PubMed · 6267899
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J Haavaldsen. 1980. Iohexol.. https://pubmed.ncbi.nlm.nih.gov/6267899/
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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 degrees 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 p beta 1 = 3.230 +/- 0.022, p beta 2 = 4.885 +/- 0.030, p beta 3 = 9.871 +/- 0.022, and p beta 4 = 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 apparent n-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.
A partial phase diagram of the system N,N-dimethyldodecylamine oxide (DDAO)/water/gramicidin D was determined by 2H-NMR. Both 2H2O and perdeuterated DDAO (DDAO-d31) were studied by solid state NMR techniques. Addition of gramicidin D to the micellar (L1), normal hexagonal (HI) and cubic (I) phases of DDAO induces phase separations, giving two-phase regions, which all contain a lamellar (L alpha) phase. The L alpha phase containing gramicidin is characterized by larger order parameters for DDAO-d31 compared with the corresponding order parameters in the L alpha and HI phases of DDAO-d31/H2O. The L alpha phase may stay in equilibrium with any other phase in the phase diagram. The DDAO exchange between the coexisting phases is slow on the NMR timescale, which is why the recorded NMR spectrum consists of superimposed spectra from the different phases occurring in the sample. Gramicidin D can be solubilized in appreciable quantities only in the lamellar phase of DDAO-d31. Increasing amounts of gramicidin in the liquid crystalline phases result in a continuous increase in the molecular ordering up to about 5 mol% gramicidin, where a plateau is reached. This is consistent with a recent theoretical model describing the influence on the ordering of lipids by a membrane protein with larger hydrophobic thickness than the lipid bilayer. The solvent used for dissolving gramicidin at the incorporation of the peptide in the lipid aggregates has no effect on the 2H-NMR lineshapes of DDAO-d31. It is concluded that gramicidin is solubilized in the L alpha phase and that it always adopts the channel conformation independent of a particular solvent. The channel conformation is also supported by CD studies. In some of the samples, macroscopic orientation of the lipid aggregates is observed. It is concluded that DDAO-d31 in the binary system favors an orientation with the long axis of the hydrocarbon chain perpendicular to the magnetic field, whereas when gramicidin D is present the hydrocarbon chain orients parallel to the magnetic field. This is explained by the fact that gramicidin aligns with its helical axis parallel to the magnetic field, thereby forcing also the DDAO-d31 molecules to obtain such an orientation.
PURPOSE: The compression behaviour and the compactability of particles have been studied. In addition, an expression describing the bond strength over a tablet cross section was derived and these calculated values were compared with the experimentally determined tablet tensile strength values. METHODS: The compression behaviour of particles of a series of size fractions of four materials were assessed by tablet surface areas (particle fragmentation propensity) and by yield pressures (particle deformability), derived from in die Heckel profiles. The porosity and the tensile strength of the tablets were also determined. RESULTS: Sodium chloride and sodium bicarbonate possessed limited fragmentation while the converse applied for sucrose and lactose. Sodium chloride and sodium bicarbonate were the extreme materials with respect to particle deformability and compactability. Except for sodium chloride, a limited effect of original particle size on the compactability of the particles was observed. CONCLUSIONS: The observations on the compactability of the powders was explained by postulating that fragmentation affects mainly the number of bonds in a compact cross section, while deformation affects mainly the bonding force of these bonds, through a relationship with the contact area between a pair of particles. The deviations between the predicted strength of particle-particle bonds and the determined tensile strength values was explained by a high bonding capacity of some particles, e.g. due to an unpredicted high surface deformability, or by a fracture mechanic effect during tablet strength determination.