Equilibrium and Kinetic Factors Influencing Bile Sequestrant Efficacy

In vitro bile salt binding equilibria and kinetic studies were performed with cholestyramine to determine how these factors influence bile sequestrant efficacy in vivo . Chloride ion at physiologic concentrations caused more than a twofold reduction in glycocholate (GCH) binding, compared to binding in the absence of salt, over a range of GCH concentrations and was also observed to displace bound GCH. In addition, chloride ion displaced from cholestyramine as a result of bile salt binding was measured using a chloride selective electrode, and the results show that bile salt binding is due to ion exchange. Comparison of the results of the equilibrium binding experiments to human data shows that the effect of anion binding competition alone cannot account for the lack of efficacy of cholestyramine. Consideration of other effects, such as additional binding competition or poor availability for binding, based on data from the literature, shows that adequate bile salt binding potential exists and that these interferences are not major factors influencing resin efficacy. In kinetic studies, both binding uptake of GCH and displacement of GCH from cholestyramine by chloride ion were relatively rapid, indicating that cholestyramine should equilibrate rapidly with bile salts in the GI tract. Based on these findings, it is suggested that the low efficacy of cholestyramine is a result mainly of its relatively poor ability to prevent bile salt reabsorption in the ileum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41572/1/11095_2004_Article_305164.pd

Evaluation of Milling Method on the Surface Energetics of Molecular Crystals Using Inverse Gas Chromatography

The objective of this study was to determine whether high shear wet milling (HSWM) has an impact on the surface properties of model pharmaceutical compounds compared to dry milling (DM, impact milling). The bulk and surface properties of milled samples were characterized by solid-state methods (XRPD, TGA, DSC, microscopy) and inverse gas chromatography (IGC). The bulk properties of both model compounds (succinic acid and sucrose) were unaffected by milling method. For succinic acid, the solvents methyl <i>tert</i>-butyl ether (MTBE) and isopropyl acetate resulted in small changes in surface properties of the powders relative to the DM material. In HSWM, the dispersive surface free energy of sucrose depended on the solvent polarity, changing from 55 to 71 to 90 mJ/m², for hexane, MTBE, and ethanol, respectively, whereas the DM material had a value of 44 mJ/m². The surface free energy difference between DM and HSWM was not attributable to specific solvent adsorption and was shown to be caused by a combination of attrition in the presence of solvent. Analysis of the slip planes and σ surfaces for the compounds supported the nature of particle attrition and its impact on surface energics. Assessment of surface energetics may be used to establish consistency of drug substance surface characteristics when previously established milling processes are modified

Quantifying crystal form content in physical mixtures of (±)-tartaric acid and (+)-tartaric acid using near infrared reflectance spectroscopy

The objective of this study was to use diffuse reflectance near infrared spectroscopy (NIRS) to determine racemic compound content in physical mixtures composed primarily of the enantiomorph and to assess the error, instrument reproducibility and limits of detection (LOD) and quantification (LOQ) of the method. Physical mixtures ranging from 0 to 25% (±)-tartaric acid in (+)-tartaric acid were prepared and spectra of the powder samples contained in glass vials were obtained using a Foss NIRSystems Model 5000 monochrometer equipped with a Rapid Content Analyzer scanning from 1100 to 2500 nm. A calibration curve was constructed by plotting (±)-tartaric acid weight percent against the 2nd derivative values of log (1/R) vs λ at a single wavelength, normalized with a denominator wavelength (1480 nm/1280 nm). Excellent linearity was observed (R2=0.9999). The standard error of calibration (SEC) was 0.07 and the standard error of prediction (SEP) for the validation set was 0.11. Instrument and method errors for samples in the 2% composition range ((±)-tartaric acid in (+)-tartaric acid) were less than 1% RSD and 3% RSD, respectively. The practical LOD and LOQ were 0.1% and 0.5%, respectively, and comparable to the calculated LOD and LOQ. These studies show that NIRS can be used as a rapid and sensitive quantitative method for determining racemate content in the presence of the enatiomerically pure crystal in the solid-state