Continuous Improvement in Tablet Coating and Dry Granulation

High efficiency in unit operations is a prequisite for achieving overall improvements in solid-dosage manufacturing. The authors examine recent advances in equipment design and operation in spraying, drying, and mixing to improve the tablet-coating process.

Cost is a crucial issue for pharmaceutical companies, generic-drug manufacturers, and CMOs, which must be attentive to overall operational costs of equipment as well as upfront capital costs. High-efficiency processing in solid-dosage manufacturing is a desired goal, and tablet coaters and granulators have undergone technology improvements to achieve continuous improvement in these operations.

L.B. Bohle

Improvements in solid-dosage manufacturing

To evaluate improvements in solid-dosage manufacturing, one must examine the advances in equipment design and operation in spraying, drying, and mixing to improve the overall tablet-coating process. Highlights of such advances are further described.

Tablet coating. Improvements to tablet-coating technologies are helping pharmaceutical manufacturers to achieve higher uniformity and waste reduction. These improvements are mostly due to mixing-system advances as well as pan and airflow configuration. Tablet coating consists of three main steps: spraying, drying, and mixing. Each step must be calibrated with the others to optimize the entire process.

Spraying. Spraying equipment includes the nozzle types, number and type of guns, and gun-to-gun spacing. Process parameters include spray rate, gun-to-tablet-bed distance and angle, atomization air pressure, and pattern air pressure. Spray-gun nozzles are key to efficient coating, and nozzles that create an oval spray pattern and a spray angle of 50° to 60° work best. The configuration of the spray boom will dictate the amount of spray-cone overlap. A slight overlap of the spray cones from each nozzle may be desirable for consistent coverage; however, too much overlap will lead to localized overwetting of the tablet bed. In most cases, the gun-to-bed distance will range from 6 in. to 10 in. although the actual distance depends on the force of the atomization air pressure and pattern air pressure on the coating-pan size.

Drying. Drying of the coating suspension takes place during the atomization and when spreading on the tablet surface. The temperature of the inlet air, volume flow and humidity of the inlet air, and the degree of pan perforation control drying. These parameters must be controlled in a way that prevents overwetting but does not cause spray-drying. The way the air moves through the coating pan also influences drying. Most coating pans draw air from the top of the pan and exhaust it to the side. Others place both the inlet and outlet at the pan's base. No matter where the inlet and outlet are, the goal is to handle the air in a way that minimizes turbulence and excessive heat in the spray zone. A balance must be struck between the temperature and volume of the inlet air and the spray rate.

Mixing. Mixing is a prerequisite for a homogeneous and uniform coating. Ideally, the pan's action will mix the tablets in a way that exposes each to the spray equally. Doing so depends on pan geometry and the use of baffles, spirals, lifting bars, or other components. Many common pans have a diameter that exceeds their length. This ratio can create a tablet bed too deep for effective mixing. It is not uncommon to find dead spots in the middle of these tablet beds. Such dead spots can cause overwetting and the formation of clumps or twins, which may damage the tablets.

To break up or prevent clumps and dead zones, some pans are fitted with a device called a baffle or shovel. The shovel is fixed within the coating pan, so as the pan turns, the tablets contact the shovel, steering them outward. Although the shovel insert may improve mixing, it can increase the risk of tablet breakage. An alternative approach is to use a pan whose length exceeds its diameter and that incorporates helical baffles for gentle tablet mixing. The longer pan creates a shallow tablet bed that is free of dead zones. The upper and lower helical baffles expose all the tablets to the spray equally. This configuration enables higher spray rates, which shortens the time required to coat tablets in each batch.

The role of coater design in manufacturing

Once pharmaceutical manufacturers understand the basic elements of tablet coating, they can determine which tablet- coater features best suit their solid-dosage product. For example, relying on a coater whose coating pan length exceeds its diameter creates a shallow tablet bed that promotes tablet exposure to the spray. It also allows the installation of more nozzles over the bed than is possible in conventional pans. This combination exponentially improves coating uniformity. There is a limit to the number of nozzles that should be added, however. Manufacturers must weigh the benefit of adding nozzles against the risk of overwetting the tablet bed. It is best to use enough nozzles to cover the bed while avoiding or minimizing overlap.

