Tableting: Preventing Powder Binding During Scale-up of a Roller-Compacted Tablet Formulation

Roller compaction is a method of dry granulation, in which a dry powder is densified into a solid mass, or compacted ribbon, which is then milled into granules. Roller compaction is often used in solid dosage manufacturing because the resulting granules have better flow properties than the original powder for tableting or capsule filling. This article describes a study scientists conducted to resolve a powder-binding problem that developed during the scale-up—from proof-of-concept scale to pilot scale—of a roller-compacted tablet formulation. 

The scientists had elected to manufacture the tablets using dry granulation because the formulation’s active pharmaceutical ingredient (Compound X) had poor flowability along with the added challenge of possible water-related instability. Compound X was available in its salt form and had been formulated for the proof-of-concept study as 12.5-milligram, 35-milligram, and 70-milligram strength tablets using the common-blend approach, with 35 percent w/w drug loading. 

Figure 1 shows a schematic representation of the manufacturing process. The scientists blended Compound X with the inactive excipients microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The granules obtained from the dry granulation process were blended with extragranular excipients and then compressed into tablets using a rotary tablet press. 

The initial proof-of-concept study was conducted using a batch size of 2,000 tablets, with no problems reported during their manufacture. However, while preparing to manufacture a 130,000-tablet batch for the pilot-scale study, the scientists observed blend compaction in the tablet press feeder. To successfully scale up the process for clinical trial, they needed to identify the cause of the blend compaction and resolve the problem.

Proof-of-concept study 

Table 1 shows the composition of the proof-of-concept tablets. The drug loading was 35 percent in the formulation, and microcrystalline cellulose was used as filler/ diluent. Since the product is an immediate-release tablet, the scientists added croscarmellose sodium as a super disintegrant. Magnesium stearate was used as a lubricant. 

For the dry granulation step of the proof-of-concept study, the scientists used a lab-scale Freund-Vector TFC roller compactor. Prior to tableting, they analyzed the blend’s bulk density, tapped density, particle size distribution, and Flodex. 

The scientists then compressed a batch of 2,000 tablets using a rotary tablet press equipped with a gravity feeder and experienced no issues during the tableting process. The scientists then analyzed the tablet physical properties, compression forces, and dissolution. The physical properties of the tablets are provided in Table 2, along with the blend’s Flodex. 

The tablet hardness was 4.46 kilopascals, the tablet thickness was 3.55 millimeters, and the friability was 0.03 percent. The Flodex of the final blend was found to be 6 millimeters, indicating a good level of flowability. The disintegration time of the tablets was found to be 31 seconds, with 90 percent of Compound X released within 30 minutes of the dissolution. 

Blend compaction during initial scale-up study 

For scale-up, the scientists initially manufactured an intermediate batch of 50,000 tablets using the same method as for the proof-of-concept batch. However, because the Freund-Vector TFC roll compactor is a labscale machine designed for a throughput of 5 grams to 1 kilogram per hour, they used a Gerteis Mini-Pactor for the granulation step. 

The Mini-Pactor is capable of handling batches as small as 10 grams up to small-scale production batches, with a maximum output of 100 kilograms per hour. Also, the TFC is a fixed-gap roll compactor, so if the amount of powder drawn into the compaction area is inconsistent, the force applied to the powder bed will vary. This can cause variability in the ribbon and granule properties. 

The Mini-Pactor, on the other hand, is a floating-gap type roll compactor, wherein the distance between the rolls changes depending on the amount of powder fed so that the force applied to the powder remains constant. This leads to a more consistent compaction process and less variability in the ribbon and granule properties. In addition, the Mini-Pactor has an in-line oscillating mill, which is gentler on the granules compared to the off-line Comil or Fitzmill that is used with the TFC. 

The blend was roller compacted at 8 kilonewtons roll force and a 2-millimeter gap. The roller compacted ribbons were milled using a star rotor equipped with a 0.8-millimeter screen. The fines were recirculated to obtain a concentration of less than 15 percent, which was consistent with the process used to granulate the proof-of- concept batch. Table 3 shows the resulting percentages of fines and granules. The percentage of fines decreased as the fines were recirculated back to the roller compaction process. 

The scientists compressed the tablets for the intermediate scale-up batch using a rotary tablet press equipped with a force feeder. They observed that the blend was severely compacted in the feeder and that the feeder compacts could be easily broken on contact. This indicated that the blend was somewhat cohesive and prone to agglomeration in the feeder. 

To determine if the energy imparted by the feeder paddles was exacerbating the blend’s cohesiveness, the scientists compressed additional tablets on a rotary tablet press equipped with a gravity feeder with no paddles and observed a similar blend compaction. The scientists then hypothesized that the blend’s high cohesive energy could be resulting in compaction of the blend in the feeder. 

