Improvement of the solubility behavior of problem drugs. 9. In vitro absorption studies using melting solidification products of iomeglamic acid

By means of the absorption apparatus according to Fürst and Neubert the solid dispersions of the iomeglamic acid were studied with regard to their in vitro absorption properties. All products showed better half lives of transport in relation to the pure compound. This was in correlation to the solubility parameters.     

Improvement of the solubility of problem drugs. 1. Production of iomeglamic acid fused and solidified products

The insoluble X-ray diagnostic iomeglamic acid could be converted to a more soluble modification by melting and solidifying it in liquid nitrogen. The amorphous state is proved by X-ray diffraction and differential thermal analysis. During storage, recristallisation of the product appears. By means of the proved amorphous state, it seems possible to determine the amount of the amorphous state, which makes the drug more soluble from solid dispersions.     

Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions

We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.     

Computer-aided differential thermal analysis of drugs

An open-loop on-line computer connection to a DTA apparatus of high time constant and the developed software for data acquisition and utilization are described. The new system was calibrated thermomentrically and calorically. The main aim is a enhanced purity estimation, especially by using of the modified Van't Hoff equation based on DTA curves, which first must be transformed to process-power-curves. Computer aided DTA provides utilization of higher quality and makes them faster and more exactly. Plotting of DTA curves which are baseline corrected and constructed as mean of equal curves as well as zooming are powerful and essential tools in optical comparison. The better estimation of the baseline under the peak and the computation of process-power-curve from DTA curve enable estimations based on curves of DTA apparatus' with high time constant as like as bases on DSC-curves.     

Ursodeoxycholic acid: Improvement of dissolution behaviour and its HPLC determination

The dissolution rate of a drug poorly soluble in water, ursodeoxycholic acid, was improved by using dissolution rate enhancers belonging to the group of cellulose and starch derivatives. Different techniques (mixing, milling and solvent evaporation) were utilized to prepare drug/carrier systems. The determination of the improved dissolution performance of the drug from the systems has been carried out by a modified in vitro dissolution test apparatus combined with HPLC analysis of the drug. The carriers and the techniques used for improving the dissolution rate, the dissolution apparatus and the HPLC method are proposed here to solve both the dissolution rate problems of the drug and its analytical determination.     

Differential effects of serotonergic and catecholaminergic drugs on ingestive behavior

The serotonergic agonists fenfluramine and fluoxetine and the catecholaminergic agonists amphetamine and phenylpropanolamine are well known to cause a reduction in intake in rats. In the studies reported here we investigated the effects of these drugs on the microstructure of licking behavior of the rat ingesting 0.4 M sucrose. The purpose was to examine the similarities in the behavioral effects within and between these two classes of anorectic agents. The serotonergic agonists fenfluramine and fluoxetine caused a reduction in intake primarily by reducing the size of bursts and clusters of licking within the test meal without affecting the duration of the meal, suggesting a reduction in the palatability of the test solution. The catecholamine agonists amphetamine and phenylpropanolamine reduced intake primarily by reducing the number of bursts and clusters without affecting their size, suggesting a fractionation in the organization of the normal pattern of ingestion. The differences between the two serotonin and the two catecholamine agonists on the microstructure of the licking behavior suggest a different effect of the two neurotransmitters on the motor system that controls ingestive behavior. The similarities between the two different agonists within each class suggests a common neurotransmitter mechanism responsible for these two different effects on the behavior of the animals.Supported by NIH Grant DK41563 (JDD).     

Improvement of solubility and dissolution rate of poorly water-soluble salicylic acid by a spray-drying technique.

Spray drying techniques have been applied to improve the solubility and dissolution rate of poorly water-soluble salicylic acid. Spray drying of the acid dispersed in acacia solutions resulted in as much as a 50% improvement in the solubility of the product. Solubility improvement was closely related not only to the concentration of acacia but also the amount of amorphous material in the spray-dried products. The heat of solution was inversely related to these parameters. The dissolution rate of spray-dried product was almost instantaneous being about 60 times faster than that of the original powder. A great improvement in the wettability of the spray-dried material seemed to be mainly responsible for the increase of dissolution rate.     

Bioavailability and dissolution behavior of trisulfapyrimidine suspensions.

The bioavailability of seven commercial trisulfapyrimidine suspensions was studied in 14 adult male volunteers. Fifteen blood samples were collected over a 48-hr period following administration of a 1-g dose of each suspension. Serum was assayed for each component (sulfadiazine, sulfamerazine, and sulfamethazine) by high-pressure liquid chromatography. Analysis of variance indicated several significant differences among the seven commercial preparations with respect to Cmax Tmax, and AUC for sulfadiazine, sulfamerazine, and sulfamethazine, The in vitro behavior of each suspension was then studied by the paddle method of the Food and Drug Administration. A 0.5-ml sample was introduced into 900 ml of hydrochloric acid (2.2 x 10(-4) M) at 37 degree and dissolved using a paddle speed of 25 rpm. Samples withdrawn at 15 and 30 min were analyzed by high-pressure liquid chromatography, and the percent of sulfadiazine, sulfamerazine, and sulfamethazine was calculated. Significant correlation was obtained between an in vivo parameter (Cmax for sulfadiazine) and an in vitro parameter (percent sulfadiazine dissolved in 30 min). Results indicate that this method is suitable for the in vitro screening of trisulapyrimidine suspensions.