Investigation on The Supersaturation and Precipitation Kinetics of Weakly Basic Bcs Ii Drugs

Precipitation of solid drug particles in the gastro-intestinal tract affects both the rate and extent of intestinal drug absorption might be a factor that significantly contributes to the low and highly variable bioavailability observed for some low solubility drugs. A pre-requisite for such precipitation is that a super-saturated solution of the drug is formed within the intestinal lumen.

Intestinal precipitation occurs for basic drugs, irrespective of drug form or formulation, because of the pH increase from acidic in the stomach to basic in the small intestine. To prevent this precipitation, the best way is to use the polymers as precipitation inhibitors which will help to prevent the precipitation from the supersaturated state and will increase its bioavailability.

The aim of the project work was to study the phenomenon of the supersaturation in the intestinal pH and to compare the precipitation inhibiting ability of the polymers with the help of turbidimetric analysis and Particle size analysis. Further, the crystalline state of precipitates was analysed by powder X-ray diffractometer to study changes in crystals during precipitation in the presence and absence of polymers.

The two drugs belonging to BCS class-II were selected as the model drugs viz albendazole and Itraconazole. Polymers that were used as precipitation inhibitors that is HPMC and Eudragit. The ability of the polymers was determined based on their turbidity profiles and their particle size.

Supersaturation was induced by “Solvent shift method” which is a reported method in literature to study drug supersaturation and precipitation. The study was covered out by varying the amount of drug and concentration of polymer. The effect of changes in the amount of drug and concentration of precipitation inhibitors were evaluated with respect to time.

This attempt will help us to screen the best possible polymer for the drugs with low solubility in the early stage for the development of supersaturated drug delivery system like solid dispersion as many supersaturated systems have failed due to instability induced by crystallization phenomenon.

The turbidity was analysed at different time points (2,4,8,12,16,20 min) and particle size was analysed at two time points (0 and 20 min). For PXRD study the precipitate was collected by centrifuging at low rpm for 1-2 minutes and air-dried.

The results of the study suggested that supersaturation is a complex process and it need to be studied more at molecular level to understand more about the process. Variance was seen for both the drugs at different polymeric concentration in the presence of the polymers.

After turbidity analysis, it can be clearly stated that for albendazole, HPMC was found to have a significant effect on precipitation inhibition in comparison to Eudragit. Among the different polymeric concentrations chosen, the inhibitory effect of 0.5 mg/ml HPMC was found to be the highest for 400 µg of ABZ and 0.25 mg/ml HPMC for lower doses (200 and 100 µg).

On the contrary, for Itraconazole, Eudragit was found to inhibit precipitation significantly in comparison to HPMC. However, Eudragit shows good antiprecipitant effect at higher concentration of 0.5 mg/ml at all the dose tested i.e., 400 µg, 200 µg and 100 µg.

The predictive methods used were easy and simple to use and approachable for anyone to study precipitation kinetics.