Roger L. Schnaare

Antimicrobial Evaluation of N-Alkyl Betaines and N-Alkyl-N,N-Dimethylamine Oxides with Variations in Chain Length

ABSTRACT Alkyl betaines and alkyl dimethylamine oxides have been shown to have pronounced antimicrobial activity when used individually or in combination. Although several studies have been conducted with these compounds in combinations, only equimolar concentrations of the C12/C12 and C16/C14chain lengths for the betaine and the amine oxide, respectively, have been investigated. This study investigates the antimicrobial activity of a wide range of chain lengths (C8 to C18) for both the betaine and amine oxide and attempts to correlate their micelle-forming capabilities with their biological activity. A broth microdilution method was used to determine the MICs of these compounds singly and in various molar ratio combinations. Activity against bothStaphylococcus aureus and Escherichia coli was investigated. Antimicrobial activity was found to increase with increasing chain length for both homologous series up to a point, exhibiting a cutoff effect at chain lengths of approximately 16 for betaine and 14 for amine oxide. Additionally, the C18 oleyl derivative of both compounds exhibited activity in the same range as the peak alkyl compounds. Critical micelle concentrations were correlated with MICs, inferring that micellar activity may contribute to the cutoff effect in biological activity.

Drug Release from Film-Coated Chlorpheniramine Maleate Nonpareil Beads: Effect of Water-Soluble Polymer, Coating Level, and Soluble Core Material

The purpose of this research was to use a new drug release model to study the effects of formulation parameters on drug release from a film-coated chlorpheniramine (CPM) nonpareil system. The film-coated CPM nonpareils were prepared by using a fluid bed apparatus. A hydroxylpropylmethylcellulose (HPMC) solution was blended with an aqueous ethylcellulose dispersion (Surelease) to adjust the permeability of the film. The apparent permeability of samples was obtained from dissolution data using a previously reported drug release equation. The apparent permeability was plotted versus the film coating level or the HPMC concentration in the film. When the natural logarithm of the apparent permeability versus coating level was graphed, a biphasic plot was observed in the group without HPMC in the film, showing the occurrence of a critical coating level. It was suggested that a mechanically formed porous film (due to an incomplete coating) could change to a nonporous film after the bead was completely coated. However, in the group that contained 12% HPMC in the film, the critical coating level was not observed. A porous film, formed by the leaching out of the water-soluble polymer, would not change to a nonporous film even after the bead is completely coated. Through a mathematical derivation, the decrease of apparent permeability versus coating level was related to the reduction of the total hole area. The apparent permeability was found to increase with the HPMC concentration. After a critical concentration was reached, the further addition of HPMC into the film caused a rapid increase in apparent permeability. The critical HPMC concentration was related to a minimum domain formation concentration (MDFC). A rapid increase of the drug release was observed when the dissolution profile of a sample made from a regular sugar nonpareil core (soluble) was compared with the sample made from a precoated nonpareil core (insoluble), which suggests that the drug release can be enhanced by the dissolution of the core. A minimum concentration of the HPMC was required to effectively modify permeability of the film. The critical coating level and critical concentration of HPMC can be determined from the apparent permeability plot using a previously published equation. The dissolution of a soluble core can greatly enhance the release of the drug from the nonpareil system.

Bead Coating. I. Change in Release Kinetics (and Mechanism) Due to Coating Levels

Beads containing 50% acetaminophen (APAP) and 50% microcrystalline cellulose (Avicel PH 101) were prepared and then coated using an aqueous ethylcellulose based dispersion (Aquacoat) to evaluate the effect of the coating level on drug release. The APAP release was shown to be dependent on levels of the coating and a change in mechanism was suggested. Drug release from incompletely coated beads at low levels of coating can be described with the square root of time model, while drug release from beads with a high level of coating appears to be best described by zero-order release. At low coating levels, the drug release rate constant based on the square root relationship seems to be linear with the coating level. At high coating levels, drug release rate in terms of a zero-order model appears to be proportional to the reciprocal of the coating level.

Synthetic cervical mucus formulation

A synthetic formulation has been developed with viscosity, spinnbarkeit, and pH comparable to that reported for human cervical mucus. The formulation contains guar gum crosslinked with borate ion, mucin (dried porcine gastric), and a mixed preservative system in pH 7.4, 0.1M phosphate buffer. The guar gum source, mucin concentration, and method of preparation were shown to be critical factors in the performance of the formulation.

