Rifaximin Polymorph Stabilization Using Polyol Intermediaries
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Solution Overview
Problem
Rifaximin's polymorphous forms are prone to undesirable transformations due to environmental humidity changes, affecting its bioavailability and stability during production and storage, which is critical for maintaining efficacy and safety in medicinal products.
Innovation Solution
The use of polyol compounds with at least two hydroxyl groups, such as 1,2-propanediol and PEG 400, is employed to stabilize the polymorphous form of rifaximin, particularly the β form, by reducing its water content to less than 4.5% and making it independent of ambient humidity, thereby preventing transformations during drying and storage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rifaximin is stored under ambient humidity conditions, then the polymorphous form remains accessible for general use, but the polymorphous form transforms undesirably affecting bioavailability and stability
Solution Approach 1:
A hydrate-forming substance acts as an intermediary between rifaximin and environmental humidity. This substance preferentially binds water molecules, creating a controlled hydrate structure that prevents direct interaction between ambient humidity and the rifaximin polymorphous form, thereby maintaining stability during storage and transport
Solution Approach 2:
The invention changes the water content parameter of rifaximin by forming a hydrate complex with a specific water-to-rifaximin ratio. This parameter change transforms the polymorphous form from being humidity-sensitive to being humidity-independent, as the hydrate structure locks the water content at a stable level that prevents polymorphous transformation
2Reliability
If rifaximin is dried to reduce water content, then stability improves, but polymorphous transformation occurs reducing bioavailability
Solution Approach 1:
The hydrate-forming substance serves as a protective intermediary during the drying process. It maintains a controlled water environment around the rifaximin molecules, preventing direct exposure to excessive drying conditions that would cause polymorphous transformation, while still allowing sufficient water removal to improve stability
Solution Approach 2:
The hydrate complex is formed preliminarily before the drying process. This preliminary action creates a stable molecular arrangement that protects the rifaximin polymorphous form during subsequent drying operations, ensuring that the desired polymorphous form is maintained even after water removal
3Reliability
If polymorphous form transformations are prevented, then bioavailability consistency improves, but additional substances must be added to the formulation
Solution Approach 1:
The hydrate-forming substance performs multiple functions simultaneously: it stabilizes the polymorphous form, controls water content, prevents transformations during storage and processing, and may also serve as a pharmaceutical excipient. This multi-functionality reduces the need for additional separate stabilizing agents in the formulation
Solution Approach 2:
The invention creates a composite material system where rifaximin is combined with a hydrate-forming substance in a specific stoichiometric ratio. This composite structure integrates the stabilizing properties of the hydrate-forming substance with the therapeutic properties of rifaximin, resulting in a unified formulation that maintains bioavailability consistency
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 stabilization of rifaximin's β form ensures consistent bioavailability and safety by maintaining its crystalline form under various conditions, reducing absorption, and preventing the induction of bacterial resistance, while also serving as a plasticizer for pharmaceutical formulations.
Implementation Method 1
The use of polyol compounds with at least two hydroxyl groups, such as 1,2-propanediol and PEG 400, is employed to stabilize the polymorphous form of rifaximin, particularly the β form, by reducing its water content to less than 4.5%
Implementation Method 2
The stabilization of rifaximin's β form ensures consistent bioavailability and safety by maintaining its crystalline form under various conditions, reducing absorption, and preventing the induction of bacterial resistance, while also serving as a plasticizer for pharmaceutical formulations
Data Source
AI summary
Polyols stabilize polymorphous form of rifaximin, in particular the β form. When polyols having at least two hydroxy groups are added to rifaximin powder, polymorph β is stable and remains stable in time independently from the environment humidity. In this invention a method to prepare formulations constituted by pure and stable polymorphous forms able to give a pharmaceutical product is described.