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Determination of Solubility of Poorly Soluble Drugs in Gastrointestinal Fluids

using a Chromatographic Method

Abstract

Purpose. Primarily, to determine the solubilities of sixteen structurally different drugs in

gastrointestinal (GI) fluids, using an HPLC-based, small-scale method. Secondary, to examine

differences in solubility between buffer, simulated GI fluids and human GI fluids. By

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

absorption of an orally administrated drug both GI solubility and permeability must be

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

enhancement of drug solubility due to solubilization by various conjugated and non-

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

volume of fluid. The possibility of automatization should also be considered.

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

substances. The increase in solubility in gastric fluid compared to HCl is somewhat


surprising, since in the fasted state gastric fluid is normally not expected to contain

solubilizing contents. Further studies should be performed on different batches of GI fluids

because of the large variation in the composition of these biological fluids. Perhaps a better

understanding could also be obtained by adding more substances of varying structures to

future studies. Any relationship between the concentration of solubilizing components in the

GI fluids and the extent of drug solubilization need to be further investigated.

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