Parenteral formulation and thermal degradation pathways of a potent rebeccamycin based indolocarbazole topoisomerase I inhibitor

• Published in: International journal of pharmaceutics Vol. 390; no. 2; pp. 128 - 133
• Main Authors: Sato, Yuichi, Breslin, David, Kitada, Hideyuki, Minagawa, Wataru, Nomoto, Takashi, Qin, Xue-Zhi, Karki, Shyam B.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10-05-2010; Elsevier
• Subjects: Biological and medical sciences; Buffer; Carbazoles - chemistry; Carbazoles - metabolism; Chemistry, Pharmaceutical - methods; Cosolvent; Drug Stability; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; General pharmacology; Hydrolysis; Indolocarbazole; Injections - methods; Medical sciences; Molecular Structure; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Propylene Glycol - chemistry; Solubility; Stability; Temperature; Topoisomerase I; Topoisomerase I Inhibitors; Buffer; Cosolvent; Stability; Solubility; PG; Topoisomerase I; Indolocarbazole; Pharmaceutical technology; Enzyme; DNA topoisomerase; Isomerases; Parenteral form; Topoisomerase I inhibitor; Physicochemical properties; Thermal degradation
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2010.01.004

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 50
mM 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.