The impact of food components on the intrinsic dissolution rate of ketoconazole.
To accurately predict the in vivo performance of drugs from an in vitro dissolution test, the dissolution conditions used are supposed to be similar to those present in the gastrointestinal milieu. Post-prandial gastric fluid contains partially digested food mixtures consisting of fat, protein and carbohydrate. Despite this, the compendia dissolution medium recommended to simulate the gastric fluid is still composed of a simple solution of hydrochloric acid and sodium chloride with or without the addition of pepsin. Therefore, in this investigation, biorelevant dissolution media were developed to evaluate the impact of food constituents; milk with different fat contents, egg albumin, gelatin, casein, gluten, carbohydrates and amino acids on the intrinsic dissolution behavior of ketoconazole. Most of the food additives that were evaluated enhanced the apparent solubility of the drug but to different extents. The greatest enhancement in dissolution was observed in media containing either neutral amino acids or media based on milk mixtures. The formation of complexes between the drug and the additives most likely accounted for the solubilizing effect and in milk-containing media, the effect was attributed to the whole complex structure of milk rather than simply its fat content. These results highlight the potential effect of the type of ingested meal on drug dissolution and subsequent bioavailability.
a School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool , UK and.
Heba S
HS
Ghazal
b Novaliq GmbH , Heidelberg , Germany.
A Mark
AM
Dyas
a School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool , UK and.
James L
JL
Ford
a School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool , UK and.
Gillian A
GA
Hutcheon
D000935:Antifungal Agents / Q000737:chemistry*; D001682:Biological Availability; D002241:Carbohydrates / Q000737:chemistry; D065546:Drug Liberation; D005223:Fats / Q000737:chemistry; D018565:Food-Drug Interactions; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000737:chemistry*; D008954:Models, Biological; D011506:Proteins / Q000737:chemistry; D012995:Solubility
D000935:Antifungal Agents; D002241:Carbohydrates; D005223:Fats; D011506:Proteins; D007654:Ketoconazole
Bioavailability; biorelevant dissolution media; dissolution; food additives; gastric fluid; solubility