Simulation of a tablet coating process at different scales using DEM.

Spray coating of tablets is an important unit operation in the pharmaceutical industry and is mainly used for modified release, enteric protection, better appearance and brand recognition. It can also be used to apply an additional active pharmaceutical ingredient to the tablet core. Scale-up of such a process is an important step in commercialization. However, scale-up is not trivial and frequently, at manufacturing scales the required coating quality cannot be reached. Thus, we propose a method where laboratory experiments are carried out, yet scale-up is done via computational methods, i.e., by extrapolating results to larger scales. In the recent years, the Discrete Element Method (DEM) has widely been used to simulate tablet behavior in a laboratory scale drum coater. Due the increasing computational power and more sophisticated DEM algorithms, it has become possible to simulate millions of particles on regular PCs and model industrial scale tablet coating devices. In this work, simulations were performed on the laboratory, pilot and industrial scales and DEM was used to study how different scale-up rules influence the bed behavior on larger scales. The material parameters of the tablets were measured in the laboratory and a glued sphere approach was applied to model the tablet shape. The results include a vast amount of qualitative and quantitative data at the different scales. In conclusion, the evolution of the inter-tablet coating variation for the different scales and process parameters is presented. The results suggest that keeping the Froude number constant during the scale up process leads to faster processes as the cycle time is shorter and the spray residence time is more uniform when compared to keeping the circumferential velocity constant.

Experimental study of wet granulation in fluidized bed: impact of the binder properties on the granule morphology.

In this work, the effect of the physicochemical properties of aqueous hydroxypropyl-cellulose (HPC) binder solutions and different pharmaceutical excipients (mannitol and anhydrous CaHPO(4)) on the agglomeration kinetics and granule properties were investigated. First, a particle size distribution (PSD) analysis together with a detailed analysis of morphological properties of the excipient particles were performed. Second, the viscosity, density, surface tension and size of the spray droplets of binder solutions with different HPC concentrations were determined and wetting characteristics of the binders on the excipients were measured. Third, several fluid bed wet granulation experiments were conducted for pure excipients and their blends with binder solution of different HPC concentrations in a pilot plant Wurster granulator. The observed granule growth for different binder concentrations was a strong function of the binder concentration and the excipient solubility. For mannitol, a significant "coating" period followed by a slow granule growth was observed for the case with the diluted 5% binder. The "coating" period was significantly shorter for the 10% HPC binder and did not exist for the 15% HPC for which immediate and fast granule growth was observed. For anhydrous CaHPO(4) (trademark A-TAB), no growth was observed for the 10% HPC binder and a long coating period followed by fast granule growth was observed for the 15% HPC. Simple physically based criteria were also evaluated, which employ the morphological properties of excipients (size and surface roughness) together with physical properties of the used binder for prediction of the coating versus agglomeration regime at given flow conditions (collision velocity). As expected, a preferential coalescence and growth of the mannitol granules from the blend of mannitol+A-TAB was observed. Finally, the mechanical and morphological properties of the produced granules were measured and correlated to the HPC concentration of the binder used in the experiments. A clear correlation between the granule porosity (evaluated by X-ray tomography) and the binder concentration was found for the mannitol granules.

Freeze drying--principles and practice for successful scale-up to manufacturing.

Freeze Drying involves transfer of heat and mass to and from the product under preparation, respectively, thus it is necessary to scale these transport phenomena appropriately from pilot plant to manufacturing-scale units to maintain product quality attributes. In this manuscript we describe the principal approach and tools utilized to successfully transfer the lyophilization process of a labile pharmaceutical product from pilot plant to manufacturing. Based on pilot plant data, the lyophilization cycle was tested during limited scale-up trials in manufacturing to identify parameter set-point values and test process parameter ranges. The limited data from manufacturing were then used in a single-vial mathematical model to determine manufacturing lyophilizer heat transfer coefficients, and subsequently evaluate the cycle robustness at scale-up operating conditions. The lyophilization cycle was then successfully demonstrated at target parameter set-point values.