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Abstract
comparing these results, it might be possible to propose changes in contents of the simulated
intestinal fluids that would improve their ability to predict intestinal solubility.
Background. Since the oral route of administration remains the most popular it is of great
importance to understand and predict oral absorption of drugs. To fully understand the
investigated. The solubility in the GI tract can be difficult to predict due to the complexity of
the GI fluids. The physicochemical properties of the drug as well as the physiological
conditions in the GI tract will determine the in vivo solubility. By increasing knowledge of
the in vivo conditions, progress could be made in developing a general in vitro method
predicting the in vivo solubility of poorly water-soluble drugs. Studies have been made on the
conjugated bile salts. An improved characterization of the intestinal contents has been
suggested for better predictions of drug solubilization (Wiedmann et al., 2002). While several
studies have been made on artificial GI fluids and buffers imitating the physiological
conditions, only a few have been made in human GI fluids (Pedersen Lomstein, Brönsted et
al., 2000; Pedersen Lomstein, Müllertz et al., 2000). By studying solubility of a number of
drugs in buffers, simulated and human GI fluids and comparing these results, an improvement
of today’s artificial GI fluids might be possible to suggest. Also, due to the high cost and
limited availability of human GI fluids, it is of primary importance to scale down the used
Methods. All solubility determinations were made in standard vials for liquid
chromatography, using 0,4-1,5 mL of fluid. The samples were incubated, centrifuged and
analysed at 37 oC. A number of gradient and isocratic methods were used for HPLC analysis.
Results The solubilities of sixteen drug substances were determined in gastric fluid, intestinal
fluid, simulated intestinal fluid, 0,01 M HCl and phosphate buffer pH 6,5, at 37oC. It was
found that for most of the studied substances, increased solubility could be seen in the
simulated intestinal fluid compared to solubility in phosphate buffer. In most cases solubility
increased further in intestinal fluid. All of the neutral substances appeared to have higher
solubility in simulated intestinal fluid than in buffer. Two of the neutral compounds appeared
to be much more soluble in simulated intestinal fluid than in human intestinal fluid. Among
the basic drugs, two of three substances were more soluble in human than in simulated
intestinal fluid. Solubilities for the acidic substances were higher in the human intestinal fluid
than in the simulated. All of the acidic NSAID substances with comparable data had higher
solubilities in the simulated intestinal fluid than in buffer. The solubilities in gastric fluid,
which were studied for five acidic drugs, were in all cases higher than the corresponding
values in HCl.
Conclusions Generally, solubility is higher in both simulated intestinal fluid and human
intestinal fluid than in phosphate buffer of the same pH. This is likely to be due to
solubilization by bile salts and lecithin. It appears as if the simulated intestinal fluid should be
further improved regarding its bile acid and lecithin content, before adopting it as a general
method for predictions of intestinal solubility. The largest differences in solubilities between
the simulated media and human intestinal fluid were found for neutral, poorly soluble
because of the large variation in the composition of these biological fluids. Perhaps a better
future studies. Any relationship between the concentration of solubilizing components in the