PARENTERAL PEPTIDE FORMULATIONS - CHEMICAL AND PHYSICAL-PROPERTIES OF NATIVE LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) AND HYDROPHOBIC ANALOGS IN AQUEOUS-SOLUTION

The degradation of native LHRH in aqueous buffers of pH approximately 1-10 obeyed the rate equation, k(obs) = k(H)+a(H)+ + k(o) + k(HO)-(a(HO)-)(x), where x at 60-100-degrees-C was approximately 0.64 and temperature independent. Extrapolation to 25-degrees-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 x 10(-4) M (0.88 mg/ml), and that for nafarelin, > 2 mg/ml. At higher concentrations (approximately 4-8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence, < 0.001). The thermo-dynamic stability of these peptide liquid crystals was probed by determining their melting points (T(cm)) 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 T(cm).