Physicochemical properties of A-75998, an antagonist of luteinizing hormone releasing hormone

• Published in: Journal of pharmaceutical sciences 1995-08, Vol.84 (8), p.953-958
• Main Authors: Cannon, John B., Krill, Steven L., Porter, William R.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Densitometry; Genital system. Reproduction; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Hydrogen-Ion Concentration; Light; Medical sciences; Molecular Weight; Oligopeptides - chemistry; Particle Size; Pharmacology. Drug treatments; Scattering, Radiation; Solubility; Surface Tension
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600840810

The physicochemical properties of A-75998, a synthetic antagonist of luteinizing hormone releasing hormone with potential for treatment of hormone-sensitive cancers and endometriosis, are described. An accelerated solution stability study indicated that the compound is relatively stable and showed a U-shaped pH-rate profile, with maximum stability between pH 4.5 and 6.5. The acid dissociation behavior of A-75998 was examined by UV-visible spectrophotometry at 25°C in a series of buffers ranging from pH 1 to 13. The data were fit to a model in which the dissociations of all four ionizable groups contributed to changes in the absorbance. The estimated macroscopic acid dissociation constants were pβ = 3.230 ± 0.022, pβ2= 4.885 ± 0.030, pβ3= 9.871 ± 0.022, and pβ4= 11.026 ± 0.157. The corresponding microscopic dissociation constants were pk1= 3.24 (nicotinyl), pk2= 4.88 (pyridyl), pk5= 9.91 (tyrosyl), and pk6= 10.99 (isopropyllysyl). The apparentn-octanol/water partition coefficients were measured from pH 2 to 13, and the profile was consistent with the expected acid-dissociation behavior. While appearing fairly water-soluble at pH < 5, dynamic light scattering of A-75998 in pH 4.5 buffer indicated the formation of aggregates of nonuniform size distribution. A-75998 exhibited reverse or thermal gelation; sodium chloride exacerbates this gel formation and self-association. Surface activity was pH-dependent, but no evidence was found for micelle formation. Based on the results, development of a parenteral formulation of A-75998 appears feasible, provided that aggregation can be minimized.