Twin Screw Extruders as Continuous Mixers for Thermal Processing: a Technical and Historical Perspective

Abstract

Developed approximately 100 years ago for natural rubber/plastics applications, processes via twin screw extrusion (TSE) now generate some of the most cutting-edge drug delivery systems available. After 25 or so years of usage in pharmaceutical environments, it has become evident why TSE processing offers significant advantages as compared to other manufacturing techniques. The well-characterized nature of the TSE process lends itself to ease of scale-up and process optimization while also affording the benefits of continuous manufacturing. Interestingly, the evolution of twin screw extrusion for pharmaceutical products has followed a similar path as previously trodden by plastics processing pioneers. Almost every plastic has been processed at some stage in the manufacturing train on a twin screw extruder, which is utilized to mix materials together to impart desired properties into a final part. The evolution of processing via TSEs since the early/mid 1900s is recounted for plastics and also for pharmaceuticals from the late 1980s until today. The similarities are apparent. The basic theory and development of continuous mixing via corotating and counterrotating TSEs for plastics and drug is also described. The similarities between plastics and pharmaceutical applications are striking. The superior mixing characteristics inherent with a TSE have allowed this device to dominate other continuous mixers and spurred intensive development efforts and experimentation that spawned highly engineered formulations for the commodity and high-tech plastic products we use every day. Today, twin screw extrusion is a battle hardened, well-proven, manufacturing process that has been validated in 24-h/day industrial settings. The same thing is happening today with new extrusion technologies being applied to advanced drug delivery systems to facilitate commodity, targeted, and alternative delivery systems. It seems that the "extrusion evolution" will continue for wide-ranging pharmaceutical products.

Keywords: amorphous solid dispersion; continuous manufacturing; continuous mixing; twin screw extrusion.

Fig. 1

Side view of a two-roll mill

Fig. 2

Side view of a conventional batch mixer

Fig. 3

Single screw extruder screw design with flood fed feed throat and the associated pressure/pumping profile

Fig. 4

Photo of a 1960s era twin screw extruder

Fig. 5

Screw design of early stage counterrotating intermeshing TSEs

Fig. 6

Illustration of pitch, outer diameter (OD), and inner diameter (ID)

Fig. 7

a–c Examples of flighted elements. a Small pitch conveying element; b large pitch conveying element; c slotted mixing/conveying element

Fig. 8

Examples of mixing (kneading) elements

Fig. 9

a Example of bilobal TSE screw elements; b Example of trilobal TSE screw elements

Fig. 10

Graphic illustration of distributive and dispersive mixing

Fig. 11

Cross section view of TSE screw denoting five shear regions

Fig. 12

Self-wiping flow effect in a corotating TSE

Fig. 13

Effect of the degree of fill on the residence time distribution in a TSE

Fig. 14

Length to diameter ratio for a TSE barrel section; this barrel section has a 4:1 L/D

Fig. 15

Paring up a twin screw extruder for high-intensity mixing with a single screw extruder for cooling and pumping

Fig. 16

Setup of multiple loss-in-weight feeders to meter excipients and APIs into a TSE

Fig. 17

Pressure gradient in a starve-fed TSE process allows for downstream unit operations

Fig. 18

Downstream side stuffing into the TSE process

Fig. 19

TSE mated to a gear pump as positive displacement pumping device

Fig. 20

Lab scale TSE with provision for probes for process monitoring

Fig. 21

a, b Evolution of shaft design and asymmetric spline shaft

Fig. 22

End view of a state-of-the-art TSE barrel

Fig. 23

TSE barrel liner outside and inserted into the barrel housing

Fig. 24

Commercially available screw configurations for TSEs. a Intermeshing corotating; b Intermeshing counterrotating; c Nonintermeshing counterrotating

Fig. 25

Mean residence time and variance were all reduced in counterrotation when compared to the corotating TSE

Fig. 26

Co- and counterrotating TSE screw elements. a Corotating; b Counterrotating; c Corotating; d Counterrotating

Fig. 27

a, b Top and end view of a calender gap of a counterrotating intermeshing TSE

Fig. 28

a, b Examples of hexalobal mixing elements for counterrotating intermeshing TSE

Fig. 29

a, b C-locked counterrotating discharge screws and the associated melt flow effect for counterrotating intermeshing TSE

Fig. 30

Processing section of a conical intermeshing counterrotating TSE

Fig. 31

Different screw configurations for counterrotating nonintermeshing TSE