Airflow must also be evaluated. Conventional coaters have top-to-side airflow, so high-velocity warm air passes through the spray zone. That implementation of the air flow causes turbulence and the possibility of spray-drying the coating droplets. Pharmaceutical manufacturers can reduce those effects by adjusting the airflow, temperature, and spray rate. That correction, however, may slow the coating operation or increase the amount of wasted coating solution.

Minimum air turbulence and improved coating applications can be achieved by using a pan with an inlet and outlet that span the pan's base. This design improvement also allows an improved control over tablet-bed temperature. Additionally, that control yields faster spray rates and reduces coating times by as much as 45%.

Companies using both coating pan designs have found that pans with top-to-side airflow are up to 85% efficient. This result means approximately 15% or more of the spray is deposited within the coating pan on the guns and spray boom or in the exhaust. Designs using base-to-base airflow, which pull the spray onto the tablet bed like a vacuum, can reach approximately 98% efficiency. They also shorten overall coating time because they enable higher spray rates without overwetting the tablet bed.

In applications requiring thick tablet coatings, the tablet bed can grow by one-third or more. This formulation requires an adjustment of the gun-to-bed distance during the process. When tablet coating involves potent substances, manufacturers can consider automating the movement of the nozzles, spray boom, or both. This feature eliminates the need to open the coating pan, thereby increasing efficiency and safety.

Finally, manufacturers should note how their coating pan mixes and handles the tablets. Homogenous mixing promotes content uniformity. Pans equipped with helical mixing baffles constantly move the tablets back and forth across the pan, thereby eliminating dead spots.

Tablet-coating studies

Researchers have performed various scientific studies in high-efficiency coating in solid-dosage manufacturing. These studies provide guidance for tablet-coater process improvements (1–6).

Scale-up effects on tablet abrasion during pan coating. A 2006 study investigated the influence of production scale-up on tablet abrasion in a pan coater (1). It examined how batch size during scale-up can affect the abrasion and edge-splitting of flat-faced tablets. The researchers looked at the weight loss of white tracer tablets mixed with a batch of blue-coated tablets in a laboratory-scale pan coater and a pilot-scale pan coater as a function of different pan speeds and mixing times. They observed that increasing batch size caused a decrease in weight loss due to less damage of the tablet edges. The researchers determined that a higher number of tablet impacts at the pan wall at laboratory scale compared with pilot scale might account for this outcome. This effect runs counter to the common belief that increasing batch size in scale-up leads to a higher abrasion or tablet damaging (1).

Raman spectroscopy as a PAT tool in active coating. Active coating is a film-coating application in which the drug's active ingredient is included in the coating layer. It presents manufacturers with the challenge of achieving the right amount of coating and uniformity on each dosage. To ensure the quality of each dosage, manufacturers can benefit by developing process analytical technology (PAT) that can monitor the coating process and detect the end of the coating cycle. In one study, researchers performed coating experiments using the drug diprophylline (2). They used a pan coater to coat placebo tablets and tablets containing diprophylline. During active coating, researchers recorded Raman spectra in-line. These spectral measurements were compared with the average weight gain and the amount of coated active ingredient at each point in time (2).

The chemometric model they created using Raman spectroscopy was tested by monitoring more coated batches. The research team also studied the effects of pan-rotation speed and working distance on the Raman signal and studied the resulting effect of the chemometric model. Using Raman spectroscopy as a PAT tool, they were able to determine the amount of active ingredient in the film when coated onto cores of placebo tablets and tablets containing the same active ingredient. Researchers also determined that this method can be used when changing the process parameters and measurement conditions within a restricted range, making it an appropriate PAT tool (2).

