Alternatives to titanium dioxide in tablet coating.

Titanium dioxide (TiO2) is one of the most commonly used pharmaceutical excipients. It is widely used as a white pigment in tablet and pellet coatings. However, it has recently been under massive criticism as a number of studies suggest a cancerogenic potential. It can therefore no longer be taken for granted that TiO2 will continue to be universally available for drug products. Finding suitable alternatives is hence of special relevance. In this study, a number of different pigments were coated on tablets and their covering potential analyzed. None of the alternative pigments showed comparable effectiveness and efficiency to TiO2, though the CaCO3/CaHPO4-based coating showed the second-best results. Regarding the ability to protect photosensitive active ingredients, ZnO showed a comparable potential as TiO2, while all other pigments failed. Using the alternative pigments as markers for in-line Raman spectroscopy as a process analytical technology was challenging and led to increased prediction errors. Again, the CaCO3/CaHPO4-based coating was the only of the tested alternatives with satisfying results, while all other pigments led to unacceptably high prediction errors.

Raman Spectroscopy as a PAT-Tool for Film-Coating Processes: In-Line Predictions Using one PLS Model for Different Cores.

Although Raman spectroscopy has been described as a potential process analytical technique for tablet coating, it has rarely been transferred from academic studies to commercial manufacturing applications. The reasons for this are probably not only the high level of process understanding and experience with multivariate data analysis required, but also the product-dependent elaborate model-building. Hence, this study represents a feasibility study to investigate, whether subtraction of core spectra is a suitable approach to generate versatile models for one specific coating that can be applied on a multitude of different tablet cores. Raman spectroscopy was used to predict the application of coatings on three different tablet cores using PLS regression. The obtained spectra were preprocessed, and differential spectra were calculated by subtraction of the core spectrum from each inline spectrum. Normalization ensured comparability between the spectral data of the different cores. It was shown that in general it is possible to build models for a specific coating suspension that can predict the application of this suspension on different cores. In the presence of a strong Raman marker (TiO2), promising results were obtained. Without the presence of a strong Raman marker this modeling approach is to be considered critical.

Real-time monitoring of multi-layered film coating processes using Raman spectroscopy.

Raman spectroscopy was used as an in-line PAT tool to predict the applied coating mass of three different coating layers on caffeine cores. The different coating suspensions contained titanium dioxide in the anatase and rutile modification and iron oxide as Raman markers. Partial least squares-regression (PLSR) and multivariate curve resolution-alternating least squares (MCR-ALS) were used for multivariate analysis. The acquired Raman spectra were correlated to the applied coating mass. MCR-ALS models were built and applied offline, while PLS-regression was implemented in the coating process to enable a real-time monitoring. Inline-measurements were optimized by a higher frequency of the spectral measurements and the implementation of a moving average. By PLS-regression analysis, all three layers could be predicted with root mean square errors (RMSEP) of less than 2.3%. Inline implementation and optimization resulted in RMSEPs less than 1.9%. MCR-ALS analysis was able to predict the application of the first and the second layer with RMSEPs less than 2.9%, but failed in predicting the application of the third layer. In conclusion, a real-time monitoring of a multi-layered coating process was achieved, PLS-regression was found to be superior to MCR-ALS and smoothing by the implementation of a moving average enhanced the predictability.

Effect of coating time on inter- and intra-tablet coating uniformity.

Film tablets are a common oral dosage from. For many of the functions film layers can have on pharmaceutical tablets, a high degree of coating uniformity is required. In studies on coating uniformity the coefficient of variation is commonly used as a marker. Previous studies regarding the trend were mostly extrapolations from simulations of short coating times. Based on these it was stated that the inter tablet coefficient of variation decreases proportionally to one over the square root of coating time and hence diverge asymptotically towards zero. Extrapolations of experimental data suggested however a decrease converging to a residual value. Based on these results it can be hypothesized that the coefficient of variation decreases proportionally to one over time towards a residual value. Regarding intra-tablet coating homogeneity, no data on time dependency has been published so far. In this study, three long time coating experiments were performed to test the described hypotheses. The inter-tablet uniformity was derived gravimetrically, while the intra-tablet data was derived using micro-computed tomography and confocal chromatic thickness determination. Towards the end of the coating experiments, a non-zero plateau of inter-tablet uniformity was reached. Furthermore, the data showed non-random deviations from the hypothesized one-over-square-root-of-time-model. The data for intra-tablet uniformity showed a non-linear decrease as well, but did not allow falsification of either hypothesis. It was additionally found that the cap-to-band ratio was below one at short coating times and increased to values above 1 during the process, which implies that existing declarations from literature might be limited to certain process durations.