The present paper describes the rheological properties of hydroxypropylcellulose (HPC) gels formulated in propylene glycol (PG), water, ethanol, and mixtures of these components. The effects of molecular weight, polymer concentration, and solvent composition on the apparent viscosity and flow characteristics have been studied by continuous shear rheometry. The HPC gels are shear thinning and do not exhibit significant yield or hysteresis in their rheograms. The apparent viscosity increases with increasing molecular weight and concentration of the polymer, as expected. Although not so pronounced at lower concentrations (< or = 1.5%), HPC gels tend to become increasingly non-Newtonian with increasing molecular weight at higher polymer concentrations (3%). A mathematical model has been proposed for the prediction of viscosities of HPC gels. There exists a high degree of dependence on molecular interactions between various solvent molecules in the prediction of mixture viscosities in ternary systems. The effects of solvent composition on the viscoelastic behavior of these gels have also been examined by dynamic mechanical analysis. The HPC gels are highly viscoelastic and exhibit greater degrees of elasticity with increased PG content in ternary solvent mixtures with water and ethanol. The study also suggests that dynamic mechanical analysis could prove to be a useful tool in the determination of zero-shear viscosities, viscosities that are representative of most realistic situations.

A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discovered during the process to improve the physicochemical and metabolic properties of BIRT377 (1, Figure 1), a previously reported hydantoin-based LFA-1 inhibitor, these compounds are characterized by an imidazole-based 5,5-bicyclic scaffold, the 1,3,3-trisubstituted 1H-imidazo[1,2-alpha]imidazol-2-one (i.e. structure 3). The structure-activity relationship (SAR) shows that electron-withdrawing groups at C5 on the imidazole ring benefit potency and that oxygen-containing functional groups attached to a C5-sulfonyl or sulfonamide group further improve potency. This latter gain in potency is attributed to the interaction(s) of the functionalized sulfonyl/sulfonamide groups with the protein, likely polar-polar in nature, as suggested by SAR data. X-ray studies revealed that these bicyclic inhibitors bind to the I-domain of LFA-1 in a pattern similar to that of compound 1.

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This study examined the use of focused beam reflectance measurement (FBRM) for qualitative and quantitative analysis of pharmaceutical suspensions with particular application to toxicology supply preparations for use in preclinical studies. Aqueous suspensions of ibuprofen were used as prototype formulations. Initial experiments were conducted to examine the effects of operational conditions including FBRM probe angle, probe location, and mixing (method and rate of mixing) on the FBRM analysis. Once experimental conditions were optimized, the homogeneity and sedimentation-redispersion of particles in the suspensions were assessed. Ibuprofen suspension under continuous agitation was monitored using FBRM for 60 h to study particle size change over time. Another study was performed to determine if particle count rates obtained by FBRM could be correlated to suspension concentration. The location and the angle of the FBRM probe relative to the beaker contents, and the rate and the method of mixing the suspension were found to be sensitive parameters during FBRM analysis. FBRM was able to monitor the process of particle sedimentation in the suspension. The attrition of ibuprofen particles was detectable by FBRM during prolonged stirring with an increase in the number of smaller particles and decrease in the number of larger particles. A strong correlation was observed between particle count rate by FBRM and ibuprofen concentration in the suspension. Also, change in content uniformity in the suspension at different locations of the beaker was represented by FBRM particle count. Overall, FBRM has potential to be a useful tool for qualitative and quantitative analysis of pharmaceutical suspensions.

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