Preformulation studies for an ultrashort-acting neuromuscular blocking agent GW280430A. I. Buffer and cosolvent effects on the solution stability

Drug Development and Industrial Pharmacy
Haijian ZhuAlison Floyd

Abstract

GW280430A is an ultrashort-acting neuromuscular blocking agent targeted at muscle relaxation to facilitate surgical intubation. The objective of this work was to study the buffer and cosolvent effects on the solution stability of GW280430A. The buffer catalytic effect was examined in citrate, malate, tartrate, and glycine by measuring the rate of degradation of GW280430A (0.2 mg/mL) at constant pH (3), ionic strength (0.15 M), and various buffer concentrations (0.01-0.05 M). The temperature dependence of the buffer catalytic effect and the degradation of the GW280430A in cosolvent (ethanol, propylene glycol, polyethylene glycol 400, N,N-dimethylacetamide)/water mixtures were studied at 40, 50, and 60 degrees C. The loss of parent drug was monitored by reverse-phase high-performance liquid chromatography. The degradation of GW280430A followed first-order kinetics in all buffer solutions. Significant buffer-catalyzed hydrolysis of GW280430A was observed with citrate, tartrate, and malate buffers, but not in glycine-buffered solutions. The activation energies in all buffered drug solutions ranged from 70 to 80 kJ/mol and decreased with increasing buffer concentration. GW280430A degradation was primarily through ester hydrolysis an...Continue Reading

References

Apr 1, 1995·Journal of Pharmaceutical Sciences·P SimamoraS H Yalkowsky
Aug 1, 1993·The Journal of Pharmacy and Pharmacology·M S Islam, M M Narurkar

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Citations

Aug 4, 2006·Drug Development and Industrial Pharmacy·P J KuehlP B Myrdal
Nov 26, 2009·Chemistry & Biodiversity·Li Di, Edward H Kerns
Feb 7, 2013·Pharmacological Reviews·Hywel D WilliamsChristopher J H Porter

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