TETA Tetrahydrochloride Crystal Form for Room-Temperature Stability
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Solution Overview
Problem
Existing forms of triethylenetetramine tetrachloride (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, requiring special storage 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
1Stability of the object's composition
If conventional crystallization methods are used to produce TETA.4HCl, then the salt 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 conditions, specifically controlling temperature (0-30°C) and the rate of anti-solvent addition to produce a new crystalline form (Form B) with improved stability properties. This resolves the contradiction by changing the physical parameters of the crystallization process to obtain a more stable polymorph.
Solution Approach 2:
The patent utilizes phase transitions by inducing controlled crystallization from solution to solid phase. By carefully controlling the phase transition conditions (temperature, anti-solvent addition rate), the patent obtains a specific crystalline form (Form B) that exhibits superior stability and reduced humidity sensitivity compared to conventionally prepared forms.
2Reliability
If TETA.2HCl is used for treating Wilson's disease, then copper chelating properties are achieved, but the salt requires storage under reduced temperature conditions
Solution Approach 1:
The patent changes the crystallization parameters (temperature range of 0-30°C, controlled anti-solvent addition) to produce TETA.4HCl in a stable crystalline form that can be stored at room temperature, eliminating the need for refrigerated storage while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent produces a composite crystalline structure (Form B) with specific molecular arrangement that inherently provides stability against humidity and temperature variations, allowing room temperature storage without compromising the copper chelating therapeutic properties.
3Ease of operation
If high humidity conditions are present, then TETA.4HCl becomes unstable and requires special storage, but ambient conditions are more convenient for patient compliance
Solution Approach 1:
The patent modifies the crystallization parameters to produce a crystalline form stable in humid environments. By controlling temperature and anti-solvent addition rate, the resulting Form B exhibits resistance to humidity-induced degradation, enabling storage under ambient conditions that improve patient compliance.
Solution Approach 2:
The patent creates a formulation that eliminates the need for expensive specialized storage infrastructure (refrigeration). The stable crystalline form can be stored in常规 conditions, reducing infrastructure costs and simplifying distribution while maintaining stability.
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 B exhibits enhanced stability at room temperature and in humid environments, allowing for the development of stable oral formulations for treating Wilson's disease without the need for special storage conditions.
Implementation Method 1
a new crystalline form of TETA.4HCl, known as Form B, can be produced by carefully controlling the conditions of manufacture, in particular the temperature and rate of crystallisation
Data Source
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.