The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

A scaled down method for identifying the optimum range of L/S ratio in twin screw wet granulation using a regime map approach.

Twin screw wet granulation (TSWG) has gained momentum in the pharmaceutical industry for effective continuous granulation of solid dosage products. Liquid-to-solid (L/S) ratio is a key process parameter affecting granule properties. Identifying an optimum range of L/S ratio while reducing the number of full scale experiments can minimize material requirements and streamline formulation and process development. In this work, microcrystalline cellulose-based (MCC) formulations of varying drug loads were granulated using a kneading element screw configuration at a wide range of L/S ratios until pasting was visually determined. Quantitative criteria based on process relevant granule size and mass % of fines were established to identify undesirable granulation conditions. Key mechanical properties of wet compacts measured using a small scale approach are discussed. The stress-strain behavior is used to predict pasting, and natural strain at peak yield stress and total work of deformation are used to identify undergranulation and overgranulation respectively. The small scale method is used to establish viable ranges of L/S ratios in advance of at-scale experiments. A quantitative predictive growth regime map is proposed based fully on small scale experiments and input process parameters. Strategies for establishing a generalized growth regime map for various systems of interest are discussed.

Raman chemical mapping of magnesium stearate delivered by a punch-face lubrication system on the surface of placebo and active tablets.

Raman chemical mapping was used to determine the distribution of magnesium stearate, a lubricant, on the surface of tablets. The lubrication was carried out via a punch-face lubrication system with different spraying rates applied on placebo and active-containing tablets. Principal component analysis was used for decomposing the matrix of Raman mapping spectra. Some of the loadings associated with minuscule variation in the data significantly overlap with the Raman spectrum of magnesium stearate in placebo tablets and allow for imaging the domains of magnesium stearate via corresponding scores. Despite the negligible variation accounted for by respective principal components, the score images seem reliable as demonstrated through thresholding the one-dimensional representation and the spectra of the hot pixels that show a weak but perceivable magnesium stearate band at 1295 cm(-1). The same approach was applied on the active formulation, but no magnesium stearate was identified, presumably due to overwhelming concentration and spectral contribution of the active pharmaceutical ingredient.