Barbara Alice Johnson

V-blender segregation patterns for free-flowing materials: effects of blender capacity and fill level.

Stable segregation patterns are shown to form in V-blenders over a wide range of vessel capacities, fill levels, and rotation rates. Slight changes in either rotation rate or fill level induce changes in pattern formation. Trajectory segregation in two regions of the flow, accumulating over many flow periods, drives segregation pattern formation. Scaling criteria derived to relate particle velocities to vessel size and rotation rate in rotating cylinders successfully predict the rotation rate for the transition between patterns across V-blenders of 0.8-26.5 quart total capacity. This agreement suggests that pattern formation is governed by the magnitude of particle velocities. Regardless of vessel size, when particle velocities at specific regions of the blender are below a certain value, one particular pattern appears, and when they increase beyond that speed (i.e. by changing the rotation rate or the vessel size), a different pattern emerges. A scaling relation between segregation pattern formation and blender fill level was not identified because the complex flow patterns in the V-blender (the length of the flowing layer and the mixture center of mass relative to the blender are constantly oscillating) preclude the determination of a relationship between blender fill level and particle velocities.

Use of the antioxidant BHT in asymmetric membrane tablet coatings to stabilize the core to the acid catalyzed peroxide oxidation of a thioether drug.

The application of a controlled-release asymmetric membrane (AM) coating containing cellulose acetate and polyethylene glycol 3350 (PEG3350) to a stable osmotic tablet core resulted in the oxidative degradation of active ingredient located in the core. It was hypothesized that the production of hydroperoxides from PEG3350 in the coating was responsible for the electrophilic oxidation of drug to the sulfoxide degradation product. The type and solubility of carboxylic acid excipient used to formulate the drug release profile of the osmotic tablet significantly influenced the amount of oxidation. By adding the antioxidant butylated hydroxytoluene (BHT) to the coating, oxidation was significantly inhibited in tablets placed on accelerated stability. Of three additives that were used to prevent oxidation [BHT, ferrous sulfate, and ethylenediaminetetraacetic acid (EDTA)], BHT was shown to be the most effective at preventing sulfoxide formation. The BHT was also shown to be more effective in the coating rather than in the core due to its location closer to the source of the oxidizing species, PEG3350, in the coating.

Effects of food on a gastrically degraded drug: azithromycin fast-dissolving gelatin capsules and HPMC capsules.

ABSTRACTPurposeCommercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with “superdisintegrants” to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect.MethodsHealthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules.ResultWhen the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®.ConclusionInteraction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin bioavailability in the fed state is largely (and probably entirely) due to gastric degradation to DCA. Capsules can provide a useful and elegant dosage form for almost all drugs, but may result in a negative food effect for drugs as acid-labile as azithromycin.

Characterizing the Structure of Pharmaceutical Granules Obtained by Wet Granulation with Varying Amounts of Water via Raman Chemical Imaging

A pharmaceutical formulation containing metformin hydrochloride (MET), hydroxypropyl cellulose (HPC), and microcrystalline cellulose (MCC) was wet granulated with varying amounts of water and the structure of the obtained granules was characterized by Raman chemical mapping. Univariate Raman mapping was found to be satisfactory for producing the images of the two components of interest (HPC and MCC). In addition to the images, the average Raman spectra from the maps as well as the micro-Raman spectra from the hot pixels were analyzed. HPC is found to strongly respond to the addition of water, with its domain dissipating and Raman bands becoming weaker as the water addition increases. MCC is also responsive to water, reacting similarly to HPC but to a much smaller extent and only for the largest amounts of water. Granules made with increasing water content also have improved tabletting properties and flow.