Stable TETA.4HCl Crystal Form for Ambient Wilson's Disease Treatment
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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 difficult 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 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 carefully controlling crystallization conditions including temperature (maintaining between 0-25°C, preferably 5-15°C), pH (maintaining between 1-3, preferably 1.5-2.5), and the rate of anti-solvent addition (0.1-1 mL/min). These parameter optimizations produce a new crystalline form (Form B) with improved stability and reduced humidity sensitivity compared to conventional methods
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process to form a specific crystalline phase (Form B) with distinct XRPD patterns. The controlled transition from solution to solid phase under specific conditions creates a stable polymorph that resists humidity-induced transformation, solving the stability issue
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 which is cumbersome for patients
Solution Approach 1:
The patent changes the physical-chemical parameters of the compound by producing a new crystalline form (TETA.4HCl Form B) with different lattice structure and intermolecular interactions. This structural modification maintains the copper chelating pharmacological activity while dramatically improving thermal and humidity stability, enabling room temperature storage without special conditions
3Productivity
If anti-solvent crystallization is performed at room temperature without controlled addition rate, then crystallization occurs quickly, but the resulting crystals have poor stability and handling properties
Solution Approach 1:
The patent applies dynamics by implementing a controlled, gradual addition of anti-solvent at a specific rate (0.1-1 mL/min) rather than rapid addition. This dynamic control of the crystallization process allows for the formation of stable crystal nuclei and proper lattice development, producing Form B crystals with both acceptable production speed and superior stability characteristics
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 maintains its crystalline structure and stability under ambient conditions, reducing the need for special storage and enhancing the formulation of stable oral treatments for Wilson's disease.
Implementation Method 1
The present inventors have found that by carefully controlling the conditions of manufacture, in particular the temperature and rate of crystallisation, a new crystalline form, known herein as Form B, can be produced
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.