Industry perspective FOCUS ON EXCIPIENTS

Nils Rottmann

NILS ROTTMANN1*, THORSTEN CECH2, THORSTEN SCHMELLER3 *Corresponding author 1. BASF SE, Pharma Ingredients and Services, Ludwigshafen, 67056, Germany 2. BASF SE, European Pharma Application Lab, Ludwigshafen, 67056, Germany 3. BASF SE, Pharma Ingredients and Services, Limburgerhof, 67117, Germany

Influence of film coating formulations on process time and CO2 emissions

Kollicoat IR is a registered trademark of BASF SE

ABSTRACT

Nowadays the buzzword process optimization has an unprecedented importance. This can be on one hand attributed to increasing cost pressure in pharmaceutical production and on the other hand, to an increasing environmental awareness in the industry. However, to address this concern, we have considered one of the most energy consuming processes in the industry the film-coating process with respect to the efficiency of several instant release film coating formulations, based on HPMC, PVA and a PEG-PVA graft co-polymer. By choosing an appropriate coating polymer or formulation, a process time reduction of more than 30 percent is achievable, a result that serves the purpose of both, cost reduction as well as environmental protection.

INTRODUCTION The first film-coated tablet was marketed by Abbott in 1959. Consequently, film-coating technology has become well established in the pharmaceutical industry and has made great advances. Improved production equipment and the development of highly efficient film-coating formulations and polymers have accelerated the acceptance of film-coating technologies. Hydroxypropyl methyl cellulose (HPMC) was typically used in film-coating formulations, as a film forming polymer, and remains in common usage. HPMC is obtained through a sumptuous serial procedure. Firstly, cellulose is extracted from either cotton flock or paper pulp and solubilised in sodium hydroxide solutions to obtain swollen cellulose. Hydroxypropyl methyl cellulose is subsequently obtained by treating the swollen cellulose with methyl chloride and propylene oxide. Finally the mass is dried, comminuted and packaged after removal of dopants. HPMC is typically sold in several grades with different viscosities. To realise high solid matter contents HPMC of low viscosity is commonly used. Optimised formulations however consist of a combination of the different grades to combine their various physical properties. Optimally developed formulations could therefore obtain up to 20 percent solid matter content if further additives (eg. sugar alcohols) are added. Since the formulation of those multi component systems is quite inconvenient the next generation of film forming polymer came up: polyvinyl alcohol (PVA). PVA is a film-forming agent produced by the hydrolysis of polyvinyl acetate. An alkali metal or inorganic acid is used as a catalyst in methanol, ethanol or a mixture of ethanol and methyl acetate, to accelerate the hydrolysis of polyvinyl acetate to yield polyvinyl alcohol (PVA). Nowadays, PVA is used as film forming agent in a number of pharmaceutical formulations. An optimized instant release film coating formulation based on PVA, can be applied on the tablets with a solid matter content of up to 25 percent, which is a major step towards achieving highly efficient film coating processes. Besides the increased solids content of the formulations, other properties, like reduced permeability of water vapour or oxygen through a film, have also been achieved. Apart from the film forming polymer and pigments, a plasticizer is typically added to HPMC as well as PVA based formulations. The addition of plasticizer improves physical properties like the flexibility of the film, or lowering of the glass transition temperature (T g). However, these plasticizers might migrate in the film and can cause stability problems of the film respectively the finished dosage form. The latest generation of film coating polymers was developed targeting an improved coating efficiency. An example of this new generation is Kollicoat IR, which is obtained by grafting polyvinyl alcohol on a polyethylene glycol backbone. The PEG as covalently bond plasticizer prevents the formulation from instability due to migration of the plasticizer through the film or incompatibilities with actives. Due to the low viscosity compared to all previous film coating materials, formulations based on Kollicoat IR can be Graph 1. Comparison of viscosity profiles of coating systems, based on HPMC, PVA and PEG-PVA grafted polymers. applied in concentrations of up to 30 percent (Graph 1).

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PEG-PVA grafted polymer formulations are easy to dissolve, form flexible films on tablets and have a similar barrier function for water vapour and oxygen as PVA based films. Using these types of polymers for film coating purposes, more convenient and more efficient coating formulations have been developed by several suppliers. These coating systems are mixtures of film-forming polymers, plasticizers, colouring agents and other excipients, which can be easily stirred into water or organic solvents, to produce the dispersion for the film coating of tablets. There are several approaches available in the market: (I) HPMC or PVA based coating systems which are often customised powder blends for every single finished dosage form (II) The PEG-PVA based systems which are sold as a seven base colour system, containing homogeneous granules, which can match hundreds of different colours by combining these coloured granules. Rapid development of film-coating formulations - in order to improve efficiency - and the increasing interest in optimisation of process times and energy consumption, suggests that a comparison of commonly-used coating systems would be in order.

