Bictegravir Polymorphs and Salts for Low-Impurity Production
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Solution Overview
Problem
Existing processes for preparing bictegravir are costly, involve the formation of high amounts of byproducts like TMU and HOAt, require silica gel chromatography for separation, and result in diastereomer impurities, making large-scale production challenging.
Innovation Solution
A novel process involving suspension or dissolution of bictegravir in solvents like methylene chloride or trifluoroethanol, followed by addition of a sodium source, and isolation of new crystalline polymorphic forms such as bictegravir sodium Form-L to Form-L6, along with the preparation of bictegravir salts and co-crystals like bictegravir diethylamine, using alternative activation agents to minimize racemization and diastereomer formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If HATU coupling agent is used for acid-amine coupling, then the reaction proceeds efficiently, but high amounts of byproducts (TMU and HOAt) are formed that are difficult to separate
Solution Approach 1:
The patent extracts and removes the harmful byproducts TMU and HOAt from the reaction system through silica gel column chromatography, separating them from the desired bictegravir product to achieve purification
Solution Approach 2:
The patent changes the purification parameters by using specific eluent systems (ethanol/methylene chloride for column chromatography, acetonitrile/water with trifluoro acetic acid for HPLC) to optimize the separation of byproducts from the product
2Manufacturing precision
If silica gel column chromatography is used for separation, then byproducts are removed, but the process becomes costly and complex
Solution Approach 1:
The patent uses silica gel as an intermediary material in column chromatography to mediate the separation between byproducts and the desired product, enabling purification through adsorption differences
Solution Approach 2:
The patent replaces mechanical filtration methods with chromatographic separation using silica gel, substituting a simpler mechanical process with a more effective but complex chemical separation system
3Productivity
If conventional processes are used for bictegravir preparation, then production can proceed, but diastereomer impurities are formed
Solution Approach 1:
The patent implements feedback control by using HPLC with trifluoro acetic acid to monitor and detect diastereomer impurities, adjusting the purification process to achieve impurity levels below 0.15%
Solution Approach 2:
The patent changes the purification parameters by using specific HPLC conditions (acetonitrile/water with 0.1% trifluoro acetic acid) to optimize the separation and removal of diastereomer impurities
4Manufacturing precision
If HPLC is used for purification, then diastereomer impurities are removed, but the process becomes more costly
Solution Approach 1:
The patent uses HPLC with trifluoro acetic acid as an intermediary system to mediate the separation of diastereomer impurities from bictegravir, enabling high-purity product recovery
Solution Approach 2:
The patent optimizes the HPLC parameters including mobile phase composition (acetonitrile/water with 0.1% trifluoro acetic acid) to achieve effective separation at reasonable cost
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 process provides cost-effective, scalable production of bictegravir with reduced diastereomer impurities and introduces new polymorphic forms and salts/co-crystals that enhance pharmaceutical performance characteristics.
Implementation Method 1
suspending or dissolving bictegravir in methylene chloride or trifluoroethanol
Implementation Method 2
adding a sodium source, and isolation of new crystalline polymorphic forms such as bictegravir sodium Form-L to Form-L6
Implementation Method 3
isolation of new crystalline polymorphic forms such as bictegravir sodium Form-L to Form-L6
Data Source
AI summary
The present invention generally relates to polymorphic forms of bictegravir, its salts, co-crystals, solvates or hydrates thereof and process for the preparation of the same and also relates to pharmaceutical compositions containing the same. The present invention also relates to a process for preparation of bictegravir substantially free from its diastereomer impurity.