PubMed · 6962162
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K F Leinfelder. Microfilled composite resins.. https://pubmed.ncbi.nlm.nih.gov/6962162/
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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.
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.
PURPOSE: This review describes a conceptual approach to the characterization of pharmaceutical solids. METHODS: Four flow charts are presented: (1) polymorphs, (2) hydrates, (3) desolvated solvates, and (4) amorphous forms. RESULTS: These flow charts (decision trees) are suggested as tools to develop information on pharmaceutical solids for both scientific and regulatory purposes. CONCLUSIONS: It is hoped that this review will lead to a more direct approach to the characterization of pharmaceutical solids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.