Tenofovir Prodrug Crystal Form A Bioavailability
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Solution Overview
Problem
Current tenofovir prodrugs, such as tenofovir disoproxil fumarate, face challenges with poor oral bioavailability and renal toxicity due to their negatively charged phosphate groups, which hinder effective membrane permeability and lead to rapid excretion and toxicity, necessitating the development of more stable and bioavailable forms.
Innovation Solution
A new crystal form of the tenofovir prodrug 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate, referred to as crystal form A, is developed, characterized by specific XRPD diffraction peaks and a sharp endothermic melting peak, which is prepared through dissolution in an organic solvent followed by cooling and filtration, offering improved stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tenofovir prodrug with phosphate group is used, then antiviral activity is achieved, but oral bioavailability is poor and renal toxicity occurs
Solution Approach 1:
The patent changes the chemical structure parameter by replacing the phosphate group with a phosphonamidate group, which alters the charge properties and membrane permeability of the drug molecule, thereby improving oral bioavailability while maintaining antiviral activity
Solution Approach 2:
The patent creates a composite molecular structure by combining the phosphonamidate group with specific amino acid derivatives (isopropoxycarbonyl-1-methyl]ethyl]amino]phenoxy), forming a complex prodrug molecule that achieves both good bioavailability and antiviral efficacy
2Duration of action of moving object
If tenofovir disoproxil fumarate is used, then pharmacokinetic properties are improved, but rapid hydrolysis occurs and renal toxicity risk increases
Solution Approach 1:
The patent changes the chemical stability parameter by using the phosphonamidate bond instead of the ester bond in TDF, which is not recognized by plasma esterases, thereby preventing rapid hydrolysis and reducing renal toxicity while maintaining duration of action
Solution Approach 2:
The patent extracts the vulnerable ester bond from the molecular structure and replaces it with a more stable phosphonamidate bond, removing the target site for esterase-mediated hydrolysis and thereby eliminating the pathway to renal toxicity
3Ease of manufacture
If different crystal forms are used, then bioavailability varies, but manufacturing consistency becomes difficult
Solution Approach 1:
The patent utilizes crystallization phase transition by dissolving the prodrug in organic solvent and controlling the cooling process to obtain a specific crystal form (Crystal Form A) with defined XRPD characteristics, ensuring consistent bioavailability and manufacturing precision
Solution Approach 2:
The patent changes the physical state parameter by controlling the crystallization conditions (solvent type, temperature, cooling rate) to obtain a specific polymorphic form with optimized bioavailability and consistent manufacturing characteristics
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
Crystal form A exhibits high bioavailability, stability, and purity, enhancing drug absorption and distribution, and is effective in maintaining therapeutic concentrations, thus improving the efficacy and safety of tenofovir treatment for HIV and hepatitis B.
Implementation Method 1
The XRPD spectrum of crystal form A according to the present invention comprises at least diffraction peaks at 2θ±0.20° of 5.08, 12.44, 13.18, 22.37, 23.37 and 28.56
Implementation Method 2
The XRPD spectrum of crystal form A according to the present invention comprises at least diffraction peaks at 2θ±0.20° of 5.08, 12.44, 13.18, 22.37, 23.37 and 28.56
Implementation Method 3
a preparation method thereof, comprising the following steps of: (1) dissolving any forms of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate into an organic solvent under heating; (2) cooling the solution of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate to precipitate a crystal
Implementation Method 4
cooling the solution of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate to precipitate a crystal
Implementation Method 5
dissolving any forms of 9-[(R)-2-[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate into an organic solvent under heating
Data Source
AI summary
A crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate of formula (I) is provided. Also provided is a preparation method and method of using the crystal form. Specifically, a crystal form of 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl]methoxyl]propyl]adenine fumarate of formula (I) having an X-ray powder diffraction (XRPD) spectrum including diffraction peaks at 2θ±0.20° of 5.08, 12.44, 13.18, 22.37, 23.37 and 28.56 is provided. The crystal form provided herein has high bioavailability, significant efficacy, good stability, high yield and high purity, and contributes to the selection and design of a drug administration route and the determination of process parameters of a pharmaceutical preparation, thereby improving drug production quality.