An interlaboratory investigation of intrinsic dissolution rate determination using surface dissolution.

The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.

Prediction of food effect by bile micelles on oral drug absorption considering free fraction in intestinal fluid.

The purpose of the present study was to derive a theoretical framework for prediction of the food effects by interactions with bile micelles on oral drug absorption. The effect of bile micelles was discussed based on the categories of permeability limited (PL), dissolution rate limited (DRL) and solubility limited (SL) absorption. SL was further categorized as the solubility-epithelial membrane limited (SL-E) and the solubility-unstirred water layer (UWL) limited (SL-U). In PL, an increase of bile micelles in the fed state was suggested to result in a negative food effect if the drug molecules bind to bile micelles because of a decrease of free monomer concentration. In DRL, a positive food effect was anticipated. In SL-E (e.g., pranlukast), little or no food effect was anticipated since the increase of apparent solubility (bile micelle bound molecule+free molecule) would be cancelled out by the decrease of effective permeability (the free monomer concentration at the epithelial membrane surface would remain the same. Total flux=solubilityxpermeability). In SL-U (e.g., danazol), a positive food effect was anticipated since the bile micelle bound molecules can permeate the UWL (however, slower than free monomer molecules). Based on this discussion, it was suggested that a formulation which could increase the free fraction at the epithelial membrane surface would be required to enhance oral absorption for SL-E (e.g., supersaturable formulations), whereas any formulation which can increase the UWL flux would be effective for SL-U (e.g., micro- to nano-emulsion systems, nano-milling and cyclodextrins). It was also suggested that a simple dissolution test would be misleading for SL-E and a simultaneous assessment of dissolution and permeation would be required.