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1Department of Formulation and Process Development, Gilead Sciences, Incorporated, Foster City, California 94404, USA.
Abstract:
The antiviral drug 9-[2-(phosphonomethoxy)ethyl]adenine, PMEA, was developed as an intravenous product for the treatment of human immunodeficiency virus infection. During the course of stability monitoring, PMEA i.v. injection was found to undergo particulate matter formation under extended storage at ambient temperature. Isolation and characterization of the particulates revealed them to be metal ion-PMEA complexes. The principle metal ions associated with the particulates were iron and zinc, present as trace impurities (< or = 40 ppm) in PMEA drug substance determined by inductively coupled argon plasma spectroscopy. These visible particles are characterized by energy-dispersive x-ray spectrometry and fourier transform infrared spectroscopy. This study describes the systematic evaluation of the observed solution phenomena and details alternative formulation systems to eliminate particulate formation in the PMEA injectable product.
Insights
The antiviral drug PMEA can form particles in solution due to trace metal impurities like iron and zinc. This study identifies these metal-PMEA complexes and explores new formulations to prevent particle formation in injectable products.
Area of Science:
- Pharmaceutical Sciences
- Drug Formulation
- Analytical Chemistry
Background:
- The antiviral drug 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) was developed for treating HIV.
- Stability monitoring of PMEA intravenous injection revealed particulate matter formation during storage.
Purpose of the Study:
- To investigate the cause of particulate matter formation in PMEA injectable solutions.
- To characterize the formed particulates and identify the associated impurities.
- To develop alternative formulations to prevent particle formation.
Main Methods:
- Inductively coupled argon plasma spectroscopy for trace metal analysis.
- Energy-dispersive X-ray spectrometry and Fourier transform infrared spectroscopy for particle characterization.
- Systematic evaluation of solution phenomena and formulation development.
Main Results:
- Particulate matter was identified as metal ion-PMEA complexes.
- Trace impurities of iron and zinc (< or = 40 ppm) in PMEA drug substance were the primary metal ions involved.
- Characterization confirmed the composition and structure of the particulates.
Conclusions:
- Trace metal impurities, specifically iron and zinc, are responsible for PMEA particulate formation in injectable solutions.
- Understanding the complexation mechanism is crucial for formulation development.
- Alternative formulation strategies are necessary to ensure the stability and safety of PMEA injectable products.