Percutaneous nitroglycerin absorption in rats.

Percutaneous nitroglycerin absorption was studied in shaved rats by monitoring unchanged plasma drug concentrations for up to 4 hr. Drug absorption from the neat liquid state or from an alcoholic solution was considerably poorer than that from a commercial ointment. This observation was unanticipated since the driving force for percutaneous drug absorption was assumed to be drug thermodynamics. Potential artifacts such as drug volatilization from the skin, reduction of surface area through droplet formation, and vehicle occlusion were investigated, but they did not appear to be responsible for the observed results. Two experimental aqueous nitroglycerin gels were prepared with polyethylene glycol 400. One gel contained just sufficient polyethylene glycol to solubilize the nitroglycerin; the other had excess polyethylene glycol to solubilize nitroglycerin far below saturation. Both gels gave extremely low plasma nitroglycerin levels. The composite data suggested that percutaneous nitroglycerin absorption is highly vehicle dependent and that this dependency cannot be explained by simple consideration of drug thermodynamic activity.

Validity of oral bioavailability estimates of phenolsulfonphthalein based on total urinary excretion from rats.

Urinary recovery of phenolsulfonphthalein from rats were determined after intracardial (0.075 mg) and oral (1.5 mg) doses. Although trace quantities of conjugated metabolites could be identified by TLC, the levels present did not introduce significant error into estimates of total phenolsulfonphthalein excretion if samples were assayed directly by colorimetric methods for only unchanged dye. The absolute availability of phenolsulfonphthalein based on urinary recovery under the present experimental conditions was estimated at 10.6%.

Multivariate cluster analysis of pharmaceutical formulation data using Andrews plots.

A multivariate clustering technique known as the Andrews Plot was applied to a set of previously published data describing a series of pharmaceutical tablet formulations. Dependent variable data were subjected to a trigonometric transform algorithm and unique sinusoidal patterns were obtained for each of 18 formulations characterized by a total of 12 granulation and tablet parameters. Three main formulation clusters were observed in close agreement with a previously published analysis of the same data set using principal components methodology. Interpretation of cluster behavior lead to conclusions closely aligned to those of the original investigators, although some alternate hypotheses also arise. Limitations of the Andrews plotting technique were explored. The method appears to have value in the analysis of complex data sets derived from pharmaceutical formulation characterizations.

Effect of storage at specified temperature and humidity on properties of three directly compressible tablet formulations.

Direct compression tablets containing sodium starch glycolate, an alginate derivative, or povidone as a disintegrant, magnesium stearate as a lubricant, amaranth as a tracer, and dibasic calcium phosphate dihydrate as the matrix were stored for 30 days at 23 degrees and 75% relative humidity (R.H.), 45 degrees and 75% R.H., and 65 degrees and 40% R.H. Samples were evaluated after 0, 10, 20, and 30 days for size, hardness, and dissolution characteristics. Although no significant changes in the dimensions or hardness of the three tablet formulations, prepared at three different compaction pressures, were observed, the dissolution efficiency of the systems showed significant changes, some systems dissolving more rapidly and some more slowly after storage. In some cases, the changes were so substantial as to indicate the possibility of significant changes of the bioavailability of drugs formulated in such systems. The relevance of this work to the problem of evaluating aging effects on the physical properties of tablets is discussed.

Relative bioavailability of chlorthalidone in humans after single oral doses.

The relative bioavailability of chlorthalidone from rapidly dissolving, stabilized, amorphous 15- and 25-mg formulations was compared in 24 normal adult male volunteers to the 25-mg market standard tablet and a 25-mg oral reference solution. When adjusted for dose, the experimental formulations were 116 and 104% of the calculated mean area under the curve for chlorthalidone reference solution compared to 81% for the tablet of the innovator. Likewise, the dose-adjusted mean peak blood levels for the 15- and 25-mg experimental tablets and the 25-mg tablet of the innovator were 112, 105 and 78% of the reference solution, respectively. Mean times-to-peak blood concentrations were 8.4 h for the 25-mg and 9.1 h for the 15-mg amorphous formulations compared to 9.2 h for the oral reference solution and 11.8 h for the market standard tablet. Drug concentrations declined monoexponentially with harmonic mean half-lives ranging from 47 to 55 h and intrinsic clearances ranging from 0.13 to 0.18 L/h regardless of formulation. The dose-adjusted relative bioavailability for the experimental formulations was not significantly different from the oral reference solution, whereas the market standard tablet was significantly (p less than 0.0001) lower than the reference solution. The urinary excretion of chlorthalidone was generally greater following the stabilized amorphous formulations than either the tablet of the innovator or the reference solution. The results of this research show that a rapidly dissolving chlorthalidone tablet can be formulated that shows complete relative bioavailability in humans.

Chlorthalidone pharmacodynamics in beagle dogs.

A pharmacodynamic approach was employed to examine the diuretic effect of chlorthalidone in beagle dogs and to identify parameters necessary for optimization of an oral dosage formulation of this drug. The extensive partitioning of chlorthalidone into erythrocytes was shown to be noninstantaneous, with an in vitro partitioning half-life of 18 min. In vivo studies using oral and intravenous solutions confirmed this finding. Additionally, the diuretic effect was demonstrated to be related to the drug concentration in the plasma fraction. These studies led to the development of a relevant pharmacokinetic model which highlighted the importance of the oral absorption rate on the diuretic efficacy of chlorthalidone. A novel, rapidly dissolving, stabilized, amorphous chlorthalidone tablet formulation was compared to various oral solution and tablet formulations. Pharmacokinetic analysis by classical compartmental models and by moment techniques demonstrated that the rapidly dissolving tablet formulation was bioequivalent to an oral solution of chlorthalidone. Preparations containing crystalline chlorthalidone are shown to be incompletely absorbed, and the rates of absorption favor partitioning into the erythrocyte fraction. It is projected from the pharmacodynamic model that the novel chlorthalidone preparation optimizes plasma levels necessary to invoke a diuretic response.