Dissolution of slightly soluble drugs. IV. Effect of particle size of sulfonamides on in vitro dissolution rate and in vivo absorption rate, and their relation to solubility.

Abstract

Effect of particle size on absorption rate of rabbit and in vitro rate of dissolution was examined using sulfonamide powder drugs with the solubility ranging from 0.1-1 mg/ml at 37.degree. C in suspension. The dependence of particle size on absorption rate constants and dissolution rate constants obtained with in vitro test under sink conditions showed the strongest correlation in the case of the lowest solubility drug of sulfadiazine and this relation decreased with an increase in solubility. Blood level showed that the peak time of the aqueous solution was the fastest of all other samples for each sulfonamide as to the relative order of peak time after the administration of different dosage forms. This fact indicated that the dissolution rate was the rate-limiting step on the absorption of these sulfonamides. Effect of particle size on absorption rate was marked but its effect on the extent of bioavailability was almost constant irrespective of particle size. Plot of percentage unabsorbed vs. time for each sulfonamide was linear and the lines for larger particle size had an inflexion about 3 h after administration of the drug. This fact indicated that absorption of these sulfonamides was apparently 1st order and an inflexion for larger particle size was considered due to that passage of the drug in the gastrointestinal tract resulted in the change of dissolution environment. The time of an inflexion appearing at 3 h corresponded to the gastric emptying time.