Preformulation studies for the development of a parenteral liquid formulation of an antitumor agent, AG337.
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.
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Agouron Pharmaceuticals, Incorporated, La Jolla, California 92037, USA.
Zamansky
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Orlov
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Tyle
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Roy
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D000964:Antimetabolites, Antineoplastic / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D019999:Pharmaceutical Solutions; D011799:Quinazolines / Q000737:chemistry*
D000964:Antimetabolites, Antineoplastic; D019999:Pharmaceutical Solutions; D011799:Quinazolines; C099178:nolatrexed