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The physicochemical properties of mesalamine and the effect of pH and buffer concentration on the dissolution rate of pure mesalamine and mesalamine with Carbopol 974P were investigated. The aqueous solubilities at 25 and 37 degrees C were 0.844 and 1.41 mg/mL, respectively. Consistent with the observed pKa1 (2.30) and pKa2 (5.69) or mesalamine, the solubility-pH profile is increased at pH < 2.0 and pH > 5.5 and is minimized from pH 2.0 to pH 5.5. The flux data were consistent with the solubility data from pH 1.0 to pH 5.5. The flux increased and plateaued at pH values 5.5 to 7.0 and was dependent on the bulk buffer concentration. At low bulk buffer concentrations, mesalamine reduces the pH in the diffusion layer, which results in a decrease in flux. The medium with the highest buffer capacity has a greater ability to increase the surface pH and dissolution rate. The addition of Carbopol reduces the flux and the sensitivity of the dissolution rate of mesalamine to increasing bulk buffer concentration. This reduction is postulated to be due to neutralization of the basic dissolution media, gel formation, and possible drug-polymer interactions.

Spray drying is a way to generate protein solids (powders), which is also true for lyophilization. Sugars are used to protect proteins from conformational changes and chemical degradations arising from drying processes and storage conditions such as the humidity. The influence of trehalose and humidity on the conformation and hydration of spray-dried recombinant human granolucyte colony stimulating factor (rhG-CSF) and recombinant consensus interferon-alpha (rConIFN) was investigated using Fourier transform IR spectroscopy. The spectral analysis of spray-dried powders in the amide I region demonstrated that trehalose stabilized the alpha-helical conformation of both rhG-CSF and rConIFN proteins. Exposure of the pure protein powders to 33% relative humidity (RH) resulted in the formation of beta sheets and loss of turns but no change in alpha-helical structure. Trehalose reduced the magnitude of the changes in beta sheets and turns. Exposure of the pure protein powders to 75% RH resulted in the loss of alpha-helical conformation with a corresponding increase in beta structures (beta sheets and turns). Trehalose did not protect proteins from the loss of alpha-helical structures, but it reduced the formation of antiparallel beta sheets. Hydrogen-deuterium exchange (H-D exchange) was used to further characterize these hydration-induced conformational changes. At 33% RH the percent exchange of the protein decreased with increasing trehalose content, indicating a greater protection of the protein from H-D exchange by a higher concentration of trehalose. Such protection correlates with decreased conformational changes of the protein by trehalose at this humidity. At 75% RH the degree of H-D exchange of the protein was insensitive to the powder composition in all powders. Surprisingly, the H-D exchange of trehalose was low at about 20-25%, which was nearly independent of the protein/trehalose ratio and humidity, indicating that the exchangeable protons on trehalose molecules are highly protected in protein-containing powders. The observed protein hydration is related to the effect of trehalose on the conformational changes of the protein under humidity.

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The release rate kinetics of mesalamine and benzoic acid correlated to the measured concentration profiles. The shape of the concentration profiles is determined by the rate of growth of the Carbopol gel layer and drug diffusivity.