Pellet Production Technologies

Areej Abu HaniehWafaa BeirutiShireen Rawajbeh

Introduction: • Pelletization can be defined as an

agglomeration process that converts fine powders or particles of bulk drugs and excipients into small, free flowing, more or less spherical units, called pellets.

• This technique enables the formation of spherical beads or pellets with a mean diameter usually ranging from 0.5 to 2.0 mm.

• It can be coated and usually used in controlled release dosage forms.

Pelletization vs. granulation.

• The general terms “granulation” and “Pelletization” are sometimes used synonymously and no clear distinction is made between them.

• generally if agglomerates size distribution within the range of 0.1 to 2.0 mm and a high porosity (about 20-50%), this process may be called granulation.

•But if the agglomerates have a narrow size range, usually with mean size from 0.5 to 2.0mm and have a low porosity (about 10%) with free flowing properties then it is called Pelletization.

1950 by pharmaceuticals scientist

Smith kline and French

improve the pellet and pelletization technique

spheroids particles

tablets , capsules and suspension

Technological Advantages• Improvement of the uniformity of the content• Prevention of dust formation.• Increasing bulk density and decreasing bulk volume.• The defined shape and weight improves the appearance of

the product.• Improvement of the handling properties, due to the free-

flowing properties .• Improvement of the hardness and friability of pellets.• Controlled release application of pellets due to the ideal low

surface area-to-volume ratio that provides an ideal shape for the application of film coatings.

Therapeutic Advantages• Pellets can disperse freely throughout an area of

the gastrointestinal tract• Pellets reduce peak plasma fluctuations and

minimize potential side effects• Avoiding the irritant effect of some drugs on the

gastric mucosa• Modified-release multiparticulate delivery

systems are less susceptible to dose dumping than single-unit dosage forms

• Often pellets can not be pressed into tablets because they are too rigid. In that case, pellets have to be encapsulated into capsules.

• The production of pellets is often an expensive process and / or requires highly specialized equipment.

• The control of the production process is difficult (e.g. the amount of water to be added is critical for the quality of the pellets and overwetting can occur very easily).

Disadvantages

Pelletization techniques: Extrusion/ Spheronisation.

Dry powder layering.

Spray-congealing.

Fluid-bed granulation.

Solution and suspension layering.

Spray-drying.

Extrusion-Spheronization:- • Extrusion is necessary first step in the extrusion-spheronization process. • The size of the sphere are determined by the diameter of the extrudate used. The extrusion-spheronization process can be broken down into following steps:-

Extru

sion

proc

ess

Screw Extruders

Screen or Basket Extruder

Gear Extruder

Screw extruder:- • Commonly used in industrial application. • Higher pressure and heat can degrade

pharmaceutical products.

Screen or basket extruder:

- Lower density

extrudate.

- Relatively high

throughput.

Gear extruder:

- produces relatively

high density.

- Gears are robust and last longer

Gear Extruder

Basket Extruder

Spheronization• spheronization is a process of forming a spherical particles

from different rod shapes , by extrusion , that has a diameter ranging from 0.5 to 1 mm .

• The size of the spheres are determined by the diameter of the extrudate used for the spheronization process. For example, in order to obtain spheres with a diameter of 1 mm, a 1 mm screen is used on the extruder.

Spheronization machine design• In principle the basic machine consists of a rotating friction disk, designed to increase

friction with the product, which spins at high speed at the bottom of a cylindrical bowl. The spinning friction disc has a carefully designed groove pattern on the processing surface. This is most often crosshatched, but several sizes and other types are available.

Spheronization mechanism of action• as the machine rotate , rods move in rotationary movement or woven rope

movement , and the most important point that rods should not be friable but it should have a plastic properties to have the ability to spheronized.

