Trientine Tetrahydrochloride Crystallization for Stable Drug Storage
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Solution Overview
Problem
Existing methods for preparing trientine tetrahydrochloride (TETA • 4HCl) suffer from stability issues and complex processes, particularly with TETA • 4HCl Form B, which is less faded and more stable but requires low-temperature crystallization and seeding, making it inconvenient.
Innovation Solution
A method involving dissolving crude TETA • 4HCl in purified water, adding an anti-solvent like methanol at controlled temperatures for crystallization, and stirring for specific durations to produce TETA • 4HCl crystals (Form N), with steps to ensure low loss on drying and using a pharmaceutically acceptable vehicle for formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If TETA·4HCl is prepared by low-temperature crystallization and seeding as disclosed in TW202002956A, then the stability of the crystalline form is improved, but the process complexity and operational inconvenience increase
Solution Approach 1:
The patent changes the crystallization temperature parameter from low-temperature (prior art) to room temperature or higher, and modifies the crystallization method from seeding-dependent to spontaneous crystallization, thereby simplifying the process while maintaining stability
Solution Approach 2:
The patent performs preliminary acidification of the TETA·2HCl solution with hydrochloric acid before crystallization to ensure complete conversion to TETA·4HCl, which prevents stability issues during storage without requiring complex seeding procedures
2Manufacturing precision
If TETA·4HCl Form A is used in tablet manufacturing, then the initial crystalline form is obtained, but faded debris appear after six-month storage at 40°C and 75% RH indicating degradation
Solution Approach 1:
The patent changes the crystallization parameters (temperature, solvent ratio, acidification) to produce a more stable crystalline form that resists degradation under storage conditions, eliminating the faded debris issue observed with Form A
Solution Approach 2:
The patent applies preliminary acidification and controlled crystallization conditions to pre-stabilize the TETA·4HCl crystals before manufacturing, providing a buffer against degradation during storage and preventing the formation of degraded products
3Productivity
If conventional methods are used to prepare TETA·4HCl, then the basic product is obtained, but the yield and purity are insufficient for pharmaceutical applications
Solution Approach 1:
The patent performs preliminary acidification with hydrochloric acid to ensure complete conversion of TETA·2HCl to TETA·4HCl before crystallization, which maximizes both yield and purity by preventing incomplete reactions and impurity formation
Solution Approach 2:
The patent uses methanol as an intermediary anti-solvent to facilitate the crystallization of TETA·4HCl from the aqueous solution, enabling high-yield precipitation of pure crystals that can be easily separated and dried
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
The method yields TETA • 4HCl crystals with high stability and anti-moisture absorption, simplifying the preparation process and improving yield rates without the drawbacks of previous methods.
Implementation Method 1
an anti-solvent at a feeding temperature is added into a trientine tetrahydrochloride solution and stirred for crystallization wherein the feeding temperature ranges from 50°C to 75°C
Implementation Method 2
the step 1 further comprises drying crystals for LOD (loss on drying) of crystals
Data Source
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AI summary
A method of preparation of trientine tetrahydrochloride crystals in which an anti-solvent at a feeding temperature is added into a trientine tetrahydrochloride solution and stirred for crystallization wherein the feeding temperature ranges from 50°C to 75°C and the anti-solvent is an alcohol solvent. A novel trientine tetrahydrochloride featuring XRPD peaks detected at 21.9, 24.8, 25.2, 28.0 and 35.6±0.1° 20 for stable storage of a pharmaceutical composition manufactured with the trientine tetrahydrochloride.