Comparing laboratory and production coating spray gun for scale-up. In a scale-up study, researchers investigated a laboratory spray gun and a product spray gun (3). They analyzed the influence of the atomization air pressure, spray-gun-to-tablet-bed distance, polymer-solution viscosity, and spray rate. The spray guns were compared based on spray width and height, droplet size and velocity, and spray density. Researchers measured spray density, droplet size, and velocity with a phase Doppler particle analyzer (3). This study gave the investigators basic information for the scale-up settings from the laboratory and production spray guns. Both were comparable with respect to droplet size and velocity, and the scale-up of droplet size can be performed by an adjustment of the atomization air pressure. Scale-up of droplet velocity can be achieved by adjusting the spray gun to tablet-bed distance. The result of the study was that the researchers' statistical model and surface plots were powerful and convenient tools for scaling up spray settings if the spray gun was changed from a laboratory spray gun to a production spray gun (3).

Dry granulation and roller compaction

Continuous dry granulation is an established process in the pharmaceutical industry. Today, it is not only applied for moisture- and temperature-sensitive materials but also for large-volume solid-dosage products. In comparison with classical wet-granulation techniques, a sophisticated drying system is not required for processing. This elimination of the drying system avoids large investments for production equipment and space and lowers manufacturing costs. An additional benefit to having an one-unit operation is its suitability for installation in a one-floor operation. The dry granulator can be fed with a single intermediate bulk container (IBC). To enable a continuous process, an enlarged power-feed hopper can be used with a level sensor and adequate holding capacity to enable the change-out of additional IBCs without interrupting the process.

On the discharge side, a simple plug-flow pneumatic conveying system can be used to transfer the resulting granulation into a receiving IBC for future blending and processing. This reduction in handling equipment can further reduce the capital costs with a dry-granulation system.

Furthermore, for large-volume throughputs, the fast roller-compaction process is paramount to efficient processing. This efficiency enables the production of different products and product batch sizes with one single machine (4). The market already offers various dry granulators, which can be described by the arrangement of the two compaction rollers. They can be mounted horizontally, vertically, or on an incline.

Depending on the supplier, the rollers differ in width, diameter, and surface properties. Furthermore, roller compactors are distinguished between fixed-gap and moveable gap compactors, whereas the moveable roller compactors are state of the art. Only moveable roller compactors, however, ensure homogeneous ribbon porosity at constant compaction pressure.

The granulation step, where the ribbons are transferred into final granules, is usually integrated in the roller-compaction equipment and is performed in one or two steps (5, 6). With this in mind, manufacturers introduced a dry granulator with an electromechanical roller drive and massive roller shafts mounted in a horizontal manner.

With this newly developed machine, minimal time is needed to achieve a steady state during process start-up, and parallel gap is ensured during the whole production time. The proportional-integral-derivative (PID) loop control minimizes the gap deviations during processing and enables constant granule porosities. The granulation step is achieved using a conical sieve, which gently transforms the ribbons into final granules even at high material throughputs. Due to different sieve setups, the desired particle-size distribution can be obtained.

Roller-compactor case study

The aim of the following study is to show and prove the functionality of this type of sophisticated dry granulator.

Materials and methods. A powder mixture (1:1 ratio) consisting of lactose and microcrystalline cellulose was used for roller compaction. For lubrication, 0.5 % magnesium stearate was added. The excipients were premixed in a bin blender. The homogeneous blend was roller-compacted at different compaction forces and different sieve setups. A smooth master roll and a grooved slave roll of 100-mm width were used for the compaction trials. Sampling was performed after the process start-up when steady state was reached. Final granules were manually subsampled and analyzed in duplicate by mechanical sieving.

Compaction force. The impact of the compaction force on the final granule particle size was analyzed at 2-rpm roller speed, 300 rpm for the 1.5-mm rasp sieve, and a gap width of 2.5 mm. The process began with an activated PID loop control for the feeding system. Steady state was achieved within 40 seconds with a constant specific compaction force and a constant gap width. Thus, a minimal material loss could be detected due to the quick loop control.

