12 AAPS NEWSMAGAZINE | MAR ’18

The Formulation Design and Development section submitted this article.

PROCESSES, CHALLENGES, AND THE FUTURE OF TWIN-SCREW GRANULATION FOR MANUFACTURING ORAL TABLETS AND CAPSULES

Adopting twin screw granulation can aid in the transition from batch to continuous processes for pharmaceuticals.

By Nada Kittikunakorn, University of Texas at Austin; James DiNunzio, Ph.D., Merck & Co., Inc.; Charlie Martin, Leistritz Extrusion; Feng Zhang, Ph.D., University of Texas at Austin

MAR ’18 | AAPS NEWSMAGAZINE 13

he majority of marketed tablets

and capsules products are manu-

factured using granulation processes

including wet, melt, and dry granula-

tion. These granulation techniques are

also used across many other industries,

such as the food and polymer industries.

Powders are granulated to prevent material

segregation and to improve powder proper-

ties (e.g., flowability and compressibility).

While other industries transitioned wet and

melt granulation from batch to continuous

processes using twin-screw extruders in

the 1970s, the adoption of twin-screw

granulation (TSG) has been slow in the

pharmaceutical industry. As pharmaceuti-

cal scientists become more familiar with TSG,

and with the recent interest in continuous

manufacturing, an increasing number of pro-

cess patents and products utilizing the TSG

platform is anticipated. This article highlights

four aspects of TSG: (a) granule formation

mechanisms, (b) benefit over conventional

batch processes, (c) process control and mon-

itoring, and (d) history, recent progresses,

and the future.

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GRANULE FORMATION MECHANISMS: TWIN-SCREW CONTINUOUS GRANULATIONThe twin-screw extruder (TSE) is available in a variety of configurations with the corotating, intermeshing, twin-screw extruder being the most commonly used for granulation appli-cations. This TSE design is also considered “self-wiping,” because the opposing surface velocities inherent with the intermeshing motion lead to material removal from the surface. The screws consist of conveying and mixing elements (Figure 1). Conveying elements transfer material along the barrel, while mixing elements contribute to both distributive mixing and dispersive mixing during TSG. Distributive mixing involves divi-sion and recombination, while dispersive mixing involves planar mixing and exten-sional mixing.1 Depending on their geom-etry, mixing elements can be predominantly distributive, predominantly dispersive, or a balance of both. Images of representative conveying and mixing elements are shown in Figure 1.

The TSE is regarded as a small volume, continuous mixer. A 27 mm Leistritz extruder at 24 length/diameter configura-tion could operate at a production rate of 15 to 30 kg/hr. The total free volume inside the extruder at this configuration is only about 250 mL. This small mixing volume and corresponding mass transfer distance

improves the product consistency by ensur-ing that all granules have similar shear-ing history. This is why the term “small volume” mixer is used to describe TSE. As shown in Figure 2, materials are bounded and divided into different regions by the screw flights and barrel wall. Depending on the location relative to the barrel and screw elements, materials experience different intensity of mixing in different regions. High-intensity mixing regions are highlighted in red, while regions of low-intensity mixing are in blue.

Twin-screw granulation has traditionally been divided into two categories: twin-screw wet granulation (TSWG) and twin-screw melt granulation (TSMG).

TWIN-SCREW WET GRANULATIONIn TSWG, granulation fluid (e.g., water or solvent, optionally containing a polymeric binder or foam) is introduced into the extruder via a liquid injection port either as liquid or foam.2 TSWG is mechanistically similar to batch high-shear wet granulation.

Figure 1. Illustration of various screw elements

CONVEYING ELEMENTS

COMBING ELEMENTSKNEADING ELEMENTS

(MOST COMMON MIXING ELEMENT)

MIXING ELEMENTS

Figure 2. Cross section view of TSE denoting different regions of mixing (courtesy of Leistritz Extrusion)

LOBAL POOL

SCREW CHANNEL

OVERFLIGHTINTERMESH GAP

LOWER APEX

UPPER APEX

MAR ’18 | AAPS NEWSMAGAZINE 15

As the granulation progresses along the barrel in TSWG, the powder blend under-goes wetting and nucleation, consolidation and coalescence, and attrition processes to transform it into granules. Wetting and nucleation take place in conveying regions to form large, nonuniform agglomerates. These agglomerates are sheared, fractured, and compressed. As a result, consolidation and coalescence take place. Granules grow denser, stronger, and more uniform in the mixing regions.3, 4

Water or solvent can be removed from wet granules via different processes post-granulation. Large-scale fluid-bed drying is still commonly used as a batch process to dry the wet granules prepared using TSWG. The ConsiGma continuous tableting system designed by GEA contains a segmented dryer consisting of multiple individual drying modules. When drying endpoint (product temperature or residual moisture) is reached

for one drying module, granules are dis-charged and a new pack of wet granules is loaded. Continuous dielectric (microwave) drying has also been utilized and was first disclosed in the continuous pharmaceutical granulation patent by Warner Lambert.5

Leistritz Extrusion Corp. has developed a continuous flash drying process (Figure 3). The drying process begins in the extruder via a vent. After discharge, hot air is then used to drive off the remaining residual water and to transfer the granules into a mill for size reduction.

