title: Preformulation studies for the development of a parenteral liquid formulation of an antitumor agent, AG337.
abstract: AG337 is a potential anticancer agent designed by using protein structure-based techniques. The objective of this work was to evaluate the feasibility of a high concentration liquid formulation of AG337 intended for intravenous administration. The solubility of AG337 in pure water was above 100 mg/mL at pH < 3. The drug's solubility decreased precipitously as the solution pH increased above 3 upon titration with 0.1 N NaOH. The solubility of AG337 in water as a function of temperature (ranged from 2-40 degrees C) was determined. As anticipated, the drug's solubility increased somewhat linearly as the solution temperature increased. Degradation kinetics of 15% and 10% AG337 solutions at elevated temperatures was determined to assess the feasibility of a liquid formulation as opposed to previously developed lyophilized powder for injection. Only one major degradation product was detected in the HPLC as a result of chemical hydrolysis of AG337 to AG408. Arrhenius plot (i.e., kobs versus 1/T) revealed an activation energy of 25 kcal/mol. The shelf life (t95%) of 10% AG337 solution of pH 2 at 25 degrees C was predicted to be roughly 8 years. Various terminal sterilization methods, which include moist/dry autoclaving (121 degrees C), e-beam, and gamma-irradiation, were evaluated for the 10% AG337 solution. Autoclaving cycles, ranged from 20 to 90 minutes, caused instantaneous degradation of AG337 solution and induced further degradation upon long-term storage. Again, AG408 was the major degradation product following autoclaving. On the other hand, irradiation techniques induced very little degradation, but turned clear glass vials to brown upon irradiation.
authors.affiliation: Agouron Pharmaceuticals, Incorporated, La Jolla, California 92037, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: I
authors.initials: I
authors.lastname: Zamansky
authors.forename: I
authors.initials: I
authors.lastname: Orlov
authors.forename: P
authors.initials: P
authors.lastname: Tyle
authors.forename: S D
authors.initials: SD
authors.lastname: Roy
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D019999:Pharmaceutical Solutions; D011799:Quinazolines / Q000737:chemistry*
chemical_list: D000964:Antimetabolites, Antineoplastic; D019999:Pharmaceutical Solutions; D011799:Quinazolines; C099178:nolatrexed