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The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids

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Purpose

This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF).

Methods

Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents.

Results

Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%).

Conclusions

Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

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Abbreviations

BCS:

biopharmaceutical classification system

C s :

saturation solubility

CV:

coefficient of variation

DIF:

dog intestinal fluid

D n :

dissolution number

D o :

dose number

ELS:

evaporative light scattering

FeSSIF:

fed simulated small intestinal fluid

H acc :

number of hydrogen acceptors

H don :

number of hydrogen donors

HIF:

human intestinal fluid

ΔH m :

change in melting entrophy

HPLC:

high-performance liquid chromatography

λ:

Wavelength

logP :

octanol/water patition coefficient

LOQ:

limit of quantification

M 0 :

the dose drug administered

M w :

molecular weight

m/z:

mass to charge

PLS:

partial least squares

S aq :

aqueuos solubility

t diss :

the time required for one particle of the drug to dissolve

T m :

melting point

t res :

the mean residence time

UV:

ultraviolet

V 0 :

the initial gastric volume

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Acknowledgments

We are thankful to Dr. Ralf Nilsson, Dr. Lars Löfgren, and Dr. Göran Hansson for their excellent technical assistance in the lipid analysis, and Angela Ku for the PLS analysis.

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Correspondence to Bertil Abrahamsson.

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Persson, E.M., Gustafsson, AS., Carlsson, A.S. et al. The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids. Pharm Res 22, 2141–2151 (2005). https://doi.org/10.1007/s11095-005-8192-x

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  • DOI: https://doi.org/10.1007/s11095-005-8192-x

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