Sodium Salt Crystal Forms for Stable HIV Integrase Inhibitors
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Solution Overview
Problem
The emergence of drug-resistant strains of integrase inhibitors for HIV treatment necessitates the development of highly stable and effective integrase inhibitors that can overcome resistance while maintaining low toxicity.
Innovation Solution
The development of sodium salt crystal forms A and B of an HIV integrase inhibitor molecule, characterized by specific X-ray powder diffraction peaks and thermal stability, is achieved through crystallization using sodium hydroxide in various organic solvents, enhancing stability, solubility, and hygroscopicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If new integrase inhibitors are developed to overcome drug-resistant strains, then antiviral efficacy against resistant strains is improved, but drug stability and formulation properties may deteriorate
Solution Approach 1:
The patent applies parameter changes by converting the compound to its sodium salt form, which fundamentally alters the chemical parameters (pKa, solubility, hygroscopicity) of the molecule. This transformation maintains antiviral efficacy against resistant strains while significantly improving storage stability and formulation properties, directly resolving the contradiction between efficacy and stability.
Solution Approach 2:
The patent creates a composite crystalline structure by forming sodium salt crystals with specific polymorphic forms (Crystal Form A and Crystal Form B). These composite crystal structures incorporate the active pharmaceutical ingredient in a stable lattice arrangement, enhancing overall drug stability while preserving the biological activity needed to combat resistant strains.
2Reliability
If integrase inhibitors are used to treat HIV, then antiviral efficacy is improved, but drug resistance develops over time
Solution Approach 1:
By transforming the compound to sodium salt form with modified physicochemical parameters, the patent creates a derivative that maintains high binding affinity to integrase enzyme while presenting a novel molecular profile to the virus. This parameter change helps prevent resistance development by altering the drug's interaction characteristics with the viral target.
3Stability of the object's composition
If compound is converted to sodium salt form, then solubility and stability are improved, but manufacturing complexity increases
Solution Approach 1:
The patent utilizes phase transition principles by controlling the crystallization process to form specific polymorphic forms (Crystal Form A or B) of the sodium salt. By manipulating crystallization conditions (solvent selection, temperature, pH), the patent achieves controlled phase transitions that yield stable, soluble crystal forms with defined manufacturing protocols, balancing improved properties with manufacturability.
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 sodium salt crystal forms exhibit high stability, solubility, and low hygroscopicity, making them suitable for pharmaceutical compositions to treat HIV infections, with improved drug processing and formulation properties.
Implementation Method 1
The development of sodium salt crystal forms A and B of an HIV integrase inhibitor molecule, characterized by specific X-ray powder diffraction peaks and thermal stability, is achieved through crystallization using sodium hydroxide
Implementation Method 2
the sodium salt crystal form A has the following X-ray powder diffraction characteristic peaks (2 θ angle): 15.587 °± 0.2 °, 9.107 °± 0.2 °, 24.121 °± 0.2 °, 7.806 °± 0.2 °, 20.828 °± 0.2 °
Implementation Method 3
the sodium salt crystal form A has the following X-ray powder diffraction characteristic peaks (2 θ angle)
Implementation Method 4
The development of sodium salt crystal forms A and B of an HIV integrase inhibitor molecule, characterized by specific X-ray powder diffraction peaks and thermal stability, is achieved through crystallization using sodium hydroxide
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
Provided in the present invention are crystal forms of the sodium salt of an HIV-1 integrase inhibitor molecule. Specifically, provided in the invention are crystal form A and crystal form B of the sodium salt of a compound as shown in formula 1. The crystal forms of the present invention can be used for preventing and/or treating diseases related to HIV infections and selectively inhibiting the activity of HIV integrase.