Absorption, Distribution and Excretion of Four Forms of Titanium Dioxide Pigment in the Rat.

Titanium dioxide (TiO2 ) is a white color additive that has a long history of global approval and use in food. There is, however, considerable confusion regarding the applicability of the biological effects of novel, engineered, nano-sized forms of TiO2 developed for nonpigmentary applications to the safety of oral exposure to food grade TiO2 pigment. The objective of this study was to assess the absorption, distribution, and routes of excretion in rats after oral exposure to food grade TiO2 . Four different grades of TiO2 (200 ppm) or control (0 ppm) diets were fed to rats for 7 consecutive days, followed by control diet only for 1, 24, or 72 h. Concentrations of titanium in liver, kidney and muscle were mainly below the limit of detection (<0.1 to < 0.2 mg/kg wet weight); tissue concentrations of titanium above the LOD were in the range of 0.1 to 0.3 mg/kg wet weight for all groups. Whole blood concentrations of titanium were <0.04 mg/L for all groups. Urinary excretion of titanium was equivalent to <2% daily dose/L of urine for all groups and was generally below the limit of quantification (<0.04 mg/L). Feces represented the predominant route of excretion. These results demonstrate that there is no accumulation of titanium in tissues following consumption of diets containing 200 ppm food grade TiO2 . No differences in systemic absorption of the 4 forms of TiO2 were observed indicating that the bioavailability of TiO2 is consistently low for the range of particle sizes and morphologies examined in this study.

Investigation of critical core formulation and process parameters for osmotic pump oral drug delivery.

Push-pull osmotic pump (PPOP) tablets of a practically insoluble model drug were developed and the effect of various formulation and process parameters on tablet performance was evaluated in order to identify critical factors. The formulation factors such as the viscosity grade of polyethylene oxide as the primary polymer as well as the level and location of osmogen within the bilayer tablets led to a difference in performance of osmotic tablets and hence should be critically evaluated in the design of such dosage forms. Modification of granulation process, i.e., the granulating liquid composition or drying method of granules, did not impact the drug release from the osmotic tablets at the evaluated scale of this study. The influence of varying dose and aqueous solubility of other model drugs (i.e., theophylline, acetaminophen, and verapamil HCl) on the developed PPOP template was also investigated. Results showed that irrespective of the perceived complexity of development and manufacturing of osmotic pumps, the osmotic tablets in this study demonstrated a robust and yet flexible platform in accommodating different types of drug candidates, regardless of solubility, for the dose levels below 25% w/w of the pull layer formulation.

Process optimization of a novel immediate release film coating system using QbD principles.

This work describes a quality-by-design (QbD) approach to determine the optimal coating process conditions and robust process operating space for an immediate release aqueous film coating system (Opadry® 200). Critical quality attributes (CQAs) or associated performance indicators of the coated tablets were measured while coating process parameters such as percent solids of the coating dispersion, coating spray rate, inlet air temperature, airflow rate and pan speed were varied, using a design of experiment protocol. The optimized process parameters were then confirmed by independent coating trials. Disintegration time of coated tablets was not affected by the coating process conditions used in this study, while tablet appearance, as determined by measurement of tablet color, coating defects and gloss was determined to be a CQA. Tablet gloss increased when low spray rate and low percent solids were used, as well as with increased coating pan speed. The study used QbD principles and experimental design models to provide a basis to identify ranges of coating process conditions which afford acceptable product quality. High productivity, color uniformity, and very low defect levels were obtained with Opadry 200 even when using a broad range of coating process conditions.

Mechanism of synergistic interactions and its influence on drug release from extended release matrices manufactured using binary mixtures of polyethylene oxide and sodium carboxymethylcellulose.

The ability of anionic polymer sodium carboxymethylcellulose to influence the release of four model cationic drugs (chlorpheniramine maleate, venlafaxine hydrochloride, propranolol hydrochloride and verapamil hydrochloride) from extended release (ER) hydrophilic matrices based on non-ionic polymer polyethylene oxide was investigated by X-ray photoelectron spectroscopy (XPS), isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). For all studied APIs, a combination of polyethylene oxide with sodium carboxymethylcellulose produced slower drug release compared to the matrices of single polymers. This behaviour was mainly attributed to the interaction of ester/carboxylic acid functionalities to yield H-bonding between the anionic polymer groups and the additionally protonated N-atoms of the active substances. X-ray photoelectron and isothermal titration calorimetry studies confirmed drug-polymer interaction and polymer-polymer interaction (i.e. the PEO binding with negatively charged NaCMC), whilst differential scanning calorimetry indicated the existence of both crystalline and molecularly dispersed active forms in the created complexes. The drug release mechanisms were fitted to various models suggesting diffusion control for the majority of the formulations. The Korsmeyer-Peppas model was found to be the most suitable for description of release profiles of all formulations. The present study showed that XPS and ITC in combination with DSC can be valuable tool to investigate the presence and nature (mechanism) of synergistic interactions between polymers and drugs in extended release matrix tablets.