Remdesivir Salt Forms Enhancing Solubility and Stability
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Solution Overview
Problem
Remdesivir exhibits low solubility and poor aqueous chemical stability, limiting its oral bioavailability and requiring intravenous administration, which restricts its widespread distribution and treatment options for viral infections like COVID-19.
Innovation Solution
Development of novel salts and crystalline forms of remdesivir, such as napsylate, tosylate, hydrochloride, phosphate, maleate, and oxalate, which offer improved properties like increased solubility, stability, and bioavailability, enabling the creation of new formulations and dosage forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If remdesivir is administered intravenously to improve solubility and stability, then aqueous solubility and chemical stability are improved, but oral bioavailability remains poor and distribution is limited
Solution Approach 1:
The patent applies parameter changes by creating multiple salt forms of remdesivir (hydrochloride, phosphate, maleate, oxalate, napsylate, tosylate) to alter the physical and chemical properties of the drug substance. These salt forms exhibit different solubility, stability, and dissolution characteristics, enabling optimization for specific administration routes and patient populations while maintaining therapeutic effectiveness.
2Ease of manufacture
If known crystalline forms of remdesivir are used, then manufacturing is simplified, but solubility and bioavailability are insufficient
Solution Approach 1:
The patent systematically varies the counterion and crystal structure parameters to generate multiple crystalline forms and salt forms of remdesivir. Each form is characterized by distinct PXRD patterns, dissolution rates, and solubility profiles, allowing selection of forms that balance manufacturability with improved pharmacokinetic properties.
3Reliability
If remdesivir is formulated with solubilizing agents like SBECD, then aqueous solubility is improved, but formulation complexity increases and oral bioavailability remains limited
Solution Approach 1:
The patent extracts and eliminates the need for complex solubilizing agents like SBECD by developing salt forms of remdesivir that inherently possess improved solubility and stability properties. The salt forms themselves serve as the solubilizing mechanism, simplifying the formulation by removing the need for separate solubilizing excipients while achieving comparable or superior aqueous solubility.
Data Source
AI summary
The present invention provides novel salts of remdesivir and crystalline forms thereof. Specific salts of remdesivir provided by the present invention include napsylate, tosylate, hydrochloride, phosphate, maleate, and oxalate. Also provided are pharmaceutical compositions including the remdesivir salts and crystalline forms thereof, the use of these salts in the treatment of a viral infection, and methods of treating viral infections using the same, and in particular, a viral infection caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2).