TWIN-SCREW MELT GRANULATIONAs a solvent-free alternative to TSWG, twin-screw continuous melt granulation (TSMG) uses a thermal binder instead of a liquid binder. The process is performed with a higher viscosity binder at elevated tempera-ture. Melt granulation is especially suitable

for drugs that undergo undesired physical or chemical changes in the presence of water or solvent.6, 7 Limited studies have investigated the mechanisms of the melt granulation pro-cess. Due to the thermal and mechanical energy input, thermal binders turn into low viscosity liquid (e.g., polyethylene glycol and glycerol behenate) or viscoelastic polymer melt (e.g., hydroxypropyl cellulose) inside the extruder barrel. Molten thermal bind-ers bridge the powder particles together to form larger agglomerates. Coating of thermal binders on the surface of granules has been observed using Time-of-Flight secondary ion mass spectrometry for the surface composi-tion analysis of granules.8

BENEFITS OF TWIN-SCREW CONTINUOUS GRANULATION OVER BATCH GRANULATIONBatch high-shear granulators generally con-sist of mixing blades positioned inside large

Figure 3. Illustration of a twin-screw wet granulation with flash drying (courtesy of Leistritz Extrusion)

Wet Granulation Process with Flash DryingFILTER

AIR OUT

CYCLONE

ROTARY VALVE

MILL

VENTURI HEATERBLOWER

AIR IN

EXTRUDER

FEEDER

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mixing chambers. The mixing and agglom-eration occur at the high shear zones, such as those located between the tips of the rotating blades and the wall of the mixing chamber for a high shear granulator. On the other hand, for TSG, different stages of the granulation process take place at different screw segments.

Batch granulation operates under the globally starved (the extruder barrel is 30 to 70 percent filled during processing) and unpressurized conditions. Even though the TSE operates under globally starved con-ditions, the processing section of a TSE consists of both starved (partially filled in conveying elements) and pressurized (fully

filled in mixing elements) segments dictated by the screw elements.9 Powder is randomly subjected to the high shear zone in a batch granulator, potentially resulting in nonuni-form mixing dynamics. In TSG, the material is forced through a sequence of starved and pressurized zones. As a result, granules pre-pared using TSG have a more uniform mixing history, where incoming blend is processed in a principle of first-in, first-out with a given residence time distribution. This allows the system to operate in a state of control and to

ensure the consistent quality of granules.9, 10 Three distinct advantages of TSG are

(1) more homogeneous distribution of drug, excipient, and binder solution; (2) reduced level of binder solution to achieve the desired granules; and (3) shorter processing time.10 Granulation time is on the order of about 10 seconds for TSG. In comparison, granulation time for a batch process is on the order of minutes. This shorter processing time makes it feasible to explore high processing temperatures that are not practical for batch process.

Besides the improved quality of gran-ules, TSG provides the following benefits when utilized as a continuous process:11

• Less binder solution is needed.• Smaller production facilities and less

capital investment are required.• Modular construction allows flexibility

in the configuration of the processing section.

• On-line and real-time monitoring of product quality is possible rather than postproduction testing.

• More efficient manufacturing with shorter production cycle and lower product cost.

• Simpler process optimization and scale up are possible.

• Use of the same equipment train for a much broader production volume and quicker response to changes in market demand is possible.

PROCESS CONTROL AND MONITORINGA TSE line consists of a drive section (motor and gearbox), a process section (barrel and screw), and an electrical and control panel. The TSE is starve-fed with the output rate controlled by the feeder. The energy required to transform the powder blend to granules predominantly comes from the mechani-cal energy input by the motor via rotating screws into the material. Heat conducted from the barrel can also play a significant role, especially for small-diameter extrud-ers. The modular design of the barrel and screw makes TSE an extremely versatile granulator. Screw elements and barrel design at any given segment can vary to accommodate various unit operations such as direct powder feeding, powder side stuff-ing, liquid injection, conveying, mixing, vent-ing, and devolatilization (removal of water and solvents).