Compaction Studies on Beads: Compression and Consolidation Parameters

AbstractThe purpose of this work was to evaluate compaction of the beads containing microcrystalline cellulose (MCC). Although MCC in its powder form is universally recognized as a very compressible material, studies in these laboratories demonstrated that MCC beads prepared by extrusion/spheronization were not. In fact, MCC beads are very hard and not easily deformable or broken. Therefore, the objectives of this work were to modify the bead composition by incorporating materials which might change the bead compactibility and to describe the effects. The dissolution properties of the compacted forms were also evaluated.To study the compaction behavior of the MCC beads it was necessary to modify the Athy-Heckel equation to describe compression and to combine that analysis with the Leuenberger equation to describe consolidation.

Effect of Spheronization Technique on Drug Release from Uncoated Beads

AbstractSpheronization techniques are finding increased utility in pharmaceutical research and production. In this investigation emphasis is on the effect of two different spheronization methods (pan versus marumerizer) on drug release from uncoated beads containing acetaminophen and microcrystalline cellulose at a 1:1 ratio. Drug release from the pan beads is much faster than that from the marumerizer beads. The pan beads disintegrate during the dissolution testing, while beads made via the extruder and marumerizer appear to behave as an inert matrix system.

Bead Coating: II. Effect of Spheronization Technique on Drug Release from Coated Spheres

AbstractThe effect of spheronization method on drug release from coated spheres may be evaluated by determining the drug release rate, the critical coating level and the release mechanism. Drug release is faster from pan beads than from marumerizer beads at the same coating level. An equation is proposed which indicates that the critical coating level is inversely proportional to sphere size and sphere density, which in turn results from the different spheronization techniques. From the calculation, the critical coating levels for 14/16 mesh cuts of marumerizer beads and pan beads are 12% and 18%, respectively. Disintegration, pore-control and barrier control are involved in the release mechanisms of drugs from coated pan beads.

In vitro test to evaluate the interaction between synthetic cervical mucus and vaginal formulations

The interaction and mixing between a bilayer sample of mucus and vaginal formulation was evaluated through viscosity measurements with respect to time and shear. Physical mixtures of mucus and vaginal formulation were used as controls. Three test protocols were designed: (1) constant shear, (2) intermittent shear, and (3) delayed shear. Several marketed vaginal products (Gynol II, KY Plus, KY, and Advantage-S) and experimental formulations (C31G with hydroxyethylcellulose [HEC]) were evaluated and compared by these tests. The results of the constant shear test showed that the shear stress profile of the bilayer approached that of the corresponding physical mixture, consistent with complete mixing of the bilayer under shear. The time taken for the bilayer to mix completely was in the following order: KY Plus > Gynol II and C31G > KY > Advantage-S. Under the intermittent shear protocol, the following order for complete mixing was observed: KY Plus > C31G > Gynol II > KY > Advantage-S. The 2 products evaluated by the delayed shear test, C31G and Gynol II, were both completely mixed at 180 minutes. The development of an in vitro test, when coupled with in vivo data, should serve in the screening and evaluation of future vaginal formulations.

Gas chromatographic analysis of theophylline in human serum.

Abstract A method is presented for the analysis of theophylline in human serum. The method is specific with no interference from theophylline metabolites, ephedrine, hydrocortisone, or caffeine and their metabolites. It is sensitive to approximately 1 μg/ml and analyses over the range of 5–11 μg/ml were found to have an average relative error of 7.5%.

A Multimechanistic Drug Release Approach in a Bead Dosage Form and In Vitro Predictions

The objective of this study was to prepare a combination of immediate release, enteric coated, and controlled release (CR) beads and to mathematically model in vitro drug release characteristics of the combination based on the release profiles of individual beads. Uncoated beads were manufactured by using extrusion/spheronization technology. Fluid-bed bottom spraying was used for coating: Eudragit-L-30D for enteric coating and Eudragit-NE-30D for CR coating. In vitro drug release profiles for uncoated and coated beads were each fitted to appropriate mathematical equations. The drug release from the bead combination dosage form was predicted from the individual mathematical models and verified experimentally in vitro. The in vitro dissolution was conducted in 0.1 N HCl for 2 hr and then in buffer (pH 6.5 phosphate, 0.05 M) to mimic in vivo conditions using USP dissolution apparatus I. The results showed that uncoated beads gave similar release profiles in water, acid, and buffer with complete release within 2 hr. The release from CR beads was about 50% at 10 hr and was independent of the dissolution medium. As expected, enteric coated beads showed drug release <5% at 2 hr in water and acid, whereas the release in buffer was comparable to that of uncoated beads. Exposure of enteric coated beads to acid for 2 hr produced a slower release rate in buffer compared with the release from beads added directly in the buffer. The release characteristics of the three beads can be described by square root and zero-order kinetics. The release characteristics from the combination dosage form were 39%, 69%, and 81% at 1, 4, and 8 hr, respectively. The experimental and predicted profiles agreed to within ±6% (residuals at individual data points). Our results suggest that release from the combined multimechanism oral dosage form can be predicted from the performance of individual beads.