Drug-plasticizer interactions causing solid state transitions of rifaximin.

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Drug Delivery

Background:

• Solid-state interactions between excipients and active pharmaceutical ingredients (APIs) are critical in solid dosage form development.
• Plasticizer migration within a solid dosage form matrix can lead to unforeseen incompatibilities and altered drug performance.
• Understanding these interactions is crucial for ensuring drug product stability and efficacy.

Purpose of the Study:

• To investigate the migration of plasticizers from coatings into the core of solid dosage forms.
• To characterize the interactions between rifaximin and various plasticizers, focusing on solvate formation.
• To elucidate the impact of plasticizer molecular structure on rifaximin solvate formation and dissolution behavior.

Main Methods:

• Incubation of rifaximin with five different plasticizers (dibutyl sebacate, tributyl citrate, triacetin, polyethylene glycol 400, propylene glycol) with varying properties.
• Solid-state characterization using Powder X-ray Diffraction (PXRD), thermogravimetric analysis (TGA), infrared spectroscopy (IR), and quantitative H Nuclear Magnetic Resonance (NMR).
• Analysis of rifaximin gastro-resistant granules, including those with enteric coatings, to detect solvate formation in a real-world formulation.

Main Results:

• Rifaximin formed solvates with certain plasticizers, leading to altered dissolution profiles.
• No direct correlation was found between rifaximin affinity for plasticizers and the type of solvate formed.
• Linear plasticizers, unlike bulkier ones (triacetin, tributyl citrate), consistently formed Type I solvates/hydrates with rifaximin.
• Propylene glycol-induced rifaximin solvate formation was observed both in direct incubation and within enteric-coated granules.

Conclusions:

• Plasticizer migration and subsequent solvate formation represent a significant incompatibility pathway in solid dosage forms.
• The linear molecular structure of a plasticizer appears to be a key factor in its ability to form solvates with rifaximin.
• These findings highlight the importance of considering plasticizer geometry and migration potential during pharmaceutical formulation design to prevent altered drug performance.