Key processing variables include screw speed, barrel temperature, and feed rate. Screw speed is controlled by a variable speed AC drive, motor, and gearbox. Gen-erally, screw speed is set between 50 to 1000 rpm. Heating and cooling of the barrel are controlled by cartridge heaters and a cooling liquid such as a water/propylene glycol mixture. Temperatures can also be set by liquid temperature control units, as required in explosion-proof rated envi-ronments. For wet granulation, the barrel temperature is set at or slightly above the ambient temperature. For melt granulation, barrel temperature is set above the melting and glass transition temperature of thermal binders and is typically in the range of 80 to 130 Celsius. Feeding of powder and binder

Granules prepared with TSWG often have improved flow and compaction

properties relative to roller compaction.

MAR ’18 | AAPS NEWSMAGAZINE 17

solution is controlled using a loss-in-weight powder feeder (the entire feeder and mate-rial are continuously weighed, and the feeder speed is adjusted automatically to achieve the target feed rate) and pump (gear or peri-staltic pump for liquid, and side-stuffer for foam), respectively. Twin-screw continuous granulation operates in an open-end dis-charge mode. A restraining plate or outboard bearing prevents the screw from moving axially without obstructing the granule flow.

Precise process control to ensure consis-tent product quality requires monitoring the process parameters at different locations along the barrel. The parameters include temperature, pressure, and torque. A ther-mocouple or infrared probe can monitor the temperature of the material. Specific mechanical energy (SME), the amount of motor power input into each kilogram of material processed, could be derived from the motor torque readout. However, SME is not as critical as that for a melt extrusion process, due to the lower energy-space at which granulation operations are conducted. Because of the multifactor nature of the TSG process, multivariate analysis can be per-formed to understand the effect of process-ing variables and to identify key risk factors.

Process analytical technology (PAT) should be implemented to monitor the properties of granules on-line and in real time. Raman and near infrared spectroscopy have been applied to monitor drug and water content. Acoustic emission is a noninvasive tool to monitor the granule size distribution.12 Gran-ule monitoring technologies, such as the Eyecon imaging system, can also be used to assess granulation characteristics.13

HISTORY, RECENT PROGRESSES, AND THE FUTURE IN PHARMACEUTICAL APPLICATIONThe food and polymer industries were dominated by products manufactured by high-shear batch granulation into the

FIND RESEARCH IN THE AAPS JOURNALS:AAPS PharmSciTech: Twin Screw Extruders as Continuous Mixers for Thermal Processing: a Technical and Historical Perspective

Pharmaceutical Research: The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation

LOOK AT ABSTRACTS FROM AAPS MEETINGS:• High Drug Load Formulations Processed by

Continuous Twin Screw Wet Granulation (W4359)• Melt Granulation using a Twin Screw Extruder to Obtain

Lipid Granules Containing Tramadol HCl (W4072)• Robustness of a Continuous Twin Screw Granulation and

Drying System (W4369)• Use of a Continuous Twin Screw Granulation and Drying

System during Formulation Development and Process Optimization (W4368)

1960s. The transition to TSG to enable continuous manufacturing in the 1970s was based on the improved “product uniformity” and “mixing quality.”14 Appli-cation of TSWG to prepare pharmaceuti-cal dosage forms was first reported by Gamlen and Eardly in 1986 to improve compaction properties of acetaminophen. Granules containing 80 percent acetamin-ophen were prepared. The granulation

process was significantly facilitated by the presence of hypromellose in the binder solution.15 In 2000, Ghebre-Sel-lasie and his colleagues at Warner Lam-bert filed the first patent application on continuous pharmaceutical wet granula-tion using TSE. The inventor disclosed a continuous granulation line consisting of twin-screw granulation, milling (optional), microwave drying, and dry milling. The

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18 AAPS NEWSMAGAZINE | MAR ’18

process was successfully demonstrated at a 15 kg per hour output rate.5

A significant amount of research in TSWG was pioneered by Dhenge’s research team at the University of Sheffield, United Kingdom, and Thompson’s research team at McMas-ter University, Canada. They have conducted extensive study in the granule formation mechanisms, effect of screw design, and effect of processing parameters (e.g., liq-uid-to-solid ratio, location of liquid injection, binder concentration, and degree of fill).3, 4, 16, 17

Eucreas tablets, an immediate-release tablet of metformin and vidagliptin, are the first commercial product prepared using TSMG. The product was developed at Novar-tis. Metformin hydrochloride granules are prepared using TSMG. Hydroxypropyl cel-lulose is used as the thermal binder. The temperature of the extruded granules is about 140 to 160 degrees Celsius (above the softening temperature of hydroxypropyl cellulose and below the melting point of metformin).7

From a theoretical perspective, melt granulation could be a viable alternative to

1. Todd DB. Mixing of Highly Vicous Fluids, Polymers, and Pastes. In Kresta SM, Atiemo-Obeng VA, Paul EL, eds. Handbook of Industrial Mixing: Science and Practice. Hoboken, NJ: John Wiley & Sons, Incorporated;2004:987–1024.

