Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution-related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-co-vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X-ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physico-chemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H-bonding) between the carbonyl group of the pyrrole ring of the polymer and a H-donor group of the drug. Indomethacin also showed evidence of H-bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4-8 weeks at 25 degrees C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25 degrees C/< 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H-bonding between the components.
To better predict food effects on the bioavailability/bioequivalence of drugs and drug products from in-vitro data, a dissolution medium that simulates the initial composition of the postprandial stomach was developed. First, the physical parameters of two homogenized standard breakfasts often administered to assess food effects in pharmacokinetic studies were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Subsequently, the match of the physical parameters of several commercially available liquid meals, including long-life milk, Ensure and Ensure Plus to those of the breakfasts was evaluated. Of the three liquid meals studied, Ensure Plus had the closest physicochemical behaviour to that of homogenized standard breakfasts. By increasing the viscosity of Ensure Plus with 0.45% pectin, it was possible to obtain a medium that closely resembles the FDA standard breakfast.
The quantities of long chain lipid that might be administered in a pharmaceutical formulation stimulate gallbladder contraction and elevate intestinal levels of bile salt and phospholipid. This effect is a likely contributor to the ability of lipid based formulations to enhance the absorption of poorly water-soluble drugs.
Research compound GWX belongs to biopharmaceutical classification system type II, and hence shows dissolution-rate-limited absorption. To improve its dissolution performance, GWX was formulated as a co-precipitate with hydroxypropyl methylcellulose phthalate (HPMCP). Co-precipitates with various drug-HPMCP ratios were prepared and characterised using modulated differential scanning calorimetry (MDSC), X-ray powder diffraction, HPLC and dissolution testing. Co-precipitates with 1:9 and 2:8 drug-HPMCP ratios showed the highest extent of dissolution after both 5 and 90 min, followed by 3:7, 4:6, and 5:5 drug-HPMCP co-precipitates, in respective order. Co-precipitates with drug-HPMCP ratios of 6:4 and greater showed no significant improvement in dissolution over crystalline drug alone. The amounts of crystalline and amorphous drug in co-precipitates, as determined by MDSC, and HPLC quantification of the total amount of drug in co-precipitates were used to determine the amount of drug incorporated into solid solution. It was found that dissolution rate and extent was correlated to the amount of drug incorporated into amorphous solid solution for the 1:9 to 5:5 drug-HPMCP ratio co-precipitates. Amorphous drug alone and physical mixtures of drug and HPMCP showed very little and no significant improvement in dissolution rate or extent, respectively, above crystalline drug alone. Amorphous drug alone re-crystallized to a large extent within 1 min of contact with the dissolution medium, whereas 4:6 drug-HPMCP co-precipitate showed a lower degree of re-crystallization and 2:8 drug-HPMCP co-precipitate showed very little re-crystallization. It was concluded that the likely mechanisms of improved dissolution of low drug-HPMCP ratio co-precipitates were improved wetting or increased surface area for mass transfer, thermodynamically enhanced dissolution of a higher energy amorphous form and inhibition of re-crystallization, when drug was incorporated into solid solution.
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