During processing, the compaction force was increased step-wise, so that the next force level was quickly achieved within seconds. Deviations of the specific compaction force were below ± 0.1 kN/cm and ± 0.1 mm for the gap, respectively. Thus, both parameters could be considered constant during processing.

Granule particle size increased with higher compaction force levels. After granulation, through a 1.5-mm rasp sieve, the amount of fines (particle size < 100 µm) ranged from 39% for the granules compacted at 5 kN/cm to 11% for granules prepared at a 15-kN/cm compaction force. Compaction at such a high force level led to a higher amount of coarse granules (> 2000 µm). Therefore, a smaller screen size between 1 mm and 1.5 mm is recommended to minimize this large granule fraction.

Gap width. Material throughput during roller compaction can be increased with a larger gap width. It was reported in the literature that a larger gap width at a constant compaction-force level leads to finer granules (4). This effect could not be observed when compacting the powder mixture at 10 kN/cm.

At 2-rpm roller speed and 300-rpm sieve speed (1.5-mm rasp sieve), comparable granule particle-size distributions were obtained although the gap width was increased from 1.5 mm up to 3.5 mm. A homogeneous application of the compaction force over the whole roller width could be one reason for the similar granule size. Thus, material throughput could be easily increased without a change in granule properties.

Sieve setup. The applied compaction force mainly affects granule particle size. Secondly, the setup of an integrated granulation unit determines the final particle-size distribution. With increasing screen size, coarser granules are obtained.

The rasp sieves with 1.5-mm and 2-mm screen size led to similar granule particle-size distributions at 300-rpm sieve speed. In comparison, the 1-mm rasp sieve led to finer granules with higher amount of fines. Finally, all three screen types led to acceptable amounts of fines due to the gentle cutting behavior of the rasp sieve during granulation. The choice of the right screen size makes it possible to influence the final granule particle size distribution.

A further possibility to vary the sieve setup is the alteration of the sieve-rotor speed. In contrast to classical rotating-sieve systems, conical sieves offer a high material throughput already at low sieve speed values. To evaluate the sieve-speed impact on final granule size, compaction was performed at a 10-kN/cm specific compaction force, 2-rpm roller speed, and increasing sieve speed values for one screen size (i.e., 1.5-mm rasp sieve).

With higher sieve speed, the amount of fines decreased. This result can be explained by the fact that, with higher rotor speed, the ribbons need less time to pass the screen. Less friction occurs during granulation and leads to a lower amount of fines. Therefore, altering the sieve speed is another possibility to adjust the desired particle-size distribution of the final granules.

Conclusion

This study proves the functionality of the new roller compactors. It was possible to precisely produce a representative placebo granule formulation with negligible material waste during process start-up. Furthermore, the study shows that a suitable sieve setup offers the possibility to achieve a desired granule size by altering screen size and sieve speed.

References

1. R. Mueller and P. Kleinebudde, Eur. J. Pharm. Biopharm. 64 (3), 388-92 (2006).

2. R. Mueller et al., Drug. Dev. Ind. Pharm. 36 (2), 234-243 (2010).

3. R. Mueller and P. Kleinebudde, AAPS PharmSciTech. 28 (1), E21-31 (2007).

4. R.W. Miller, Pharm. Technol. 18 (3), 154-162 (1994).

5. P. Kleinebudde, Eur. J. Pharm. Biopharm. 58 (2), 317-326 (2004).

6. Y. Teng, Z. Qiu, and H. Wen, Eur. J. Pharm. Biopharm. 73 (2), 219-229 (2009).

Martin Hack* is vice-president and general manager, and Dejan Djuric, PhD, is manager of scientific operations, both at L.B. Bohle, 700 Veterans Circle, Suite 100, Warminster, PA 18974, tel. 215.957.1240, mhack@lbbohle.com

* To whom all correspondence should be addressed.