Crystalline Indocyanine Green for Stable Aqueous Injection
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Solution Overview
Problem
Existing indocyanine green (ICG) formulations suffer from poor stability and solubility, especially in aqueous environments, limiting their use in time-sensitive medical procedures and posing safety risks due to the use of iodine as a solubility enhancer.
Innovation Solution
A method for preparing a crystalline form of ICG using sodium chloride salification, followed by purification steps, resulting in a crystalline form with specific X-ray diffraction peaks and improved purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If ICG is supplied as lyophilized powder and dissolved in sterile water, then it can be administered intravenously, but it exhibits poor stability in aqueous environments and degrades rapidly
Solution Approach 1:
The patent changes the physical state parameter of ICG from amorphous solid to crystalline solid, which fundamentally alters its stability characteristics. The crystalline form exhibits enhanced structural order and reduced molecular mobility, preventing degradation pathways that occur in amorphous forms, thereby achieving both injectability and long-term aqueous stability.
Solution Approach 2:
The patent utilizes phase transition from amorphous to crystalline state to transform the stability profile of ICG. This phase change reorganizes the molecular packing and intermolecular interactions, creating a more stable solid form that maintains integrity both in solid state and upon dissolution, thus resolving the contradiction between ease of administration and aqueous stability.
2Quantity of substance
If ICG concentration in aqueous solution exceeds 5 mg/ml, then adequate levels for medical applications are achieved, but solubility decreases
Solution Approach 1:
The patent changes the physical form of ICG from amorphous to crystalline, which alters its solubility characteristics. The crystalline form provides a more ordered molecular structure that dissolves more efficiently in aqueous environments, enabling higher concentrations (>5 mg/ml) to be achieved without precipitation or solubility limitations.
3Ease of manufacture
If sodium iodide is added to improve ICG solubility, then solubility increases, but iodine poses allergen risk and safety concerns
Solution Approach 1:
The patent extracts and eliminates the harmful iodine component from the solubility enhancement strategy. Instead of relying on iodine-containing additives, the invention achieves improved solubility through the inherent properties of the crystalline ICG form itself, thereby removing the allergen risk while maintaining the desired solubility and concentration capabilities.
4Ease of manufacture
If amorphous form of ICG is used, then preparation is simpler, but long-term storage stability is limited
Solution Approach 1:
The patent applies phase transition from amorphous to crystalline state to transform the storage stability of ICG. The crystalline form, with its ordered molecular structure and reduced molecular mobility, resists degradation pathways that plague amorphous forms, thereby achieving long-term storage stability while maintaining preparation feasibility through controlled crystallization processes.
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 crystalline ICG exhibits enhanced purity (>99.8%), stability up to 2 years in solid form and 6 days in aqueous solution, and reduced impurities, making it suitable for long-term storage and use in medical diagnostics.
Implementation Method 1
A method for preparing a crystalline form of ICG using sodium chloride salification
Implementation Method 2
characterized by a powder X-ray diffraction pattern presenting at least peaks at 20.66, 14.38, 12.81, 4.22 and 3.83 degrees 2 theta
Implementation Method 3
crystalline form of indocyanine green which is characterized by a powder X-ray diffraction pattern
Implementation Method 4
followed by purification steps, resulting in a crystalline form with specific X-ray diffraction peaks and improved purity and stability
Data Source
AI summary
A novel method for the preparation of indocyanine green. The method involves converting 4-[2-[7-[1, 1-dimethyl-3-(4-sulfobutyl)benzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonic acid to indocyanine green by treatment with sodium chloride. A crystalline form of indocyanine green is also described, along with a, pharmaceutical compositions comprising the same, and to methods of using the same as a medicament or a diagnostic agent.