Local analysis of the tablet coating process: Impact of operation conditions on film quality
Introduction
Coating is an important step in the production of many solid oral dosage forms, such as tablets and granules. The goal of film coating is the application of a thin polymer-based film on top of a tablet or a granule containing the active pharmaceutical ingredients (APIs). In the last years, more than half of all the pharmaceutical tablets were coated (IMS Midas Database, 2007). Functional coatings are usually adopted for taste masking or to alter the tablet’s dissolution behavior, for example by controlling the rate of dissolution via semi-permeable membranes or by making it resistant to gastric juice through enteric coatings. Furthermore, active ingredients may be incorporated in the film layer. Colored non-functional coatings are commonly used to improve visual attractiveness, handling and brand recognition. A well-known example is the “blue pill” VIAGRA® by Pfizer Inc. Depending on the tablet’s dimension and coating functionality, the film thickness varies between 5 and 100 μm. A detailed description of the coating process and the different coater devices is presented in the book of Cole et al. (1995).
Historically, this process was developed by the confectionery industry to sugar-coat different types of candies. The pharmaceutical industry implemented this technique using open bowl-shaped pan. Nowadays, sugar-coated tablets are rarely developed due to the intricacy of the process and the high degree of operator skill required. Instead, tablets are typically coated with a polymer film of various compositions using modern equipment, such as drum and pan coaters.
The first commercially available pharmaceutical film-coated tablet was introduced to the market in 1954 by Abbott Laboratories. Tablets were produced in a fluidized bed coating column based on the Wurster principle (Wurster, 1953), which was further developed by Merck in their US and UK plants. This new technique could be realized due to the development of new coating materials based on cellulose derivatives, e.g., hydroxypropyl methylcellulose. Nevertheless, in the following decades coating columns were substituted by side-vented pans and the use of aqueous film solutions, which reduce the use of organic solvents and the related costs of the recovery systems.
Nowadays, tablet coating is typically carried out in pan coaters or fluidized bed systems. Modern production-scale pan coaters have batch sizes ranging from 500 g to 2000 kg, have a fully perforated cylindrical drum and use two-material nozzles for an effective spray generation. Today’s fluidized bed coaters allow continuous coating or have special internals to allow for coating processes involving coating solutions with high solid content (Porter, 2006). In this study we focus on pan coaters.
Although coating processes have been used for many decades, there are still serious challenges, as there is a lack of understanding of how material and operating parameters impact product quality and cause problems, such as chipping (i.e., films become chipped due to attrition), blistering (i.e., local formation of blisters due to entrapment of gas), cratering (i.e., penetration of the coating solution into the bulk of the tablet causing crater-like structures), pitting (i.e., pits occur on the surface due to overheating of the tablet and partial melting), picking (i.e., parts of the film are removed due to sticking to other wet tablets), blushing (i.e., formation of spots due to phase-transitions of the polymer film), blooming (i.e., plasticizer concentrates at the surface, leading to a change of appearance), film cracking (i.e., cracking of the film upon cooling due to high stresses) and many others. Quite often, poor scale-up of the process and/or insufficient process understanding is the cause of such production problems and batch failures Pandey et al. (2006a). Although the reasons for these manufacturing problems are more or less understood, it is still a challenge to predict the occurrence of such effects for new systems.
Therefore, in our work we focus on a basic understanding of the film formation process on single tablets, with the goal of being able to predict the impact of material and operation parameters on the film quality. The current study is a first step in this direction. We investigate the spray fluid dynamics and the film formation of a glycerin–water mixture on two different tablet shapes, i.e., a sphere and a biconvex tablet, held in one position. Our analysis is based on a rigorous computational model that uses well established physical submodels for momentum, heat and mass transfer. Thus, we are able to predict the transient development of the mean film thickness of a wetting coating solution on arbitrarily shaped surfaces. Our main objective is to provide, for the first time, a science-based and quantitative understanding of which physicochemical parameters influence the uniformity of the coating layer on a single tablet. This knowledge is the key for the design, optimization and the rational scale-up of such processes and can form the basis for further studies on rotating tablets or whole tablet beds.
Section snippets
Spray system
A modern coating system is conceptually shown in Fig. 1, where the coating suspension is sprayed on top of a moving bed of the solid dosage form. The spray guns are usually mounted on an arm inside the pan and are directed towards the tablet bed. As the bed is moving, a tablet spends a fraction of a second in the spraying zone. The wet surface of the tablet needs to be dried to avoid sticking of the tablet to neighboring tablets, leading to manufacturing problems such as picking. However, too
Objectives
Currently, the optimization of industrial coaters is mostly done by means of experimental and empirical analysis. State-of-the-art computational approaches include the use of Discrete Elements Method (DEM) , which already represents a consolidated practice in particle technology. However, current studies lack a detailed description of the film formation process on individual tablets or granules as only statistical tools for the film deposition on the tablet surface are used. Such an approach
Model and numerical solution
In this section we present the 3D model used for the numerical analysis of the spray and the wall film. We adopted the 3D-CFD code AVL FIRE v2008 to simulate the dynamics of the coating spray and the film evolution on the tablet. We treat the coating process as a gas–liquid multiphase flow with deposition of a liquid film on the surface. For the description of the gas flow around the object to be coated we used the Reynolds averaged Navier–Stokes (RANS) equations including an appropriate
Base case definition
As mentioned above, our goal was to investigate the influence of different operating parameters on the film formation on coated tablets. In order to define a realistic base set of parameters for our simulations, experimental investigations of a spray gun via Phase Doppler Anemometry (PDA) technique have been performed (for the technique refer to Hirleman (1996), the measurements have been performed by us at Duesen-Schlick GmbH, Germany). This experimental method is capable of simultaneously
Conclusions and outlook
In this work we have analyzed the process of tablet spraying, as well as wetting, by means of a multiphase CFD solver. Sophisticated models for the gas flow, droplet motion, as well as for the flow of the liquid film on two different objects, i.e., a sphere and a convex tablet, have been developed. Using these models we have performed a detailed variation study and analyzed the impact of the system properties on quality attributes of the resulting liquid film. Our variation study has been
Nomenclature
- A
area (m2)
- BM,j, BT
spalding mass and heat transfer number (dimensionless)
- k
constant (dimensionless)
- cp
specific heat capacity at constant pressure (J/kg K)
- d
particle diameter (m)
- D
diameter (m)
- F
force (N)
- FM,j, FT
mass and temperature correction functions (dimensionless)
- fR
fractional residence time (dimensionless)
- g
gravitational acceleration (m/s2)
- h
specific enthalpy (J/kg)
- k
thermal conductivity (W/(m K))
- km
mass transfer coefficient (m/s)
- L
latent heat (J/kg)
- L
characteristic length, length of the spray zone (m)
- m
Latin symbols
Acknowledgement
We thank the reviewers for their extremely helpful comments with respect to tablet flow and droplet spreading on surfaces.
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