title: Parenteral formulation and thermal degradation pathways of a potent rebeccamycin based indolocarbazole topoisomerase I inhibitor.
abstract: The development of a practical and pharmaceutically acceptable parenteral dosage form of 1 is described. A cosolvent formulation strategy was selected to achieve the necessary human dose of 1 for administration via intravenous infusion. The final market formulation of 1 chosen for commercial development and Phase II clinical supplies was the topoisomerase inhibitor dissolved in a 50% aqueous propylene glycol solution vehicle with 50mM citrate buffered to pH 4. The thermal degradation pathways of 1 in this aqueous propylene glycol vehicle in the pH range of 3-5 were determined by relative kinetics and degradation product identification using LC/MS, LC/MS/MS, and NMR analysis. The primary mode of degradation of 1 in this aqueous cosolvent formulation is hydrolysis affording the anhydride 2 (in equilibrium with the dicarboxylic acid 3) and release of the hydrazine diol side chain 11. Subsequent oxidative degradation of 11 occurs in several chemical steps which yield a complicated mixture of secondary reaction products that have been structurally identified.
authors.affiliation: PreClinical Development, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. panydc3@gmail.com
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sato
authors.forename: David
authors.initials: D
authors.lastname: Breslin
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kitada
authors.forename: Wataru
authors.initials: W
authors.lastname: Minagawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomoto
authors.forename: Xue-Zhi
authors.initials: XZ
authors.lastname: Qin
authors.forename: Shyam B
authors.initials: SB
authors.lastname: Karki
mesh_terms: D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006868:Hydrolysis; D007267:Injections / Q000379:methods*; D015394:Molecular Structure; D019946:Propylene Glycol / Q000737:chemistry; D012995:Solubility; D013696:Temperature; D059004:Topoisomerase I Inhibitors
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D019946:Propylene Glycol; C053339:rebeccamycin