The impact of biorelevant media on the in-vitro dissolution of azole anti-fungal drugs

Dissolution of drugs is a prerequisite for oral absorption and bioavailability. Drugs in the gastrointestinal tract are exposed to a medium of partially digested food, comprising mixtures of fat, protein and carbohydrate in addition to bile components. Despite this, the compendial. media are still simple hydrochloric acid solutions or phosphate buffers. In this investigation, biorelevant dissolution media were developed to examine the impact of fat, protein, carbohydrate, amino acids and bile components on the dissolution behaviours of two azole anti-fungal drugs (itraconazole and ketoconazole). The drugs are Biopharmaceutics Classification System Class Il (poorly soluble with good permeability) and so they are more likely to exhibit dissolution rate-limited absorption. Furthermore, their bioavailability is affected by food ingestion.

The intrinsic dissolution rates of the drugs were evaluated using the stationary disk method in USP Apparatus II. Powders of the drugs were compressed to form disks with a constant surface area. No evidence of polymorphic change was observed due to drug compaction.

The dissolution and solubility of the drugs were assessed in simulated gastric fluid (SGF) containing milk with different fat contents, SGF containing albumin (hen egg white), gelatin (bovine skin), casein (bovine milk), gluten (wheat), carbohydrates (glucose, lactose and starch) and amino acids (glycine, alanine, leucin, lysine and aspartic acid) to mimic gastric fluid at fed state. Most of the dietary components enhanced the solubility compared to SGF but to differing extents. The greatest increase in dissolution of itraconazole was observed with the addition of milk or albumin. The greatest enhancement of ketoconazole dissolution was observed in media containing neutral amino acids or milk. The rate and extent of the increase in solubility and dissolution varied between the two drugs and this was attributed to differences in their physical and chemical structure, in particular their lipophilicity. The formation of complexes with food additives likely accounted for the solubilising effect and in milk- containing media the effect was attributed to the whole complex structure of milk.

The dissolution and solubility were assessed in simulated gastric fluid at fasted state (FaSSGF) using formulations based on natural (bile salts and phospholipids) and synthetic surfactants. The inclusion of surfactants increased the dissolution however i variable dissolution profiles in the media were obtained. This was presumably due to different solubilising mechanisms of the surfactant-containing media which rendered the formulations of synthetic surfactants as inappropriate alternative for FaSSGF which contained natural surfactants.

The dissolution was also assessed in the presence of key endogenous surfactants in conditions representing fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF). The dissolution in the fed simulated medium was higher than the fasting simulated medium due to the greater amount of bile components and the lower pH of the fed simulating medium. The dissolution profiles of the drugs in FaSSIF and FeSSIF were compared to the profiles acquired in simplified media containing synthetic surfactants, sodium dodecyl sulphate and hexadecyltrimethyl ammonium bromide. These simplified media did not provide identical dissolution to that in FaSSIF and FeSSIF, however, approximate simulation was achieved which may be of value for replacing FaSSIF and FeSSIF for the quality control tests of the dosage forms.

The physical properties of the media were assessed in terms of viscosity and surface tension. The viscosity of the media did not show important variations, apar-t from media containing milk, albumin, and gelatin. Surface tension was an important determinate of dissolution as media with high surface activity exhibited high solubilising capacity of the drugs in addition to enhancing the wettability of drugs.

Thus, the results confirm the importance of using biorelevant media in dissolution studies and highlight the potential effect of the ingested meals on drug dissolution and subsequent bioavailability.