title: The isolation and identification of a toxic impurity in XP315 drug substance.
abstract: In early safety assessment studies with the experimental anti-neoplastic drug XP315, a toxic reaction was observed in dogs immediately after intravenous (iv) infusion. The reaction was characterized by severe erythema around the ears, eyes, face and body; ocular hyperemia; head shaking; swelling around the eyes, face, paws, head, neck and legs; scratching; and reddened gums, which lasted several hours after dosing. By fractionating the drug substance using preparative HPLC and then infusing the residues into dogs by iv, this reaction was traced to an impurity in the drug substance. Following the preparative isolation of the toxic impurity, characterization was performed using a combination of NMR and mass spectral methods. The proposed impurity was found to be structurally related and nearly twice the molecular weight of XP315, resulting from a dimerization by ring fusion of two 3-aminonaphthalene fragments during the synthetic process. This paper details the steps taken to isolate the toxic impurity and characterize its structure using off-line methods.
authors.affiliation: DuPont Pharmaceuticals Company, Experimental Station, PO Box 80353, Wilmington, DE 19880-0353, USA. ken.w.sigvardson@dupontpharma.com
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Sigvardson
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Adams
authors.forename: T Bradford
authors.initials: TB
authors.lastname: Barnes
authors.forename: Karl F
authors.initials: KF
authors.lastname: Blom
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Fortunak
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Reilly
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Repta
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Nemeth
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005021:Ethylamines / Q000032:analysis* / Q000633:toxicity; D006571:Heterocyclic Compounds / Q000032:analysis / Q000633:toxicity; D007094:Imides / Q000032:analysis* / Q000633:toxicity; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D008970:Molecular Weight; D011786:Quality Control
chemical_list: C444010:1-(2-(6-azaphenanthrene-1,10-dicarboximido)propylamino)-2-(2-(3-nitronaphthalene-1,8-dicarboximido)propylamino)ethane; D000970:Antineoplastic Agents; D005021:Ethylamines; D006571:Heterocyclic Compounds; D007094:Imides