Bictegravir Sodium Form II Crystalline Polymorph Solubility
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Solution Overview
Problem
Bictegravir sodium, a low-solubility HIV-1 integrase strand transfer inhibitor, faces challenges with bioavailability due to its thermodynamically stable form being the least soluble, which complicates pharmaceutical processing and storage, necessitating a more stable and soluble polymorph that maintains stability during standard pharmaceutical processes.
Innovation Solution
A metastable polymorph of bictegravir sodium, designated as Form II, is developed, exhibiting high kinetic stability with a transition temperature above 300 °C, enhanced solubility, and reduced hygroscopicity, suitable for pharmaceutical compositions, characterized by specific PXRD, FTIR, and Raman spectra.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the thermodynamically stable form of bictegravir sodium is used, then the pharmaceutical composition has high stability during storage and processing, but the solubility and bioavailability are decreased
Solution Approach 1:
The patent changes the crystalline structure parameters of bictegravir sodium from the thermodynamically stable Form I to the metastable Form II, which has different molecular packing and hydrogen bonding patterns. This parameter change in crystal structure results in improved solubility and bioavailability while maintaining sufficient stability for pharmaceutical use.
Solution Approach 2:
The patent utilizes the dynamic nature of polymorphic forms by selecting a metastable form (Form II) that can be controlled to remain stable under pharmaceutical storage and processing conditions. The metastable form provides a window of opportunity to achieve both solubility improvement and adequate stability through controlled formulation and storage conditions.
2Quantity of substance
If a metastable polymorph is used to improve solubility, then the bioavailability increases, but the risk of solid form transitions during processing and storage increases
Solution Approach 1:
The patent performs preliminary characterization of the metastable Form II to establish its transition temperature (>300°C) and stability profile before formulation development. This preliminary knowledge allows formulation scientists to design processing and storage conditions that remain well below the transition temperature, preventing solid form transitions during pharmaceutical manufacturing and storage.
Solution Approach 2:
The patent builds in a large safety margin by identifying that Form II transforms to Form I at temperatures above 300°C. This creates a substantial temperature cushion between normal pharmaceutical processing temperatures (typically <100°C) and the transition temperature, effectively preventing unwanted polymorphic transitions during standard manufacturing and storage operations.
3Ease of manufacture
If the known Form I of bictegravir sodium is used, then the processing and handling are simplified, but the dissolution profile and bioavailability are suboptimal
Solution Approach 1:
The patent changes the crystalline form parameter from Form I to Form II, which alters the dissolution kinetics without significantly impacting processing and handling properties. Both forms are solids with similar mechanical properties, allowing Form II to maintain ease of manufacture while providing superior dissolution and bioavailability.
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
Form II of bictegravir sodium offers improved bioavailability and stability during processing and storage, ensuring effective pharmaceutical compositions with increased solubility and dissolution rates, addressing the limitations of the thermodynamically stable form.
Implementation Method 1
A metastable polymorph of bictegravir sodium, designated as Form II, is developed, exhibiting high kinetic stability with a transition temperature above 300 °C
Implementation Method 2
The transition temperature at which Form II of the present invention transforms to Form I of WO 2015/196116 A1 was found to be well above 300 °C, when measured with DSC at a heating rate of 10 K/min
Implementation Method 3
Form II possesses a higher solubility compared to Form I. Hence, bictegravir sodium Form II of the present invention combines the advantageous properties of high physical stability and high solubility
Implementation Method 4
Further advantageous properties of bictegravir sodium Form II are low hygroscopicity and a good behavior during grinding and compression
Data Source
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AI summary
The present invention relates to a crystalline form of bictegravir sodium and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising said crystalline form of bictegravir sodium, preferably in a predetermined and/or effective amount, at least one pharmaceutically acceptable excipient and optionally one or more additional antiviral agent(s). The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prophylaxis of HIV-1 infections.