ENERGY FLUX IN COATING PROCESS The thermodynamic model (equation 1) introduced below, potentially describes the energy flux in a model film coating process (Graph 2) and helps to provide an understanding of this process. For the calculation of the energy flux in a film coating process, the first law of thermodynamics can be applied. Since the sum of all energies in a closed system remains the same, the total energy can be described as: Q
inlet air

=Q

heat tablets

+ Q heat coater + Q

heat solution

+Q

evap. solvent

+ Q loss + Q

exhaust air

(Equation 1)

For the film coating process itself various energies are of importance. However, focusing on ecological and economical aspects enthalpies derived from atomizing air and dispersion can be disregarded, as these energies do not depend on energy consumption of heaters. Q inlet air (Equation 1) describes the energy introduced into the coating process through the heated and conditioned process air. Yet this amount of energy has to be used for any kind of economical and ecological considerations, as it represents the main amount of energy, introduced in the film Graph 2. Sketch of a typical film coating process and its influencing parameters. coating process. Besides the amount of energy introduced due to the inlet air and atomizing air, energy is also required to revolve the coating drum or to convey the coating dispersion to the spray nozzles. Due to the fact, that the amount of energy for this is minor, compared to the total energy and that the process settings (and hence the required energy) is the same in all compared cases, this energy is not considered in the calculation of energy savings. It can be said, that the inlet air energy is not just the main energy portion introduced in the coating process, but also the main energy input demanded by the coating material, since it is used to evaporate the solvent on the tablet surface (drying). Consequently the values for the inlet air quantity and inlet air conditions are commonly displayed by the instrumentation of the coating equipment during a coating process. These values are taken into account in this evaluation. Depending on the batch size typical values for a coating process carried out in a Perfima 200 (IMA) drum coater are: Table 1. Summary of considered process parameters in a Perfima 200 perforated drum coater.

For the calculation of the required energy, heat flux needs to be calculated, based on the values given by the instrumentation of the Perfima side vented drum coater. In order to calculate the heat flux of this process, the equation below can be used: Qtotal = Qair + QHumidity Qtotal = mair cPair (Taim Tconditioner) + mwater cPwater (Taim Tconditioner) Qtotal = (mair cPair + mwater cPwater) (Taim Tconditioner) (Equation 2) (Equation 3) (Equation 4)

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It is assumed to start with air coming out of a conditioner, at 10C with a water content of 7.5g per kg air (dew point). This air is heated up to 65C, which is a common inlet air temperature for a coating process, depending on the coating material used. The energy required for conditioning the process air is not considered, due to the fact that it can vary a lot, depending on the conditioning method used (thermal dehumidification or electrical dehumidification) and would thus unduly complicate the energy calculations However, this energy does not influence the Table 2. Explanation of terms used in equeation 1, 2, 3 and 4. result of this consideration, since we keep the inlet air conditions constant for all the trials. Coating process time can be a useful parameter to use when making comparisons between various types of coating formulations. In this example, a coating level of 3.5 percent weight gain (based on the related batch size) is assumed, which is a usual coating level for the compared instant release formulations. The spray time is strongly related to the solid matter content of the coating dispersion. Common concentrations for HPMC or PVA based formulations are 15-20 percent. Since these coating systems have similar solid matter content, they are summarized as reference coating system in the Tables below (Table 3 and 4). Due to the lower viscosity of Kollicoat IR based instant release coatings (see Graph 1), concentrations of up to 30 percent are applicable. Hence a faster coating deposition on the tablets and shorter process times can be achieved. Considering the calculated heat flux (equation 2-4) and the process time, the total heat quantity and the required amount of energy can be calculated respectively. If one compares the total heat quantity r e q u i r e d f o r e a c h c o a t i n g p r o cess, the savings that can be achieved when using a higher solids coating system, resulting in shorter process times, can be calculated. These results are compiled in Table 3. The reduction of CO 2 emission is of increasing importance in terms of environmental Table 3. Comparison of energy flux and process times with related saving potentials. protection, therefore the saving potential of the film coating process was converted into CO 2 saving potentials per batch. For the conversion of the saved energy, the CO 2 conversion factors, given by Carbon Trust (1) were considered. They mention about 0.537kg CO 2 emission per KWh electrical power, calculated from the current energy mix. Table 4. Comparison of CO2 saving potentials per batch.

Taking a standard batch size of 300 kg into account, which is very common in the pharmaceutical industry, the CO 2 savings are roughly 26 kg per lot. Considering a finished product of 350 mg per tablet and 2 billion tablets per year, the annual savings add up to almost 60 metric tons of CO 2 . CONCLUSION In this study, we have shown that high solids coating systems such as PVA-PEG can be successfully used to achieve significant savings in both process time and overall energy consumption Even if a quite small fragment of the total resource consumption in the pharmaceutical processes was considered, the saving potential in terms of process time and CO 2 emissions is immense (>30 percent). Hence one can conclude that PEG-PVA based polymers are highly effective in achieving reduced process time and energy consumption, for the production of pharmaceutical formulations.

REFERENCES AND NOTES

1. Carbon Trust, 06.2009, http://www.carbontrust.co.uk/resource/conversion_factors.

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