Preformulation Studies for an Ultrashort-Acting Neuromuscular Blocking Agent GW280430A. I. Buffer and Cosolvent Effects on the Solution Stability

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 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 and followed first-order kinetics in aqueous solutions. In cosolvent/water mixtures, new degradation products were observed, indicating a chemical reaction between GW280430A and cosolvents. The reaction activation energies in the cosolvent/water mixtures ranged from 75 to 85 kJ/mol, with the longest t 0.9 at 5 C equal to approximately 12 months and at 25 C equal to Drug Dev Ind Pharm Downloaded from informahealthcare.com by University of Mississippi on 11/03/14For personal use only. ORDER REPRINTS 36 days. Consideration should be given to the incorporation of glycine or a low concentration of citrate, malate, or tartrate buffer in the parenteral formulation development of GW280430A. Cosolvents prolonged the predicted t 0.9 for GW280430A in solution, but the enhancement was not significant enough to pursue a liquid formulation.

Stability Challenges in Drug Discovery

“…It has been reported that hydrolysis of the ester GW280430 at pH 3 was affected by the different counterions [16]. The hydrolytic rate decreases in the order of citrate > tartrate > malate > glycine, suggesting counterions had different catalytic effects on the hydrolysis of the compound.…”

“…For example, in the stability study of GW280430A, EtOH cosolvent reacted with the compound to form the ethyl ester degradation product [16].…”

The Hydrolysis of Diclofenac Esters: Synthetic Prodrug Building Blocks for Biodegradable Drug–Polymer Conjugates

“…For instance, citric acid buffer has shown a catalytic effect on the hydrolysis of a neuromuscular blocking candidate that contained two ester linkages. 29 It is highly possible that a catalytic contribution from the citric acid buffer is responsible for the observed discontinuity in the pH rate profile as it occurred in the pH region covered by the citrate buffer (pH 3.0-5.5) and is close to pKa 1 for citric acid (3.1). As the discontinuity occurred in a region that was not of interest for wound care application, we did not further investigate buffer catalysis by examining changes in buffer concentration.…”

Excipient–Drug Interactions in Parenteral Formulations

“…Zhu et al43 presented a poster describing a study in which an unstable drug needed to be buffer stabilized at pH 3. Four buffer systems (citrate, glycinate, maleate, and tartrate) were studied using the same pH; only one buffer (glycinate) did not catalyze drug degradation (see Fig.…”