Remdesivir-DMSO Crystalline Form for Oral Bioavailability
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Solution Overview
Problem
Remdesivir's limited aqueous solubility and poor oral bioavailability due to its crystalline forms require intravenous administration, limiting its widespread distribution for COVID-19 treatment, and existing forms are chemically unstable in aqueous environments, necessitating the development of novel crystalline forms with improved properties.
Innovation Solution
A crystalline form of remdesivir is developed that incorporates dimethyl sulfoxide in its crystal lattice, characterized by specific PXRD and DSC patterns, and prepared through a process involving solution preparation and cooling with an organic anti-solvent, enhancing solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If Form II crystalline form of remdesivir is used, then the drug can be manufactured with established crystalline form, but the aqueous solubility is limited requiring intravenous administration
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing a new crystalline form (Form I) of remdesivir with different physical properties, specifically higher aqueous solubility compared to Form II. This allows the drug to potentially be administered orally instead of intravenously, while still being manufacturable using crystallization processes.
Solution Approach 2:
The patent creates a composite crystalline system by forming a co-crystal or solvate structure of remdesivir with dimethyl sulfoxide (DMSO). This composite structure fundamentally alters the solubility properties of remdesivir, enabling improved aqueous solubility and potential oral bioavailability while maintaining the active pharmaceutical ingredient's therapeutic function.
2Ease of manufacture
If Form II crystalline form of remdesivir is used, then the manufacturing process is established, but the chemical stability in aqueous environment is poor
Solution Approach 1:
The patent changes the crystalline form parameter from Form II to Form I, which exhibits superior chemical stability in aqueous environments. This parameter change resolves the contradiction by maintaining manufacturability through crystallization while achieving the desired stability profile for drug storage and administration.
Solution Approach 2:
The formation of a composite crystalline structure with DMSO creates a more stable molecular arrangement that protects remdesivir from degradation in aqueous environments. This composite material approach simultaneously improves both the stability and solubility properties of the drug substance.
3Reliability
If poor oral bioavailability is accepted, then intravenous administration can be implemented, but widespread distribution is limited
Solution Approach 1:
The patent changes the bioavailability parameter by discovering Crystalline Form I with improved aqueous solubility characteristics. This enables the development of oral dosage forms, significantly expanding distribution capability and accessibility while maintaining reliable efficacy delivery through the same active ingredient.
4Quantity of substance
If different crystalline forms are used, then solubility properties may improve, but the crystal packing and physical characteristics change affecting formulation
Solution Approach 1:
The patent carefully controls the crystallization parameters to produce Crystalline Form I with consistent and reproducible physical characteristics. By establishing specific crystallization conditions, the patent achieves both improved solubility and formulation consistency, resolving the contradiction between solubility improvement and manufacturing precision.
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 remdesivir-dimethyl sulfoxide crystalline form improves solubility and stability, potentially enabling oral administration and broader distribution for COVID-19 treatment, while maintaining safety and industrial compatibility.
Implementation Method 1
A crystalline form of remdesivir is developed that incorporates dimethyl sulfoxide in its crystal lattice
Implementation Method 2
preparation process involving solution preparation and cooling with an organic anti-solvent
Data Source
AI summary
The present invention provides a novel crystalline form of remdesivir, remdesivir Form APO-I, including remdesivir and dimethyl sulfoxide, compositions and processes for the preparation thereof, the use of this crystalline form 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).