To study the issue, the scientists manufactured a larger batch using the TFC roll compactor to see if blend compaction was an effect of the larger batch size, or whether it might be related to feeding-mechanism differences between the two different roll compactors. 

With the TFC roller compactor, the same blend compaction occurred at the neck of the hopper after 15 minutes of run time that had occurred with the Mini-Pactor. The scientists observed the blend adhering to the rollers and the neck of the hopper, as shown in Figure 2. This indicated that blend compaction was a result of the larger batch size and not of the equipment.

Having determined that the compaction was not the result of the roller compactor type, the scientists introduced talc to the scale-up formulation to improve its flow and minimize sticking. The scientists selected talc because literature research revealed that talc can help improve lubrication efficacy. The small particle size of powders means that the material’s overall surface area is relatively large, which increases interparticle friction and the development of electrostatic charges, causing cohesiveness and poor flow. Talc coats the particles, reducing interparticle friction and improving flow. However, the amount of talc used must be optimized to match the level of cohesiveness. 

According to some studies, talc also increases a roller compactor’s mass throughput. This is important because it can allow a high rate of production for scale-up. Additionally, talc reduces the tensile strength of the roller compacted ribbons. 

The proportion of fines versus granules after roller compaction was shown to play a large role in the probability of compaction occurring. To study the optimal amount of talc to add to the formulation, the scientists manufactured two prototype batches, one with 3 percent intragranular talc and one with 5 percent intragranular talc. They added 1 percent extragranular talc to each prototype batch. 

The compositions of the prototype batches are shown in Table 4. To compensate for the addition of talc, the scientists reduced the percentage of microcrystalline cellulose diluent by an equivalent percentage while keeping the percentages of the rest of the ingredients the same. The physical properties of prototype tablets are shown in Table 5 along with the Flodex of the prototype blends. The hardness of Prototype 1 tablets was higher than that of Prototype 2 tablets, while the disintegration of Prototype 2 tablets was slower compared to that of Prototype 1 tablets. However, both prototypes disintegrated within 25 seconds. 

The physical properties of the tablets in both prototype batches were similar, but the Flodex of the Prototype 1 blend was higher compared to that of Prototype 2, indicating poor flowability for Prototype 1. This reduced flowability resulted in weight variation in the Prototype 1 tablets and ratholing of the blend in the tablet press hopper, which is when a cohesive mass of stagnant material forms around the perimeter of the hopper with an empty channel in the center above the hopper discharge. This is undesirable because it leads to inconsistent feeding of material into the tablet press dies and results in tablet weight variation. 

Due to the poor flow of the Prototype 1 formulation, the scientists selected Prototype 2, which contained 5 percent intragranular talc and 1 percent extragranular talc. The dissolution profiles of the prototype batches are shown in Figure 3. As the figure shows, increasing the amount of talc slowed the drug release but only to a minimal extent. 

Scaling up the reformulated blend 

After the formulation change, the scientists prepared a second intermediate batch of 40,000 tablets processed using the Gerteis Mini-Pactor. To study the effects of roll force on the granulated blend, they compacted tablets at both 10 and 12 kilonewtons roll force with a roll speed of 2 rpm and a gap of 2 millimeters. Table 6 shows the percentage of granules versus fines obtained at each roll force.

As the percentage of fines was nearly the same at both roll force levels, the scientists used the 10-kilonewton roll force to compact the batch and recirculated the fines to yield less than 15 percent fines in the final blend. The reformulated blend’s physical properties are shown in Table 7. The blend had a Flodex of 10, which is slightly higher than that of the first intermediate batch processed using the TFC roll compactor but still indicates excellent flow.

Figure 4 shows the paricle size distribution of the final blend for the reformulated intermediate batch. The final fines content was 18.02 percent, and the powder blend was compressed on a rotary tablet press with no issues. 

The scientists then scaled up the reformulated blend to a pilot batch size of 130,000 tablets. The particle size distribution of the final blend of the scale-up batch is given in Figure 5. While the fines content of the final blend for this scaled-up pilot batch was greater than for the reformulated intermediate batch, the slight increase in fines did not cause any powder flow problems during tableting. 

The batch was compressed on a rotary tablet press equipped with a force feeder. The tablet press speed was 60 rpm, and the entire batch was compressed within 2 hours and 10 minutes. The scientists performed tablet thickness, hardness, and weight checks every 15 minutes during the compression run.

The tablet thickness and hardness are shown in Table 8. As the table shows, there was very little variation in the tablet thickness and hardness. 

Table 9 shows the initial and composite sample friability and disintegration time for the pilot batch. All the parameters were within specifications, indicating that, by adding talc to the formulation, the scientists were able to successfully scale up the process from proof-of-concept to a pilot scale of 130,000 tablets.