PT  - JOURNAL ARTICLE
AU  - Li, Shihong
AU  - Zamansky, Irina
AU  - Orlov, Irina
AU  - Tyle, Praveen
AU  - Roy, Samir D.
TI  - Preformulation Studies for the Development of a Parenteral Liquid Formulation of an Antitumor Agent, AG337
DP  - 1997 Sep 01
TA  - PDA Journal of Pharmaceutical Science and Technology
PG  - 181--186
VI  - 51
IP  - 5
4099  - http://journal.pda.org/content/51/5/181.short
4100  - http://journal.pda.org/content/51/5/181.full
SO  - PDA J Pharm Sci Technol1997 Sep 01; 51
AB  - 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°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., Kabs versus 1/T) revealed an activation energy of 25 kcal/mol. The shelf life (t95%) of 10% AG337 solution of pH 2 at 25°C was predicted to be roughly 8 years. Various terminal sterilization methods, which include moist/dry autoclaving (121°C), e-beam, and y- 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.