Video for Spheronization

Key Spheronization Factors:

• Disc speed and load• Disc groove geometry• Disc diameter and speed• Retention time• Product paramaters• Other factors

Disc SpeedThere is an optimum disc speed and load for each disc diameter:

- Momentum too low:

Extrudate not densified sufficiently.

No spheres formed.

Granules fracturing.

- Momentum too high (from under loading or disc speed too high):

Too much force on the granules.Compression of particles within the granules.

Minimum porosity.

Disc Groove Geometry:• Both radial and cross hatched will work effectively.• Radial disc had gentler and more controlled action.• Radial not suitable for large diameter discs.

Cross Hatched Disk Radial Disk

Retention time:• Typical retention time to obtain spheres range

from 2 to 6 minutes.• The edges of cylindrical granules are the most

fragile part and they will generate dust during handling .

• Spheronization with short retention time can help to reduce dust significantly.

Table summarizing the different types of caleva spheronizers for pharmaceutical production and

development :

Equipment Description Main use

Micro spheronizer A Bench Top Laboratory Unit

Laboratory:small quantity

Spheronizer-120 Bench top Laboratory/experimental

Spheronizer-250 Lab scale bench top Low cost high output

Spheronizer-380 A Production or Pilot Plant Spheronizer

Quality spheroids output

Spheronizer-500 A Production or Pilot Plant Spheronizer

Quality spheroids output

Main stages in the fluid bedDrying:

Granulation / agglomeration:

• Powder coating / particle coating:

Pelletizing

Types of fluid bed technologies

Top spray Bottom spray Tangential spray

Tangential Spray(Rotor Process)Parameters:•Liquid addition rate•Inlet air temp.•Humidity•Atomization air pressure•Binder type and concentration•Disk speed•Disk gap

ROTOGRANULATIONRotogranulation is one of the most recent methods for the production of spheroids. The single-unit spheronizing system can be described using terms like centrifugal granulator, rotary fluidized-bed granulator, rotary fluid bed, rotary processor or rotor granulator : 1)The preblending of the formulation powder, including the active ingredients, fillers, disintegrants, in a flow of air. 2)The granulation of the mixture by spraying a suitable liquid binder onto the fl uidized (suspended) powder bed. 3) The drying of the granulated product to the desired moisture content.

• During processing, three mechanical forces cause particle movement, mixing, and granulating.

• First, the spinning of the disk generates a centrifugal force.• Second, a lifting force is generated by the hot air passes

through the adjustable disk gap.• Third, gravitational force causes material to fall down onto

the disk.• These forces provide good mixing and result in granules,

drying, coating with good content uniformity.

During spraying-drying, a drug is solution or suspension is sprayed, with or without excipients, into a hot-air stream, generating dry and highly spherical particles.

Spray-drying

Spray-drying represents another process based on globulation.

Inlet air temperature: 180- 250 Co .

Outlet air temperature: 80-115Co ..

Inlet moisture content: 75-85%.

outlet moisture content: 3-3.5%.

Operating conditions

: Spray rate: 2290kg\hr

Air flow rate:

31500kg\hr.

Advantages: • This technique is suitable for

development of controlled-released pellets.

• It is generally employed to improve dissolution rates and bioavailability of poor soluble drugs.

• This method is applied for heat sensitive pharmaceuticals: amino acids, antibiotics, ascorbic acid, liver extracts, pepsin and similar enzymes, protein hydrosylate and thiamine.

• Particle size and size distribution, bulk density, porosity, moisture content, flowability and friability can be easily controlled by the design and operation of the spray drier.

The spray-dried powder particles are homogenous, approximately spherical, nearly uniform in size.

Spray-congealing: Spray-congealing is similar to spray-drying, it is also called

spray-chilling.

In spray-congealing the drug is allowed to melt, disperse or dissolve in hot melts of gums, waxes, fatty acids, or other melting solids.

The dispersion is them sprayed into a stream of air and other gases with a temperature below the melting point of the formulation components, under appropriate processing conditions, spherical congealed pellets are obtained.