Remdesivir Isomorphs for Aqueous Solubility and Stability
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Solution Overview
Problem
Remdesivir, a broad-spectrum antiviral drug, faces challenges due to its limited aqueous solubility and chemical instability in aqueous media, requiring solubilizers that can have undesirable effects, and there is a need for improved synthesis methods and forms with enhanced pharmacological properties for effective parenteral administration.
Innovation Solution
A new method for synthesizing Remdesivir involves reacting (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one with iodopyrazole, followed by cyanation, hydrolysis, and condensation with 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate, resulting in a more aqueous-soluble form, and pharmaceutical compositions are developed for improved stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Remdesivir is administered parenterally, then effective treatment of viral infections is achieved, but poor aqueous solubility and chemical instability in aqueous media prevent effective formulation
Solution Approach 1:
The patent changes the physical form of Remdesivir from conventional crystalline forms to amorphous solid dispersions and liquid formulations, fundamentally altering the physical state parameters to achieve both parenteral administrability and aqueous solubility while maintaining antiviral effectiveness
Solution Approach 2:
The patent creates composite formulations by combining Remdesivir with suitable excipients and carriers in amorphous solid dispersion and liquid formulation systems, achieving synergistic effects that improve solubility and stability while maintaining therapeutic activity
2Stability of the object's composition
If solubilizers are combined with Remdesivir to improve solubility, then parenteral administration is enabled, but undesirable physiological effects and limitations are introduced
Solution Approach 1:
The patent extracts and eliminates the need for traditional solubilizers like polysorbate 80 and beta-cyclodextrin derivatives by developing alternative formulation approaches including amorphous solid dispersions and liquid formulations that achieve solubility without these problematic additives
Solution Approach 2:
The patent employs transient amorphous forms and liquid formulations that provide the necessary solubility and stability during administration but do not require long-term stability or leave harmful residues, effectively treating the problem without creating new ones
3Ease of manufacture
If conventional forms of Remdesivir are used, then manufacturing is established, but cold-chain storage and transport are required due to poor room-temperature stability
Solution Approach 1:
The patent changes the physical and chemical parameters of Remdesivir through amorphous solid dispersion and liquid formulation, fundamentally altering the stability characteristics to enable room-temperature storage and transport while maintaining manufacturability through adapted synthesis 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 new form of Remdesivir exhibits improved aqueous solubility and stability at room temperature, reducing the need for cold-chain storage and transport, and provides effective treatment for viral infections like COVID-19 with enhanced pharmacological properties.
Implementation Method 1
reacting (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one with iodopyrazole, followed by cyanation, hydrolysis, and condensation
Implementation Method 2
reacting (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one with iodopyrazole, followed by cyanation, hydrolysis, and condensation
Implementation Method 3
reacting (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one with iodopyrazole, followed by cyanation, hydrolysis, and condensation with 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate
Data Source
AI summary
A new isoform of 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3/4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate (Remdesivir) having increased water solubility is disclosed, along with methods for making the same. Also disclosed are solid and liquid pharmaceutical compositions suitable for treating viral infections such as Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, or Paramyxoviridae viral infections which contain an effective amount of Remdesivir prepared according to the inventive method and the use of those compositions for treating such viral infections.