Water-Soluble Butylphthalide Derivatives for Injectable Stroke Therapy
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Solution Overview
Problem
The S-configuration of 3-(3'-hydroxy)butylphthalide, an oily liquid insoluble in water, requires modification to form a water-soluble compound suitable for injectable formulations for treating ischemic stroke, as the R-configuration lacks efficacy in reducing cerebral infarct volume and improving symptoms.
Innovation Solution
Forming an ester with pharmaceutically acceptable acids, such as glycine, succinic acid, or phosphoric acid, and subsequently creating a salt to enhance water solubility, allowing for the preparation of injectable solutions or lyophilized powders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the S-configuration of 3-(3'-hydroxy)butylphthalide is used to treat ischemic stroke, then the therapeutic effect is improved, but the water solubility deteriorates because it is an oily liquid insoluble in water
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of the S-configuration of 3-(3'-hydroxy)butylphthalide through esterification reactions. The hydroxyl group is converted to ester groups with different acid radicals (aliphatic, aromatic, heterocyclic acids), which fundamentally changes the solubility parameter while preserving the therapeutic configuration. This allows the compound to become water-soluble or form soluble salts, resolving the contradiction between maintaining therapeutic efficacy and improving solubility for injectable formulations.
2Ease of operation
If the compound is modified to form water-soluble derivatives, then the ease of operation for injectable formulations is improved, but the chemical structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the modification approach into distinct categories: esterification with different types of acids (aliphatic, aromatic, heterocyclic), and subsequent salt formation with various bases. This systematic segmentation allows selection of the simplest effective derivative for each specific formulation need, balancing chemical structure complexity with ease of operation for injectable preparations.
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 resulting water-soluble compound effectively reduces cerebral infarct volume, improves ischemic stroke symptoms, and enhances sleep quality, with no observed muscular or vascular irritations upon administration, making it suitable for pharmaceutical use.
Implementation Method 1
Forming an ester with pharmaceutically acceptable acids, such as glycine, succinic acid, or phosphoric acid
Implementation Method 2
subsequently creating a salt to enhance water solubility, allowing for the preparation of injectable solutions or lyophilized powders
Data Source
AI summary
(-)-(S)-3-(3'-hydroxy)-butylphthalide (a compound shown by Formula I) and an ester formed of the same and an acid are proved by experiments to be applicable to treatment and prevention of cerebral ischemic diseases and have a sleep-improving function. The acid refers to a pharmaceutically acceptable inorganic or organic acid. The inorganic acid refers to nitric acid, sulfuric acid, or phosphoric acid. In addition to an acid radical, the organic acid at least comprises at least one of an amino group, a hydroxyl group, and a carboxyl group. None of the compound shown by Formula I and the ester thereof is water-soluble. An ester generated from the compound and the acid further react with an acid or a base to generate a salt which is water-soluble and is used to prepare injection preparation. The experiment proves that the salt does not stimulate vessels.