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

Abstract

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.

Use of biorelevant media for assessment of a poorly soluble weakly basic drug in the form of liquisolid compacts: in vitro and in vivo study

“…For the specific case of poorly soluble weak bases like MC, one must not only consider solubility and dissolution but also the possibility of precipitation as the drug moves from the favorable pH conditions in the stomach to a less favorable pH environment in the small intestine. As the pH approaches or even exceeds the pKa of the basic drug, its solubility undergoes a sharp decrease and the concentration of the drug may in fact exceed the solubility (Kostewicz et al, 2004). The question is does the drug stay in supersaturated solution till complete absorption occurs or does it precipitate and become no longer available for absorption.…”

“…In this model, a solution of the drug dissolved in the simulated gastric fluid is allowed to transfer into simulated intestinal fluid at a suitable rate of (0.5-9 ml/min) under paddle rotation. Drug precipitation in the acceptor medium is examined via concentration time measurements (Kostewicz et al, 2004). This is performed under both fasting and fed conditions.…”

“…Moreover, Figure 4 shows that when pure drug was transferred from acidic to alkaline pH in FaSSIF, the amount of dissolved drug decreased from 91.3% to 10.5% after 60 min. MC is a poorly soluble weak basic drug, which when moves from the favorable pH conditions in the stomach to a less favorable pH environment in the small intestine that is almost equal to, or even exceeds, the pKa of the base (6.5), its solubility undergoes a sharp decrease and the concentration of the drug in the solution may, in fact, exceed the solubility and hence turbidity occurs in the vessel (Kostewicz et al, 2004). On the other hand, the conventional market tablets showed slight turbidity in the vessels and the amount of MC dissolved after their transfer from simulated gastric fluid SGFfast pH ¼ 2 to FaSSIF decreased from 93.87% to 81.11% (Figure 4).…”

Drug release from matrix tablets: physiological parameters and the effect of food

“…Garbacz et al have also showed diclofenac and nifedipine drug dissolution profiles to be predicted using a dissolution apparatus that mimics in vivo physical stresses [146,147]. Kostewicz et al [148] also developed a two-compartmental apparatus using a peristaltic pump using fasted and fed state-simulated media. Their sampling was performed manually with a syringe filtration step and a high-performance liquid chromatography analysis.…”

“…Also, pH was also not raised back to the original value as it was maintained only by the action of the contained buffer. In the second apparatus, however, pH, volume and the composition of the duodenal fluid were all left without intervention [65,148]. Psachoulias et al [149] presented an improved method, where although a gastric and a duodenal compartment were used, the dilution of the duodenal fluid which was the FaSSIF V2 plus was compensated by an inflow of a concentrated medium from a third vessel.…”