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In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this study, a T-shaped partial least squares (TPLS) model was developed to link raw material properties, the ratios in which these raw materials were combined and the applied process parameters for the twin-screw wet granulation process with the granule quality attributes. In addition, the predictive ability of the TPLS model was used to find a suitable combination of formulation composition and twin-screw granulation process settings for a new API leading to desired granule quality attributes. Overall, this study helped to better understand the link between raw material properties, formulation composition and process settings on granule quality attributes. Moreover, as TPLS can provide a reasonable starting point for formulation and process development for new APIs, it can reduce the experimental development efforts and consequently the consumption of expensive (and often limited available) new API.

The objective of this study was to enhance the inter-tablet coating uniformity in an active coating process at lab and pilot scale by statistical design of experiments. The API candesartan cilexetil was applied onto gastrointestinal therapeutic systems containing the API nifedipine to obtain fixed dose combinations of these two drugs with different release profiles. At lab scale, the parameters pan load, pan speed, spray rate and number of spray nozzles were examined. At pilot scale, the parameters pan load, pan speed, spray rate, spray time, and spray pressure were investigated. A low spray rate and a high pan speed improved the coating uniformity at both scales. The number of spray nozzles was identified as the most influential variable at lab scale. With four spray nozzles, the highest CV value was equal to 6.4%, compared to 13.4% obtained with two spray nozzles. The lowest CV of 4.5% obtained with two spray nozzles was further reduced to 2.3% when using four spray nozzles. At pilot scale, CV values between 2.7% and 11.1% were achieved. Since the test of uniformity of dosage units accepts CV values of up to 6.25%, this active coating process is well suited to comply with the pharmacopoeial requirements.

In the pharmaceutical industry, drum coating is routinely used for the production of film tablets. In order to produce a high-quality product, it is important to understand this seemingly simple process in great detail. In our study we present the implementation of three different methods to include spray coating in DEM simulations: (1) an enhanced “spray zone approach” working during run-time, (2) the “discrete drop method”, a novel approach for tablet coating also applied at run-time, and (3) the “ray-tracing method”, which is applied after the DEM simulation using the saved data. Each method is described in detail. For evaluation purposes, the different models were applied to simulate the same coating process, and the comparability, advantages and limitations are discussed. In general, all three methods can give comparable results. However, the spray zone approach depended heavily on its model parameters; the discrete drop method was more reliable and versatile. While the time resolution is higher for the first two methods listed above, the third is faster and more flexible.

Formulation of layered pellets can be a useful method for the preparation of multiparticulate systems. The aims of this work were to study the properties of hydrophilic active agent (pirenzepine dihydrochloride) layers formed on different pellet cores, the efficacy of layering and the connection between the core and the layers. The carrier pellets were prepared from mixtures of a hydrophilic (microcrystalline cellulose) and a hydrophobic (magnesium stearate) component in different ratios. These cores were coated in a fluid bed apparatus with an aqueous solution of active agent, with or without the addition of hydroxypropyl methyl cellulose (HPMC) as an adhesive component. The wettability of the pharmaceutical powders was assessed by means of Enslin number and contact angle measurements, and the surface energy was determined. Spreading coefficients of the components were also calculated and correlated with pellet properties such as the content of active agent, the friability and the morphological appearance of the layered product. An increased friability of the layer formed and the lower effectiveness of the process were experienced with a reduction in the wetting of the core. The efficiency of layering on a less polar core could be increased by the addition of HPMC, but the sensitivity of these pirenzepine layers to mechanical stress was higher. The type of the abrasion of these particles was dissimilar to that for samples prepared without HPMC. Peeling of the layers containing HPMC was observed for hydrophobic cores, but this phenomenon was not detected for the hydrophilic ones. These results can be explained by the spreading coefficients, which revealed an insufficient adhesion of layers for the samples that exhibited peeling.

A comparison was made between two twin-screw extruders (APV Baker and Leistritz Micro) used for continuous wet granulation. Both extruders had similar screw configurations, based on the length-to-diameter ratio of the screws, existing out of a conveying zone of 20 D, i.e. 20 times the screw diameter and a granulation zone of 4D. The kneading blocks in the granulation zone were 2.2 and 2.5D for the Leistritz and APV extruders, respectively. An experimental design was used to investigate the influence of process parameters (total input rate and screw speed) and extruder type on granule and tablet quality. Dicalcium phosphate and alpha-lactose monohydrate were used as water-insoluble and water-soluble excipients, respectively. For dicalcium phosphate, the amount of fines (

The influence of different screw element types on wet granulation process with a twin-screw extruder was investigated. Lactose granules were prepared with different screw configurations such as conveying, combing mixer and kneading elements. The use of kneading blocks led to an almost complete agglomeration of lactose, whereas kneading and combing mixer elements resulted in smaller granules in comparison. Granule porosity varied between 17.4% and 50.6%. Granule friability values ranged from 1.2% to 38.5%. Conveying elements led to the most porous and friable granules, whereas kneading blocks produced the densest and least friable granules. Combing mixer elements produced granules with median properties. A linear correlation between granule porosity and the natural logarithm of granule friability was detected. Flowability of granules was also influenced by the element type. Compressed granules with higher granule porosities resulted in tablets with higher tensile strength values and vice versa. Twin-screw extruders proved to be a versatile tool for wet granulation. By the choice of a suitable screw element granule and tablet characteristics were influenced.