Ulrich Brauns

Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine

Solubility and dissolution relationships in the gastrointestinal tract can be critical for the oral bioavailability of poorly soluble drugs. In the case of poorly soluble weak bases, the possibility of drug precipitation upon entry into the small intestine may also affect the amount of drug available for uptake through the intestinal mucosa. To simulate the transfer out of the stomach into the intestine, a transfer model was devised, in which a solution of the drug in simulated gastric fluid is continuously pumped into a simulated intestinal fluid, and drug precipitation in the acceptor medium is examined via concentration–time measurements. The in‐vitro precipitation of three poorly soluble weakly basic drugs, dipyridamole, BIBU 104 XX and BIMT 17 BS, was investigated. For all three, extensive supersaturation was achieved in the acceptor medium. Under simulated fasted‐state conditions, precipitation occurred for all three compounds whereas under simulated fed‐state conditions, the higher concentrations of bile components and the lower pH value in the acceptor medium inhibited precipitation at concentrations corresponding to usual doses in all cases. Comparison with pharmacokinetic data indicated that a combination of transfer model data with solubility and dissolution profiles should lead to better predictions of in‐vivo behaviour of poorly soluble weak bases.

Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media.

The rate at which a drug goes into solution is an important determinant of drug absorption from the gastrointestinal tract. Factors that are important to the kinetics of drug dissolution, as identified by the Nernst-Brunner and Levich modifications of the Noyes-Whitney model (1–3), are the physicochemical properties of the compound itself such as pKa, solubility, crystalline energy and specific surface area, and certain aspects of the prevailing conditions in the gastrointestinal (GI) tract. The physiological parameters that can play an important role include pH, surface tension, solubilization, buffer capacity, and the volume of the lumenal contents. These parameters not only change following the ingestion of food, but also can vary widely with position in the GI tract. Amphiphilic bile components including bile salts and lecithin, the concentration of which increase following a meal (4), have been shown to increase the in vitro dissolution rate for numerous poorly soluble compounds (5,6) either by an increase in solubility via micellar solubilization (at concentrations above the critical micelle concentration) and/or by the enhancement of the wettability of the compound. Dipyridamole, BIMT 17 BS and BIBU 104 XX (Fig. 1), were chosen as structurally diverse examples of poorly soluble weak bases each displaying a dissolution-rate limited component to their absorption behavior, with intrinsic solubilities of 0.008, 0.0075, and 0.0028 mg/ml, respectively (Table I). The pKa values of the compounds, 6.4 (dipyridamole), 6.03 (BIMT 17 BS), and 5.8 (BIBU 104 XX) suggest that the dissolution characteristics could vary considerably during transit through the GI tract. Furthermore, the relatively high log D values for both dipyridamole (3.95 at pH 7.0) and BIMT 17 BS (3.3 at pH 7.4) indicate that the dissolution of these compounds may be influenced by the solubilizing effects of bile salts and lecithin. The lower log D value for BIBU 104 XX (2.3 at pH 7.4) suggests a lesser solubilization effect. In the present study the aim was to assess the potential of in vitro solubility and dissolution studies using physiological relevant GI media to predict the in vivo absorption behavior of the aforementioned three poorly soluble weak bases.