Dehydration kinetics of prostaglandin E1 in a lipid emulsion.

The overall dehydration kinetics of prostaglandin E1 (PGE1) in a lipid emulsion at 35 degrees C were found to fit a model whereby the kapparent measured at each pH is simply the sum of the product of the fraction of the PGE1 at the interface, fi, and the rate constant at the interface, ki, plus the product of the fraction of the PGE1 in the aqueous phase, faq, and the rate constant in the aqueous phase, kaq. The values for fi and faq were reported earlier as a function of pH at 35 degrees C. The kaq and kapparent were experimentally determined as a function of pH at 35 degrees C. The ki was indirectly determined from the stability data in the emulsion. Microscopic rate constants for dehydration of PGE1 in the aqueous phase and interface at 35 degrees C were estimated from the experimental data. Based on the kinetic evaluation performed, it appears that the dehydration kinetics might be manipulated by the addition of charged surface active agents.

Determination of the pH-dependent phase distribution of prostaglandin E1 in a lipid emulsion by ultrafiltration.

The distribution of prostaglandin E1 (PGE1) in a lipid emulsion has been shown to be consistent with a three-phase model which assumes that solute may reside in the bulk aqueous and oil phases and at the oil/water interface. Calculations suggest that, in a lipid emulsion having an average particle size of 0.11 micron, it is theoretically possible for a surface active species such as PGE1 to exist predominantly at the interface. Aqueous phase concentrations of PGE1 versus pH were measured in an emulsion having an oil/water phase volume ratio of 0.1 by the use of an ultrafiltration technique in order to estimate the relative percentages of PGE1 in each phase. From bulk oil/water partition coefficient determinations, the amount of PGE1 present in the bulk oil phase of the emulsion was concluded to be insignificant. At emulsion pH values less than 5, PGE1 resides preferentially (greater than 97%) at the interface. With increasing pH's, the percentage of PGE1 in the aqueous phase increases, reaching 51% at high pH's. A model which assumes that both the nonionized and the ionized PGE1 species may be present at the interface, depending on the pH, was shown to be consistent with the data. Estimates were made of the distribution coefficients of the ionized and nonionized PGE1 between the interface and the aqueous phase and their concentration dependence. The apparent pKa of PGE1 at the interface derived from these data was 6.8. The distribution coefficients were used to generate a distribution profile of the various PGE1 species as a function of the pH. This distribution profile will be useful in explaining kinetic data of PGE1 in the emulsion as a function of pH.

Comparison between circulating interferon and drug levels following administration of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) to different animal species.

Using a high-performance liquid chromatographic assay, these studies attempted to correlate circulating levels of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) with the serum interferon response induced in mice, cats, dogs, cattle, and rabbits. The order of greatest sensitivity for interferon induction by ABPP was mice greater than cats greater than dogs greater than cattle greater than rabbits. Experiments to date indicate that the circulating drug levels associated with a detectable interferon response were 10-15 microgram/ml (mice), 15-30 micrograms/ml (cats and dogs), and 30-50 micrograms/ml (cattle). Whereas rabbits produced large amounts (greater than 10(4) units/ml) of interferon when induced with Newcastle disease virus, we could not demonstrate unequivocally that rabbits were induced by ABPP even when circulating drug levels reached 50 micrograms/ml, or greater. We also observed differences in the pharmacokinetics of ABPP in the different species which may contribute to the differences described for the interferon responses. The data point out the need for cautious selection of animal models for preclinical efficacy evaluation and cautious extrapolation of data from preclinical studies to eventual clinical evaluation.

Aluminum chlorohydrate I: Structure studies.

X-ray diffraction and IR and 27AI-NMR spectroscopy indicate that aluminum chlorohydrate is composed of a central aluminum in a tetrahedral configuration surrounded by 12 aluminum atoms in octahedral configuration. The complex, AI13O4(OH)24(H2O)7+12, is essentially spherical, with the +7 charge equally distributed on the surface. Seven chloride ions are associated with the complex as counterions. This structure is consistent with both the method of synthesis and the proposed mechanism of antiperspirant activity.

Aluminum chlorohydrate II: Physicochemical properties.

Determination of the chloride content of aluminum chlorohydrate by a chloride-selective indicated that gamma Cl leads to 1. IR analysis demonstrated that chloride was exchanged readily by nitrate and that the IR bands of the anion were not perturbed significantly. Thus, chloride is believed to act as a counterion. A high positive charge is predicted based o the critical coagulation concentration of aluminum chlorohydrate and the stability of aluminum chlorohydrate to attack by protons, as demonstrated by pH-stat titration Potentiometric titration with sodium hydroxide showed adsorption of hydroxyl anions initially, but a higher pH than expected was observed at the end-point. This behavior is consistent with the Al13O4(OH)24(H2O)7+12 complex, which would adsorb hydroxyl anions initially and in which the central tetrahedral aluminum is shielded from the added hydroxyl anions. The reaction rate with ferron (8-hydroxy-7-iodo-5-quinolinesulfonic acid) suggests that the major species in aluminum chlorohydrate is a large aluminum poly-cation. A platey morphology for lyophilized, air-dried, and spray-dried aluminum chlorohydrate was observed by scanning electron microscopy. The platey appearance is consistent with the structure of Al13O4(OH)24(H2O)7+12 since the spherical nature and high uneven charge of the complex make stacking difficult.

Aluminum chlorohydrate III: Conversion to aluminum hydroxide.

Bayerite, an aluminum hydroxide polymorph, readily forms when the hydroxyl to aluminum ratio of aluminum chlorohydrate is raised to 3 by titration with sodium hydroxide. Dilution of aluminum chlorhydrate solutions with water leads to the formation of gibbsite, another aluminum hydroxide polymorph. The mechanism of conversion in each instance is related to the structure of the Al13O4(OH)24(H2O)7+(12) complex.