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Hot-melt extrusion in the pharmaceutical industry

Pharmaceutical manufacturers are using twin-screw extruders to mix molecules of active pharmaceutical ingredients (APIs) with appropriate polymers in situations where drug ingredients are poorly soluble or unstable during processing. Extruders are also useful in preparing enteric coated medication, developing sustained release dosages, in taste-masking, and in creating specific forms such as films.

Hot-melt extrusion process

Hot-melt extrusion (HME) is the processing of polymeric materials above their glass transition temperature (Tg) to effect molecular level mixing of thermoplastic binders and/or polymers with active compounds. Used in several industries, HME uses a combination of thermal and mechanical energy to improve continuous processing for reproducible processing of materials, along with dust and solvent reduction and online monitoring.

 

In pharmaceutical manufacturing, HME is used to disperse APIs in a matrix at the molecular level, thus forming solid solutions. This enables drug delivery systems for poorly soluble drugs or specialized drug forms such as films for transdermal patches.


Hot-melt extrusion polymers

The choice of an adequate polymer as a matrix to form stable solid solutions is crucial in HME. Polymers with a high solubilization capacity are particularly suitable because they can dissolve large quantities of drugs. Polymers for hot-melt extrusion experiments are based on different monomers and chemical structures, such as homopolymers, copolymers, amphiphilic copolymers as well as solubilizers and plasticizers. Consideration for each material must take into accountconsider the polymer's solubility in a solvent, which can vary from high lipophilicity to high hydrophilicity.

 

Polymers for hot-melt extrusion must exhibit thermoplastic characteristics and must be thermally stable at the proper extrusion temperature. In developing a HME drug system, the glass transition and melting temperatures are critical factors. The extrudability of a polymer is mainly determined by Tg or Tm and melt viscosity. Most polymers demonstrate thixotropic behavior where the viscosity reduces as a function of increasing shear stress.


Pharmaceutical extrusion technology

Present drug discovery methodology produces candidate drugs of increasing molecular size and lipophilicity, which results in poor solubility and permeability. Less than 10% of new drug candidates demonstrate both high solubility and permeability, and 30–40% of the drugs that appear on the World Health Organization Essential Drug List were reported to be poorly water-soluble or lipophilic. HME disperses the drug in the matrix at a molecular level by forming a solid solution.

 

HME is available for numerous applications, including amorphous solid dispersion, controlled release systems, polymorph generation, novel co-crystallization (solvent-free continuous co-crystallization), and porous polymeric systems.


Hot melt extrusion process parameters

In the hot-melt extrusion process, the API and the excipients are fed into the extruder. All components are sheared, heated, plastified, mixed and dispersed, and finally shaped by pressing them through a die opening. Developing a HME-based manufacturing project requires control of several processing parameters that affect final product quality: Residence time distribution and specific mechanical energy consumption (SMEC) must be considered, and also the temperature of the melt at the extruder die, the pressure at the die, and screw torque.


Scale-up of pilot projects to commercial scale for hot melt extrusion

Identify drug candidates at lab scale

Thermo Scientific twin-screw extruders are built with similar geometries across their different sizes. This enables experimentation and feasibility projects developed with a lab-scale (11 mm screw) instrument to be scaled-up to commercial size using a scientific approach. Using a lab-scale extruder minimizes the use of expensive APIs and enables fast and easy clean-up between experiments.

Micro-compounder finds drug candidates

Finding the right API/excipients formulation and testing if this formulation is the right candidate for hot-melt extrusion can be difficult. The Thermo Scientific Pharma mini HME Micro Compounder requires as little as 3 grams of total material to identify the right drug candidates for hot melt extrusion. The compounder with conical co- or counter-rotating screws is designed to minimize waste and reduce downtime necessary for cleaning.

Benchtop extruder for research and small-scale production

With a minimum throughput of 20 g/h, a benchtop extruder is ideal for Phase 1 research applications, especially when developing and testing recipes with expensive API and associated compounds. As a GMP-compliant unit, the Thermo Scientific Pharma 11 Twin Screw Extruder is also suitable for clinical trials and small-scale production for throughputs up to 2.5 kg/h. The screw and barrel designs are geometrically scalable across the whole Thermo Scientific portfolio of extruders from lab and pilot through to production scale.

Formulation development platform

Designed to fit between the development lab and production line, the modular Thermo Scientific Pharma 16 Twin-Screw Extruder can manage several drug formulation projects, including controlled release formulations, solubility enhancement, co-extrusion and implants, abuse deterrent formulations, and wet and melt granulation projects. A modular design enables formulation scientists to switch from hot-melt extrusion and continuous granulation projects without engineering the extruder system.

Production-scale HME

For consistent, controllable processing of hot-melt drug formulations that are suitable for utilizing PAT, the Thermo Scientific Pharma 24 Twin-screw Extruder promises reduced product changeover time and minimized scale-up risk, while allowing for fast and easy cleaning.

 

This platform includes integrated ancillary equipment for both project development and commercial production including pre-mixers, feeders, chill rolls, air-cooled conveyors, pelletizers, and sheet or blown film lines. GMP standard pharmaceutical versions of the ancillaries are available with stainless steel construction and dust-tight touch-screen operator interface.


Pharmaceutical twin-screw extruders selection guide

Quickly find the right Pharma pharma twin-screw extruder to fit your formulation development and production needs.

 

 

Pharma Twin-Screw Extruders

Pharma Mini HME

Pharma 11

Pharma 16

Pharma 24

Pharma 24 TSG

Recommended for

Feasibility

Research

Research/Pilot

Manufacturing

Manufacturing

Typical throughput HME*

3 g batch or 100 g/h

20 g/h - 2.5 kg/h

0.5 kg/h - 10 kg/h

1 kg/h - 30 kg/h

N/A

Typical throughput TSG*

N/A

up to 3 kg/h

up to 20 kg/h

up to 80 kg/h

up to 80 kg/h

Dimensions
(L × W × H)

58 x 37 x 34 cm

83 x 48 x 41 cm

210 x 76 x 176 cm

210 x 85 x 173 cm

195 x 32 x 42 cm

Downstream Options

take-off belt
laser based calibration and cutting device

conveyor belt
pelletizer
sheet take-off

conveyor belt
pelletizer
chill-roll
face cut pelletizer

conveyor belt
pelletizer
chill-roll
face cut pelletizer

for line integration

Screw Design

conical, co- counter rotating

parallel, co-rotating

parallel, co-rotating

parallel, co-rotating

parallel, co-rotating

Max. Torque

5 Nm

6 Nm / shaft

18 Nm / shaft

52.5 Nm / shaft

18 Nm / shaft

*actual throughput dependent on formulation

 


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