mixture to 0-15°C before initiating anti-solvent addition and maintaining this temperature throughout the crystallization process. This preliminary temperature control ensures that the stable crystalline form (Form B) nucleates and grows correctly, preventing formation of the unstable room temperature form
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
TETA.4HCl Form B exhibits enhanced storage stability at ambient conditions, reducing the risk of discoloration and maintaining its crystalline form over time, suitable for formulation into stable oral treatments.
Implementation Method 1
a new crystalline form, known herein as Form B, can be produced by carefully controlling the conditions of manufacture, in particular the temperature and rate of crystallisation
Data Source
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AI summary
The present invention describes a new crystalline form of triethylenetetramine tetrachloride which has improved room temperature stability over known forms and over the dichloride salt. The new crystalline form is characterised by having peaks in an XRPD spectrum at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3 ± 0.1°2Θ and Raman shifts 943, 1173, 1527 and 1612 ± 5 cm-1. The crystalline form of triethylenetetramine tetrachloride is useful in the treatment of Wilson's disease. Also disclosed is a method for preparing a crystalline form of triethylenetetramine tetrachloride comprising the addition of an anti- solvent to an aqueous solution of the compound.