Development of a topically active imiquimod formulation.

The purpose of this work was to develop a topical formulation of imiquimod, a novel immune response modifier, to induce local cytokine production for the treatment of external genital and perianal warts. A pH-solubility profile and titration data were used to calculate a pKa of 7.3, indicative of a weak base. Solubility experiments were conducted to identify a solvent that dissolves imiquimod to achieve a 5% formulation concentration. Studies to select surfactants, preservatives, and viscosity-enhancing excipients to formulate an oil-in-water cream indicated that fatty acids were the preferred solvent for topical imiquimod formulations, and isostearic acid (ISA) was selected. A relationship existed between the fatty acid composition of four commercially available ISA sources and the solubility of imiquimod. A combination of polysorbate 60, sorbitan monostearate, and xanthan gum was used to produce a physically stable cream. The preservative system included parabens and benzyl alcohol to meet the USP criteria for preservative activity. An in vitro method was developed to demonstrate that imiquimod was released from the formulation. Topical application of the formulation induced local cytokine activity in mice.

Solubility behavior of lamivudine crystal forms in recrystallization solvents.

Lamivudine can be obtained as acicular crystals (form I, 0.2 hydrate) from water or methanol and as bipyramidal crystals (form II, nonsolvated) from many nonaqueous solvents. Form II is thermodynamically favored in the solid state (higher melting point and greater density than form I) at ambient relative humidities. Solubility measurements on both forms versus solvent and temperature was used to determine whether entropy or enthalpy was the driving force for solubility. Solution calorimetry data indicated that form I is favored (less soluble) in all solvents studied on the basis of enthalpy alone. In higher alcohols and other organic solvents, form I has a larger entropy of solution than form II, which compensates for the enthalpic factors and results in physical stability for form II in these systems. The metastable crystal form solubility at 25 degrees C was estimated to be 1.2-2.3 times as high as the equilibrium solubility of the stable form, depending on the temperature, solvent, and crystal form. Binary solvent studies showed that > 18-20% water must be present in ethanol to convert the excess solid to form I at equilibrium.

Characterization of a hot-melt fluid bed coating process for fine granules.

The equipment modifications and process changes necessary to perform hot-melt particle coating in a fluid bed granulator are reviewed. A specific case is presented in which partially hydrogenated cottonseed oil is coated onto fine granules (mean particle size, 77 microns; range, 10-150 microns; one standard deviation is 10 microns) composed of a hydrophobic drug and sucrose. The major variables were product bed temperature, temperature of the wax, spray rate, and atomization air pressure. The product bed temperature was selected to give the optimum congealing rate, and the latter three variables were varied in a statistically designed experiment. The physical properties of wax-coated granules fabricated using combinations of process variables were examined. Response surface analysis was used to determine the optimum process settings in terms of dissolution, particle size, and density of the coated product. This system proved quite adequate for the production of uniformly coated granules, with the best product being obtained at the optimized conditions using 120 degrees C atomization air and molten coating temperature, 30 g/min as the spray rate, and an atomization air pressure of 5 bar.

Studies on adsorptiochromism. II: Diffuse reflectance spectroscopy of adsorptiochromic spiropyrans adsorbed to some pharmaceutically useful solids.

The colored powders produced by the adsorption of four adsorptiochromic spiropyrans to many solids (silica gel, silicic acid, fumed silica, alumina, microcrystalline cellulose, talc, titanium dioxide) were examined by diffuse reflectance spectroscopy. The reflectance spectra were dominated by two bands, one at 550 nm and the other in the range 400-500 nm, often at 472 nm. Plots of the Kubelka-Munk function [F(R' infinity)] against g, the coverage expressed in nmol/m2, were linear at very low g and approached a limiting value independent of g at high coverage. The color formation upon adsorption terminates at coverages much lower than the maximum binding capacity of the solid. The slope of the plot of F(R' infinity) against g, at low g (denoted f0), appears to be sensitive to the scattering properties of the solid. For a single solid (silica gel), comparison of f0 for adsorptiochromic adsorbates with f0 for permanent dyes allowed estimates to be made of the fraction of adsorbed spiropyran in the colored form on the surface.

Studies on adsorptiochromism. I: Binding of adsorptiochromic spiropyrans to some pharmaceutically useful solids.

The adsorption of four adsorptiochromic spiropyrans to many solids (silica gel, silicic acid, fumed silica, alumina, microcrystalline cellulose, talc, titanium dioxide) was studied at 25 degrees C from cyclohexane solution. Nineteen adsorption isotherms were determined; and the binding data were fitted to the Langmuir equation. A model for binding of adsorptiochromic substances is described, and the parameters of the model are related to the experimental binding constant K.

Estimation of surface polarity of silicas by absorption spectroscopy of glycerin suspensions of adsorbed 6-nitrobenzoindolinopyran.

The title compound (6-NO2-BIPS) is adsorptiochromic, becoming colored upon adsorption to a polar surface. Powders of 6-NO2-BIPS adsorbed to silica gel or silicic acid are suspended in glycerin, and the absorption spectrum of the adsorbate is recorded by conventional absorption spectroscopy. The wave number of maximum absorption is related to the effective surface polarity by v*/cm-1 = 90.85 Z + 11,571, where Z is the Kosower polarity measure. Silica surface polarity corresponds to Z = 86-89.