Roller compactor for dry granulation
Multi-ton quantities of bulk raw materials such as buffers, salts, and stabilizing chemicals are used throughout pharmaceutical and biopharmaceutical manufacturing workflows and typically prepared using a just-in-time approach to maximize efficiency. However, handling bulk powders at a large scale can be challenging for several reasons including:
Handling caked raw material increases operational and safety risks as manual de-caking of solid blocks of bulk powders becomes necessary. This process not only delays project timelines, but it can also pose a risk of injury to the operator to break apart the solid mass manually. Caking, and especially severity of caking cannot be predicted, as it is caused and influenced by various parameters such as chemical characteristics, pressure, moisture, as well as transport and storage condition.
This process can also result in quality deviations, increase the risk of contamination, and escalate operational costs due to:
The mentioned difficulties and efforts that come along with caked raw materials also result in elevated costs. Figure 1 shows additional cost that can result from caking of bulk raw materials in an exemplary production setting.
Figure 1.Increased costs of manufacturing associated with the caking of raw materials in a typical production setting, resulting in estimated annual caking costs of ~200 k€**.
* Source: US Occupational Safety and Health Administration - www.osha.gov/safetypays/estimator
** Material and batch loss calculations highly depended on customer application and material
While minimizing material storage time and ordering smaller packaging sizes can help avoiding solidified material to a certain extent, it does not prevent it and also comes along with other difficulties, such as hampering just-in-time manufacturing processes.
The underlying cause of raw material caking can be addressed by changing the physical form of the chemicals using granulation techniques. Compared to powders, granulated materials experience far less caking and as such, have better flowability and are easier to handle, even after long-term storage. Small clumps that may occasionally occur are typically easy to break, unlike the solidified blocks that can occur with powders. Granules thus offer better processability, accelerate manufacturing processes, and improve operator safety.
Granulation can be performed by two different main techniques: Dry granulation and wet granulation (Table 2). Dry granulation incorporates mechanical compression either by slugging or roller compaction while wet granulation typically uses a liquid and a binder to facilitate agglomeration of dry powder particles. Because dry granulation does not require a liquid/binder, it is preferred for compaction of chemical raw materials as their chemical composition is not altered.
With the slugging process, tableting machines or rotary presses form slugs which are then broken by a hammer mill to form granules. In roller compaction, the raw material is compressed into plates or sheets between two rotating rollers, which are then milled into granules. Compared to slugging, roller compaction is gentler, making it the preferred approach for heat- and moisture-sensitive raw materials. (1, 2, 3)
Figure 2 provides an overview of dry granulation using roller compaction. Bulk material is added to a funnel with a mixer and tamp auger that transports the material toward the rotating rollers. Hydraulic compression is then applied to form the plates. Because the high pressure can lead to an increase in temperature, the rollers are temperature-controlled to protect the raw material. The plates are pressed together and transported to the rotor sieve mill to produce the final granules at the desired size. Because fine particles that fall below the desired size can increase the probability of re-caking, they are recirculated to the funnel for a second round of granulation, thus minimizing product loss.
Figure 2.Principle of dry granulation by roller compaction. A typical roller compactor setup comprises (1) bulk material, (2) funnel with mixer and tamp auger, (3) hydraulic compression rolls (temperature controlled), (4) rotor sieve mill, (5) vibrating sieve, (6) final granules, (7) fine particles re-circulation.
Several process parameters must be considered to produce high-quality particles of a consistent size range using dry granulation and roller compaction.
Granulated raw materials produced using roller compaction have beneficial characteristics which translate into important advantages for drug manufacturing workflows. To systematically assess potential advantages of granulated materials, a case study was performed evaluating urea, glycine, and potassium chloride as model materials prone to caking in their granulated and bulk powder form.
Particle size of granules is always a distribution and is influenced by the mesh size of the milling sieve and the material itself. Figure 3 shows the distribution of urea particles following dry granulation with roller compaction using a milling sieve mesh size of 6 mm. The data confirm a very low portion of fine particles (< 1 mm) following an optimized process with recirculation of fines.
Figure 3.Urea particle size distribution following dry granulation using roller compaction.
Figure 4 shows the appearance of granulated urea (A) and potassium chloride (B) following a long-term stability study of 12 months at ambient conditions (25 °C / 60% relative humidity). The non-granulated bulk materials showed a high percentage of solidified blocks that were difficult to break apart (68% for urea and 42% for the potassium chloride). In contrast, the granulated urea and potassium chloride had significantly less caking (12% and 0% clumping, respectively) after 12 months in storage compared to the bulk material. The observed small clumps of granulated urea were easy to break apart in contrast to the hard clumps observed with the powder material.
Figure 4a.Appearance of granulated urea (A) and potassium chloride (B) following a 12-month stability study at ambient conditions (25 °C / 60% relative humidity).
Figure 4b.Appearance of granulated urea (A) and potassium chloride (B) following a 12-month stability study at ambient conditions (25 °C / 60% relative humidity).
Granulated particles have increased flowability compared to bulk material as measured by a powder analyzer (Figure 5). In this study, material is placed on a rotating plate whose angle is then increased; the avalanche angle is that at which material starts to flow down the plate and ranges from non-satisfactory to excellent flowability. A lower avalanche angle indicates better flowability which translates to improved handling and processability.
Figure 5.Comparison of flowability of granulated and bulk raw materials. Flowability was determined based on the avalanche angle as measured using a powder analyzer: <45° excellent; 45–55° good; 55–62.5° average; >62.5° non-satisfactory.
The mechanical stability of granulated particles can be evaluated under simulated stress conditions using a friability tester to determine the risk of crushing during transport, handling, and storage. In this study, granules were placed in an abrasion drum with heavy ceramic balls and the mass percentage of fine particles generated was determined. Abrasion of different granulated materials varied but was always less than 4%, indicating excellent integrity (Figure 6).
Figure 6.Abrasion of granulated materials under simulated mechanical stress conditions using a friability tester.
Focused beam reflectance measurement (FBRM) was used to determine dissolution kinetics for granulated and non-granulated material. In this method, a laser beam detects and counts particles within the solution. The dissolution behavior of granulated materials was comparable to the bulk material (Figure 7; Table 3), requiring only a slightly longer time which can be attributed to the lower surface area of the granulated material. Even with a slightly slower dissolution, the overall time savings as compared to caked bulk material is evident as manual de-caking, sampling, and weighing are not needed.
Figure 7.Dissolution kinetics of sodium chloride in granulated and bulk powder form as measured with focused beam reflectance measurement (FBRM).
Granulated chemical raw materials offer distinct advantages over raw materials in their non-granulated, powder bulk form. These materials:
Importantly, use of granulated materials offers important benefits to the pharmaceutical and biopharmaceutical manufacturing process. By significantly reducing the tendency of bulk materials to cake, flowability and processability are improved, enabling accelerated workflows, just-in-time production, and increased operator safety.
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