2. Sheskey P, Keary C, Clark D, et al. Scale-up trials of foam-granulation technology: high shear. Pharm Technol Eur. 2007;19(9):37–46.

3. Dhenge RM, Cartwright JJ, Hounslow MJ, et al. Twin screw granulation: Steps in granule growth. Int J Pharm. 2012;438(1):20–32.

4. Dhenge RM, Cartwright JJ, Hounslow MJ, et al. Twin screw wet granulation: Effects of properties of granulation liquid. Powder Technol. 2012;229 (Supplement C):126–136.

5. Ghebre-Sellassie I, Mollan MJ, Pathak N, et al, inventors; Warner-Lambert Co., as-signee. Continuous production of pharmaceutical granulation. US Patent 6,499,984 B1. December 31, 2002.

6. Vasanthavada M, Wang Y, Haefele T, et al. Application of melt granulation technology using twin-screw extruder in development of high-dose modified-release tablet formu-lation. J Pharm Sci. 2011;100(5):1923–1934.

7. Lakshman JP, Kowalski J, Vasanthavada M, et al. Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs. J Pharm Sci. 2011;100(4):1553–1565.

8. N. Kittikunakorn, D. White, T. Listro, et al. Granulation mechanisms and the effect of processing conditions on physicochemical properties of gabapentin granules prepared by continuous twin-screw extrusion. Poster presented at 2017 AAPS Annual Meeting and Exhibition; November 14, 2017; San Diego, CA.

9. White JL, Bumm SH. Perspectives on the Transition from Batch to Continuous

Mixing Technologies in the Compounding Industry. Intern Polymer Processing. 2010;25(5):322–326.

10. Chen B, Zhu L, Zhang F, et al. Process Development and Scale-Up Twin-Screw Extru-sion. In Qiu Y, Chen Y, Zhang GGZ, et al., eds. Developing Solid Oral Dosage Forms: Pharm Theory Practice. Burlington, MA: Academic Press;2016.

11. Lodaya M, Mollan M, Ghebre-Sellassie I. Twin-screw wet granulation. In Ghebre-Sellassie I, Martin C, eds. Pharmaceutical Extrusion Technology. Boca Raton, FL: CRC Press;2003:323–344.

12. Markarian J. Scaling Up a Continuous Granulation Process. Pharm Technol. 2017;41(9):30–31.

13. Kumar A, Dhondt J, De Leersnyder F, et al. Evaluation of an in-line particle imaging tool for monitoring twin-screw granulation performance. Powder Technol. 2015;285(Supple-ment C):80–87.

14. Martin C. Twin Screw Extruders as Continuous Mixers for Thermal Processing: a Technical and Historical Perspective. AAPS PharmSciTech. 2016;17(1):3–19.

15. Gamlen MJ, Eardley C. Continuous Extrusion Using a Raker Perkins MP50 (Multipur-pose) Extruder. Drug Dev Ind Pharm. 1986;12(11–13):1701–1713.

16. Dhenge RM, Fyles RS, Cartwright JJ, et al. Twin screw wet granulation: Granule properties. Chem Eng J. 2010;164(2):322–329.

17. Thompson MR. Twin screw granulation–review of current progress. Drug Dev Ind Pharm. 2015;41(8):1223–1231.

18. Miller RW. Roller Compaction Technology. In Parikh DM, ed. Handbook of Pharmaceu-tical Granulation Technology. Boca Raton, FL: CRC Press;2005:159–190.

REFERENCES

the roller compaction process. Roller com-paction is the most common granulation process to manufacture oral dosage forms. However, the well-recognized problems of roller compaction include: 1. a limited ability to accommodate very

low or very high doses, 2. irregularly shaped granules and gen-

eration of fine particles that negatively affect flowability and potentially content uniformity, and

3. poor mechanical properties of granules for tableting.18

Granules prepared with TSWG often have improved flow and compaction properties relative to roller compaction. For TSMG, the particle “rolling” inside the extruder also has a spheronization effect on the granules. The coating of particles with molten binders during the extrusion process significantly improves the compaction properties of the granules.8

CONCLUSIONThe adoption, implementation, and expanded applications of twin-screw granulation and

the potential to integrate it into continuous manufacturing systems in the pharmaceuti-cal industry resemble what occurred in the food and polymer industry five decades ago. Valuable knowledge, technical expertise, and manufacturing experience gained in these industries would allow for expeditious adop-tion and implementation of this established processing technology to replace existing batch granulation processing. With con-certed effort and commitment from the pharmaceutical industry, equipment suppli-ers, excipients companies, and regulatory agencies around the advancement of con-tinuous manufacturing, the evolution of twin-screw continuous granulation is expected to continue.

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