A Novel Multicompartment Dissolution Apparatus for Evaluation of Floating Dosage Form Containing Poorly Soluble Weakly Basic Drug

Abstract

Introduction Oral controlled release (CR) dosage forms generally have a transit time of 1–3 hours in the stomach,3–5 hours in the intestine and 4–11 hours in the colon(1). However,some drugs require more retention time in the stomach for better results. Gastro-retentive drug delivery is superior for drugs such as (a) drugs having a narrow absorption window,(b) drugs having their local effect in stomach (for example,antacids and anti helicobacter pylori agents), (c) drugs having pH-dependent stability, (d) drugs having low solubility at intestinal pH,and (e) drugs having colonic degradation (2,3). Approaches to achieve higher gastric residence time include (a) low density systems that float on gastric fluid, (b) bioadhesive systems that adhere to mucosal surface of stomach,(c) expandable systems that increase in size by swelling or unfolding to retard passage through the pylorus, (d) high density systems that sink in the lower curvature of the stomach,(e) magnetically controlled systems that operate by incorporation of magnetite oxide or coated magnets (4–6). Weakly basic drugs have lower pKa values and remain in ionized form at stomach pH having higher solubility,and in un-ionized form at intestinal pH having lower solubility (7). According to pH partition theory (14),drug is absorbed in un-ionized form,thus weakly basic drug absorbs from the intestine. When weakly basic drug is incorporated in a conventional CR dosage form,only a fraction of the drug is dissolved due to lesser solubility at its absorption site,such as the intestine. Incorporation of weakly basic drug into a gastro-retentive dosage form is beneficial over a conventional CR dosage form so that released drug continuously reaches its absorption site such as the intestine (8). Cinnarizine is a weak base (pKa 1.95,7.5) having higher solubility at lower pH (0.29 mg/mL in 0.1 N HCl) and lower solubility at higher pH (0.002 mg/mL in phosphate buffer pH 7.2),and thus is selected as the model drug for the floating dosage form (9,10). In vitro dissolution testing is generally carried out for quality control purposes and to establish an in vivo in vitro correlation. The currently used in vitro dissolution method for the floating dosage form is conducted at a constant pH 1.2 to mimic the stomach environment. The general prediction is that when drug is dissolved in vitro, it is considered that the drug is also absorbed in vivo. However, in vivo,the drug is exposed to varying dissolution environments in the gastrointestinal (GI) tract. Particularly,the pH in the GI tract Abstract Incorporation of a weakly basic drug into a gastro-retentive dosage form yields better biomedical benefits compared to incorporation into a conventional controlled release dosage form. Poorly soluble weakly basic drugs may precipitate upon entry into the small intestine,and this can affect absorption. To study drug release from floating dosage forms and simultaneously examine the effect of pH change on poorly soluble weakly basic drugs,a novel multicompartment dissolution system was developed by modifying beakers. The system consists of three serially placed compartments providing gastric, intestinal, and absorption compartment to mimic the in vivo dissolution and absorption in the gastrointestinal tract. A dosage form remained buoyant in the gastric compartment,released drug was allowed to transfer to the intestinal compartment,and soluble drug in the intestinal compartment was allowed to transfer to the absorption compartment through a filter. Dissolution profiles of 75 mg cinnarizine in conventional and floating tablets were studied. The results of conventional tablet showed that although cinnarizine was completely dissolved in the gastric compartment,approximately 50% of cinnarizine was precipitated in the intestinal compartment. A floating cinnarizine tablet showed complete release within 24 hours with nearly zero order release rate,and no precipitation observed in the intestinal compartment,giving 100% of cinnarizine transferred into the absorption compartment. The floating controlled release of poorly soluble weakly basic drug may give considerable biomedical benefits over conventional tablet formulation,which was demonstrated by the proposed novel multicompartment system. Variability of volume in the gastric and intestinal compartments was studied by making further modification in the apparatus. The proposed system may give good in vivo in vitro correlation,as attempts can be made to mimic in vivo conditions such as gastric volume,gastric secretion,gastric emptying to the intestine,and intestinal absorption.