title: Pharmaceutical development, quality control, stability and compatibility of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum antineoplastic agent AP5346.
abstract: AP5346 is a low molecular weight polymer-conjugated platinum antineoplastic agent. The lyophilized drug product has completed a phase I clinical trial. In order to guarantee a constant quality of AP5346 pharmaceutical products, quality control and analysis of the drug substance and final product were performed. The identity of AP5346 was confirmed using 1H NMR, 195Pt NMR and IR spectroscopy. Furthermore, the free platinum content, platinum release characteristics, molecular size and size distribution were established. With the selected analytical techniques, AP5346 could be distinguished very well from its polymeric analogues, such as AP5280 and AP5279. Stability experiments revealed that AP5346 final product is stable for 12 months at 5 degrees C, in the dark. For administration to patients, AP5346 final product is reconstituted with 5% w/v dextrose and diluted in infusion containers. To investigate the influence of container materials, the stability of AP5346 after reconstitution and dilution in infusion containers was determined. The infusion containers investigated were composed of glass, polyvinyl chloride (PVC, intraflex) and low density polyethylene (LD-PE, Ecoflac). AP5346 was shown to be stable after reconstitution and dilution with 5% w/v dextrose in these infusion containers for at least 96 h at 2-8 degrees C in the dark and at room temperature with ambient light conditions.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. apsvs@slz.nl
authors.forename: S C
authors.initials: SC
authors.lastname: Van der Schoot
authors.forename: B
authors.initials: B
authors.lastname: Nuijen
authors.forename: P
authors.initials: P
authors.lastname: Sood
authors.forename: K B
authors.initials: KB
authors.lastname: Thurmond
authors.forename: D R
authors.initials: DR
authors.lastname: Stewart
authors.forename: J R
authors.initials: JR
authors.lastname: Rice
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002850:Chromatography, Gel; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004339:Drug Compounding; D004344:Drug Incompatibility; D005612:Freeze Drying; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry*; D019999:Pharmaceutical Solutions; D010984:Platinum / Q000032:analysis; D011786:Quality Control; D013054:Spectrophotometry, Atomic; D013055:Spectrophotometry, Infrared; D013242:Sterilization
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; D019999:Pharmaceutical Solutions; C511763:ProLindac; D010984:Platinum; D004247:DNA