Comparison of biorelevant simulated media mimicking the intestinal environment to assess the solubility profiles of poorly soluble drugs.

During the discovery stage in lead identification/optimization, compounds are characterized for their solubilities in biorelevant media and these data are often used to model the in vivo behavior of the compounds and predict the fraction absorbed. These media are selected to closely approximate the composition of human intestinal fluid. Owing to the complexity and variability in human intestinal fluid composition, it is essential that the chosen simulated media mimic the in vivo condition as closely as possible. Several recipes have been developed and are routinely used in assessing the solubilities of compounds. It is necessary to revisit these recipes and modify them as the understanding of the human GI tract increases. In the present work, we have evaluated the solubilities of six model compounds in several media and have proposed slight modifications to the currently used recipes based on our own data and that reported in the literature.

Correlation of inhibitory effects of polymers on indomethacin precipitation in solution and amorphous solid crystallization based on molecular interaction.

PURPOSE: To correlate the polymer's degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state. METHODS: Precipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers. RESULTS: PVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90 > Eudragit E100 > HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers. CONCLUSIONS: Correlation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.