Characterization of metal-ion-nucleotide based particulate matter in solutions of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).
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.
Yuan
L C
LC
Department of Formulation and Process Development, Gilead Sciences, Incorporated, Foster City, California 94404, USA.
Visor
G C
GC
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry*; D004355:Drug Stability; D007501:Iron / Q000032:analysis; D063065:Organophosphonates; D012996:Solutions; D015032:Zinc / Q000032:analysis
D000998:Antiviral Agents; D063065:Organophosphonates; D012996:Solutions; C053001:adefovir; D007501:Iron; D015032:Zinc; D000225:Adenine