HIV Integrase Inhibitor Solid Forms for Stability–Bioavailability Balance
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Solution Overview
Problem
There is a need for improved antiviral agents and methods for treating HIV infections, as well as better pharmaceutical formulations of these agents, including their preparation and purification.
Innovation Solution
The development of crystalline forms, salts, and co-crystals of the HIV integrase inhibitor (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide, which offer improved bioavailability, stability, and manufacturability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the HIV integrase inhibitor is developed as a crystalline form, then stability and storability are improved, but bioavailability may be reduced
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs, solvates, hydrates) with different physical and chemical parameters. Each crystalline form has distinct properties such as solubility, dissolution rate, and stability, allowing optimization of the balance between stability and bioavailability through selection of appropriate crystalline forms
Solution Approach 2:
The patent employs composite materials by creating co-crystals that combine the HIV integrase inhibitor with co-formers. These co-crystal compositions exhibit improved properties compared to the parent compound, including enhanced stability and maintained or improved bioavailability, effectively resolving the contradiction between these two parameters
2Ease of manufacture
If crystalline forms are developed for the HIV integrase inhibitor, then manufacturability is improved, but formulation complexity increases
Solution Approach 1:
The patent applies segmentation by isolating and characterizing individual crystalline forms (Forms I, II, III, etc.) with distinct XRPD patterns and properties. This segmentation allows each form to be independently optimized for manufacturing while simplifying the overall formulation development process through systematic evaluation of discrete forms
Solution Approach 2:
By systematically varying crystallization parameters (solvent type, temperature, pH, additives) to produce different crystalline forms, the patent enables optimization of manufacturability for each form while maintaining a manageable formulation complexity through understanding the structure-property relationships
Data Source
AI summary
The present disclosure relates generally to solid forms of the compound of Formula I:Also disclosed are pharmaceutical compositions comprising said solid forms and methods of making said solid forms. The solid forms of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection.