Parenteral peptide formulations: chemical and physical properties of native luteinizing hormone-releasing hormone (LHRH) and hydrophobic analogues in aqueous solution.
The degradation of native LHRH in aqueous buffers of pH approximately 1-10 obeyed the rate equation, kobs = kH + alpha H+ + ko + kHO-(alpha 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, greater than 2 mg/ml. At higher concentrations (approximately 4-8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence, less than 0.001). The thermodynamic stability of these peptide liquid crystals was probed by determining their melting points (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.
Powell
M F
MF
Institute of Pharmaceutical Sciences, Syntex Research, Palo Alto, California.
Sanders
L M
LM
Rogerson
A
A
Si
V
V
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D004355:Drug Stability; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D017274:Nafarelin; D012996:Solutions; D013499:Surface Properties; D013501:Surface-Active Agents / Q000737:chemistry; D013696:Temperature
D012996:Solutions; D013501:Surface-Active Agents; C043699:detirelix; D017274:Nafarelin; D007987:Gonadotropin-Releasing Hormone