Parenteral Peptide Formulations: Chemical and Physical Properties of Native Luteinizing Hormone-Releasing Hormone (LHRH) and Hydrophobic Analogues in Aqueous Solution

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Abstract
The degradation of native LHRH in aqueous buffers of pH ∼1–10 obeyed the rate equation, kobs = kH+aH+ + ko + kHO-(aHO-) x , where x at 60–100°C was ∼0.64 and temperature independent. Extrapolation to 25°C using the Arrhenius equation and secondary rate constants showed that native LHRH is reasonably stable at pH 5.4, giving a shelf life (t90) of approximately 5 years. Regarding physical properties, hydrophobic LHRH analogues nafarelin and detirelix were found to be surface active as demonstrated by a decrease in apparent surface tension with increased peptide concentration. The CMC for detirelix at pH 7.4 was determined to be 5.3 × 10−4M (0.88 mg/ml), and that for nafarelin, >2 mg/ml. At higher concentrations (∼4–8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence, Tcm) in the presence of propylene glycol, a solvent which proved to be efficacious at suppressing gelation and at destabilizing liquid crystals as measured by a reduction in Tcm.