L-lysine Salt Crystallization of Rx100 Phosphorothioate
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Solution Overview
Problem
The existing forms of (Z)-O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate (Rx100) have poor stability, solubility, and handling issues due to its oily nature and sensitivity, and previous attempts to form desirable salt forms like sodium or potassium salts have been unsuccessful, leading to instability and impurity incorporation.
Innovation Solution
Formation of crystalline or semi-crystalline salts with L-lysine base, specifically mono-, sesqui-, or di-L-lysine salts, which exhibit improved solubility, stability, and purity, and are characterized by XRPD, NMR, and thermal analysis, resulting in a more stable and filterable form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If Rx100.FA is stored at less than -20°C, then short-term stability is preserved, but handling difficulty and operational complexity increase
Solution Approach 1:
The patent transforms the physical state parameter of Rx100 from oily liquid to crystalline solid through salt formation with L-lysine, enabling storage at ambient temperatures while maintaining stability, thus eliminating the need for cold storage and improving handling ease
2Quantity of substance
If sodium or potassium salts are formed, then solubility may improve, but filterability deteriorates as they fail to yield filterable solids
Solution Approach 1:
The patent changes the counterion parameter from sodium/potassium to L-lysine, which enables the formation of filterable crystalline solids that maintain good solubility properties, simultaneously satisfying both filterability and solubility requirements
3Ease of manufacture
If ammonia salt is formed through freeze-drying, then a solid powder is obtained, but stability and purity worsen due to ammonia loss, moisture absorption, and impurity incorporation
Solution Approach 1:
The patent replaces the unstable ammonia salt with L-lysine salt that does not lose its counterion during storage, eliminating the need for freeze-drying and providing a stable solid form that resists moisture absorption and impurity incorporation
Solution Approach 2:
The patent changes the counterion from ammonia to L-lysine, which provides a stable crystalline solid that maintains its composition during storage and handling, improving both stability and purity
4Ease of operation
If Rx100.FA is used in oily form, then it is easy to handle initially, but stability and solubility deteriorate over time
Solution Approach 1:
The patent transforms the physical state from oily liquid to crystalline solid through salt formation, which improves long-term stability and solubility while maintaining ease of handling in solid form through standard pharmaceutical processing
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 L-lysine salts of Rx100 display enhanced stability, solubility, and reduced impurity levels, offering a more practical and effective pharmaceutical form for use, particularly in mitigating gastrointestinal acute radiation syndrome by activating LPAR2 receptors.
Implementation Method 1
Formation of crystalline or semi-crystalline salts with L-lysine base
Implementation Method 2
characterized by XRPD, NMR, and thermal analysis
Implementation Method 3
characterized by XRPD, NMR, and thermal analysis
Data Source
Figure 1
Figure 2
Figure 2a
AI summary
Here provided are a salt of Z)-O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate with an L-lysine addition in crystalline form and methods of making and using the same.