An insight into powder entrainment and drug delivery mechanisms from a modified Rotahaler®.

This study aims to improve understanding of the powder fluidisation and aerosolisation processes unique to a split capsule dry powder inhaler. It uses a combination of dynamic real-time methods and a suite of powder material physicochemical characterisation methods. The study focused on examining the effect of different characteristics of lactose carrier employed, and considered specifically the powder fluidisation, entrainment and de-agglomeration mechanisms. A GSK Rotahaler(®) was selected as the inhaler device. Powder fluidisation and entrainment were investigated using the ensemble technique of laser diffraction and high-speed imaging. This ensemble technique afforded both the powder entrainment profile and simultaneous visual confirmation of the capsule movement and powder fluidisation within the Rotahaler. The results showed that powder fluidisation from a dynamic split capsule was substantially different to that from a static powder bed. Furthermore, the presence of the split capsule dominated powder emission mechanisms from the Rotahaler, regulated by its impaction on the grid/Rotahaler wall and the rotational movement in the entrained air. Of all the material characterisation metrics, the most significant linear correlation was revealed between powder permeability and the aerosolisation efficiency as measured by fine particle fraction (R(2)=0.98). This indicates that drug delivery from the Rotahaler was mainly governed by the influence of the cohesive fine particle size component. Powder permeability as a practical test may afford an effective and practical predictive link between the raw excipients and drug delivery performance from the capsule device.

Investigating dissolution performance critical areas on coated tablets: a case study using terahertz pulsed imaging.

During the process development of coated tablets, knowledge on the formation and the location of film coating 'weak spots' is a key factor to the success of the process and the resulting product batch. It is understood that the performance of the product batch may be greatly limited, and often compromised, by weak spots on the tablet film coat. This study uses circular, biconvex tablets to investigate the ability of terahertz pulsed imaging (TPI) to identify the affected areas on the tablet film coat that are critical for dissolution performance. From the TPI analysis we determined that the tablet central band exhibited the thinnest film coating, lowest coating density and highest surface roughness and thus was the performance limiting area of the film coating. Dissolution tests confirmed that the film coating on the tablet central band was indeed dissolution rate determining, with a faster mean dissolution time (MDT) of 7.4 h in comparison to 10.4 h for the convex top/bottom surface. TPI, as a nondestructive analytical technique, showed potential to be employed as a process analytical tool to probe film coating weak spots during film coating development and to assess the effect on the subsequent dissolution performance.

Effects of film coating thickness and drug layer uniformity on in vitro drug release from sustained-release coated pellets: a case study using terahertz pulsed imaging.

Film coating thickness and terahertz electric field peak strength (TEFPS) were determined using terahertz pulsed imaging (TPI) and employed for the analysis of sustained-release coated pellets (theophylline layered sugar cores coated with Kollicoat SR:Kollicoat IR polymer blends). The effects of coating thickness, drug layer uniformity and optional curing were investigated using eight batches of pellets. Ten pellets from each batch were imaged with TPI to analyse the coating morphology (depicted in TEFPS) and thickness prior to release measurements. The results showed TEFPS values of 15.8% and 14.5% for pellets with a smooth drug layer coated at 8.2 and 12.5% (w/w) polymer weight-gain, respectively. Whereas 6.7% was derived for pellets with a coarse drug layer coated at both weight-gains. Although there were major differences in TEFPS, the resulting drug release kinetics were very similar. It was also shown that a 36 microm coating thickness difference was not drug release rate determining. These results suggested that drug release for the pellets studied was not predominately governed by drug diffusion through the polymeric film coating but probably to a large extent limited by drug solubility. TPI proved to be highly suitable to detect non-homogeneities in the drug layer and polymeric film coating.

Monitoring the film coating unit operation and predicting drug dissolution using terahertz pulsed imaging.

Understanding the coating unit operation is imperative to improve product quality and reduce output risks for coated solid dosage forms. Three batches of sustained-release tablets coated with the same process parameters (pan speed, spray rate, etc.) were subjected to terahertz pulsed imaging (TPI) analysis followed by dissolution testing. Mean dissolution times (MDT) from conventional dissolution testing were correlated with terahertz waveforms, which yielded a multivariate, partial least squares regression (PLS) model with an R(2) of 0.92 for the calibration set and 0.91 for the validation set. This two-component, PLS model was built from batch I that was coated in the same environmental conditions (air temperature, humidity, etc.) to that of batch II but at different environmental conditions from batch III. The MDTs of batch II was predicted in a nondestructive manner with the developed PLS model and the accuracy of the predicted values were subsequently validated with conventional dissolution testing and found to be in good agreement. The terahertz PLS model was also shown to be sensitive to changes in the coating conditions, successfully identifying the larger coating variability in batch III. In this study, we demonstrated that TPI in conjunction with PLS analysis could be employed to assist with film coating process understanding and provide predictions on drug dissolution.

Terahertz pulsed imaging as an analytical tool for sustained-release tablet film coating.

The ability of terahertz pulsed imaging (TPI) to be employed as an analytical tool for monitoring a film coating unit operation and to assess the success of a subsequent process scale-up was explored in this study. As part of a process scale-up development, a total of 190 sustained-release tablets were sampled at 10% increments of the amount of polymer applied, from a lab-scale and a pilot-scale coating run. These tablets were subjected to TPI analysis, followed by dissolution testing. Information on tablet film coating layer thickness and variations in coating density were extracted using TPI. It was found that both terahertz parameters were more sensitive and informative to product quality when compared with measuring the amount of polymer applied. For monitoring the film coating unit operation, coating layer thickness showed a strong influence on the dissolution behaviour for both the lab-scale and the pilot-scale batches. An R(2) of 0.89, root mean square error (RMSE)=0.22 h (MDT range=3.21-5.48 h) and an R(2) of 0.92, RMSE=0.23 h (MDT range=5.43-8.12 h) were derived from the lab-scale and pilot-scale, respectively. The scale-up process led to significant changes in MDT between the lab-scale and pilot-scale. These changes in MDT could be explained by the differences observed in the film coating density on samples with similar amount of polymer applied between the lab and the pilot-scale. Overall, TPI demonstrated potential to be employed as an analytical tool to help refine the coating unit operation and the scale-up procedure.

Applications of terahertz pulsed imaging to sustained-release tablet film coating quality assessment and dissolution performance.

The potential of terahertz pulsed imaging (TPI) to predict the dissolution performance in sustained-release tablets was investigated in this study. Batches of coated tablets with similar weight gain during the coating process at the lab and pilot scales were subjected to non-destructive imaging by TPI and subsequently analysed by dissolution testing. The results from the dissolution tests revealed significant differences in the product performance between the lab and pilot scales (Student t-test, P<0.05). The model-independent dissolution parameters in the pilot scale showed a prolonged mean dissolution time. This indicated that the pharmaceutical active ingredient was released at a slower rate in the pilot compared to the lab scale. While weight gain measurements (the traditional coating quality parameter), failed to provide an early indication of the product functional performance; terahertz parameters (terahertz electric field peak strength and coating layer thickness) provided insight into the subsequent dissolution behaviour. Correlations between terahertz parameters and dissolution were much stronger than correlations between weight gain and dissolution; with the R(2) value for terahertz correlations typically around 0.84 as opposed to 0.07 for weight gain correlations. This study presents the initial finding of correlations between terahertz parameters for assessing the coating quality to the dissolution performance of the coated tablet. The contributing factors for these particular correlations are also discussed.