Contact angles of pharmaceutical powders.

Contact angles of pharmaceutical powders were determined by measuring the maximum height of a drop of a saturated solution on a presaturated compact of the material. The results for a series of drugs are presented.

Effect of hydrophilization of hydrophobic drugs on release rate from capsules.

The release of poorly soluble hydrophobic drugs from capsules can be improved significantly by the creation of a hydrophilic surface by intensive mixing of the hydrophobic drug with a small amount of a solution of a hydrophilic excipient. This technique was introduced previously for the production of microgranules. The data presented indicate that the hydrophilic material is mechanically distributed over the hydrophobic surface. The creation of hydrophilic capillaries in a capsule or tablet allowed the rapid penetration of the dissolution fluid, resulting in a dispersion of well-wetted particles, so that the maximum surface area of the powder was exposed to the dissolution medium. Moreover, hydrophilization of hydrophobic drugs has the important benefit that the release rate from capsules is independent of the surface tension of the dissolution medium.

In vitro and in vivo availability of hydrophilized phenytoin from capsules.

The effect of phenytoin hydrophilization on the liquid penetration rate into prepared plugs, on the disintegration time, on the in vitro release rate, and on in vivo absorption in humans was studied. Hydrophilization was performed by intensive mixing of the hydrophobic drug with a small amount of methylcellulose solution. Liquid penetration into the treated plugs was independent of the liquid wetting potency and extremely high compared to the pure drug plugs. Analogous results were obtained for the disintegration time and in vitro release rates from capsules loaded with pure and treated drug. A bioavailability study in seven healthy volunteers showed immediate absorption of the treated drug but a 1-hr absorption lag time for the pure drug.

Sublingual nitroglycerin. I. Comparative evaluation of the physical stability of commercially available tablets.

The physical stability of one type of stabilized molded and three types of compressed nitroglycerin tablets was studied. The evaporation rate of nitroglycerin was controlled by its vapour pressure and by the matrix effect of the dosage forms. The four products showed different vapour pressures and matrix effects. In time nitroglycerin escapes from the outmost layers of the tablets; the dosage form in which the drug showed the lowest vapour pressure (the stabilized molded tablet) was found to be the most stable one. However, from the time when the drug had escaped from the outmost layers of the dosage form, the matrix effect became dominant. When nitroglycerin tablets were stored in tightly closed containers at room temperature potency loss was minimal. Even when the bottles were opened regularly this did not result in a significant loss of the drug. Measures are suggested to minimize drug evaporation.

Sublingual nitroglycerin. II. In vitro and in vivo availability of Nitrostat and Nitrobaat tablets.

The in vitro and in vivo availability of nitroglycerin from three compressed and one stabilized molded tablet have been studied. Compressed nitroglycerin tablets have to disintegrate before the drug is released. The disintegration and release of nitroglycerin from these tablets appeared to be strongly dependent upon conditions in the in vitro dissolution tests, such as the degree of agitation, and in vivo factors, such as tongue pressure and/or movement. The stabilized molded nitroglycerin tablet did not disintegrate but dissolved completely. Because the dissolution of the molded tablet was fast, the release rate of nitroglycerin was far less influenced by the in vitro and in vivo factors described above. The potency and in vitro and in vivo availability of fresh tablets and tablets which had been stored in tightly closed glass containers for over one year did not differ significantly. It is conjectured that the supposed potency loss of properly stored compressed nitroglycerin tablets is rather a release problem than a stability problem.

Greatly enhanced bioavailability of theophylline on postprandial administration of a sustained release tablet.

The bioavailability of theophylline after oral administration of a new sustained release tablet Theograd-250 mg was studied in 7 healthy volunteers, under fasting and non-fasting conditions. Whilst fasting the bioavailability was moderate at 64 +/- 22% (mean +/- SD), whereas in the non-fasting state the relatively high bioavailability of 90 +/- 13% was found. The drug appeared to be significantly more slowly absorbed when a tablet was taken after a meal, than when it was ingested on an empty stomach. In the former case, the peak level was reached after 6.9 +/- 1.0 h, whereas in the fasting state the maximum serum concentration occurred 4.0 +/- 1.7 h after administration of the drug. Despite the slow absorption, the peak non-fasting level of 4.4 +/- 1.4 mg . 1(-1) was significantly higher than the 3.1 +/- 1.0 mg . 1(-1) observed in the fasting state. The profiles of the serum concentration-time curves showed that the concentration remained above 75% of Cmax for 8.7 +/- 1.3 h in the fasting and 9.0 +/- 1.1 h in the non-fasting state. It was concluded that to define the optimal dosage regime for sustained release oral dosage forms of theophylline, the influence of food on absorption from these preparations should be taken into account. Based on the present results, Theograd-250 mg tablets have predictable absorption and a high (90%) bioavailability if taken after a meal.

Influence of food on the rate and extent of absorption of theophylline after single dose oral administration of a controlled release tablet.

Rate and extent of absorption of theophylline were determined in 7 healthy volunteers on pre- as well as on postprandial administration of commercially available controlled release tablets (Theograd-350 mg). In fasting subjects, maximum serum theophylline concentrations of 3.8 +/- 1.2 mg X 1(-1) (mean +/- SD) were reached at 3.4 +/- 1.2 hours after dosing, whereas under non-fasting conditions maximum serum levels of 5.8 +/- 1.3 mg X 1(-1) were found at 7.4 +/- 1.4 hours after the tablet was given. The bioavailability increased from 65 +/- 8%, observed on preprandial administration to 87 +/- 14%, when Theograd-350 mg tablets were taken after a meal. In conclusion, Theograd-350 mg tablets have a predictable absorption and give relatively high (87%) bioavailability, if the tablets are taken after a meal.

Food and a sustained release theophylline tablet on chronic dosing: bioavailability, peak-trough and trough-trough differences.

The bioavailability of theophylline and the serum concentration fluctuations after administration of a sustained release tablet (Theograd 250 mg, one tablet twice daily) were studied in the steady state in six volunteers. On postprandial administration of the 250 mg tablets the bioavailability was 89 +/- 16%. Good sustained release properties were obtained provided that the tablets were taken after a meal; Cmax was 7.9 +/- 2.0 mg X 1(-1), tmax was 5.3 +/- 1.6 h, the peak-trough difference was 2.3 +/- 0.6 mg X 1(-1) and the serum concentration fluctuation was accounted for 42.8 +/- 11.2%. It was shown that on postprandial administration the mean serum concentration-time profile could be successfully calculated by means of multiple dose projection from single dose data. However, when the a.m. dose was given on an empty stomach and the p.m. dose 3 h after a meal, it appeared not to be possible to use the single diurnal dose data for calculation of the steady state serum concentration-time profile: the experimentally observed a.m. trough levels were significantly higher than the p.m. trough values and also the observed mean serum concentration was significantly higher than the calculated level. The possible causes for this discrepancy are extensively discussed.