Spheronisation
In the production of pharmaceutical pellets, the process of Extrusion & Spheronization (ES) is commonly used (A trademark of Caleva Process Solutions - www.caleva.com). This four step process consists of wet mixing, extrusion, spheronization, and drying/coating. The pellets are then encapsulated, tabeleted, or dosed into sachets. Pharmaceutical pellets range in size from 0.6 to 1.2 mm. Spheronization, also known as Marumerization (Japanese origin and a trademark of Fuji Paudal Ltd), is the third step in the Extrusion and Spheronization process. During this step, cylindrical extrudates (from the previous step) are converted into spheres.
The EMEA and the Extrusion and Spheronization Process
The EMEA (The European Medicines Agency) regulation CPMP/QWP/604/96 states:- "The development of single unit non-disintegrating dosage forms is discouraged since their residence time in the stomach is unpredictable and in general longer than disintegrating dosage forms with multiple units of pellets. There, such single unit non-disintegrating dosage forms are liable to a higher risk of dose dumping."
The process is well known and widely used in the pharmaceutical industries but its use is becoming increasing recognized in other industries.
Therapeutic Advantages of Pellets made by the Extrusion and Spheronization Process (relevant to pharmaceutical industries)
- Easy to coat
- Separation of incompatible drugs
- Ability to mix pellets with different release rates
- Reduced risk of dose dumping
- Reduced risk of local irritation in the gastro-intestinal tract
- Less variable bio-availability
- Particles of 1mm or less behave more like liquids in terms of gastric emptying
- Even distribution over the gastro-intestinal tract
- Easy formulation and mixing of otherwise incompatible drugs.
Physical Advantages of Pellets made by the Extrusion and Spheronization Process
- Improved flow characteristics
- Narrow particle size distribution (PSD)
- Uniform packing characteristics
- Dust free
- Low friability
The 4 steps of the Extrusion and Spheronization Process
Step 1: Wet Mixing
The ingredients are generally mixed (or granulated - the process is called granulation) in either a high-shear granulator or a more simple planetary mixer.
Step 2: Extrusion
The wet mass (or granulation) is extruded to form cylindrical extrudates of a constant diameter (normally 0.6 - 1.2 mm). The wet mass is passed through the screen forming soft, pliable extrudates (similar to pasta) which break by their own weight into shorter units. The size of the final pellets (spheres) is principally determined by the hole diameter of the screen (or die) used in the extrusion step. For example in order to obtain spheres with a diameter of 1 mm, a 1 mm screen is used on the extruder, although spheres with a distribution of 0.8-1.2 mm may often be obtained.
Types of Extrusion and Extruders for making pellets
All extrusion processes are based on the generation of pressure within the material and when materials are put under pressure heat is generated. This cannot be avoided but different extrusion types generate different amounts of heat. There are basically three different types of extruder and the one chosen may have far reaching implications on production operations. It is vitally important that the right type of extruder is chosen as this is a critical decision that will have long term implications.
Screw driven extruders (with radial or axial output) Screw driven extruders move the product to the extrusion die head along an axis by the use of a screw thread. The product is worked hard for quite a long time and it is a fact that this process generates a huge amount of heat. This cannot be avoided and all screw extruders do this. The generation of heat is useful in many industries such as plastics or food but for pharmaceutical products or any other products that can be damaged by heat this can be a disaster. This is especially true when high volumes and continuous extrusion are required. It is possible to add cooling systems to screw driven extruders but these are often not very efficient at keep the product cool during the process even though they may keep the equipment cool! It is recommended if you have restrictions on the amount of heat allowed, that any screw driven extruder is avoided. This is particularly true if you want to extrude product through very small holes (which you will if you need very small pellets). The diameter of the final pellets is largely determined by the diameter of the extrudate you will be extruding through small holes in the extrusion die. A screw extruder film http://www.youtube.com/watch?v=h6YHjgTV3gU
Basket or screen extruders: There are two main types of mechanisms. One type scrapes the product through the screen and the other type uses rollers that push the product through the screen. The type with the roller action is marginally gentler on the product but both types do generate some heat. The heat generated in screen extruders is significantly less that the amount of heat generated with screw driven extruders. Screen extruders are generally suitable for a great number of pharmaceutical formulations and they are widely used in the pharmaceutical industry. They are also the lowest cost extruder to make for any particular required capacity. This is why they are widely used. A production screen extruder in operation http://www.youtube.com/watch?v=dQViDKzUm3A
Gear Extruders: Gear extruders are less well known but have significant and real advantages when extrudate is required of products that are sensitive to heat. The principle of operation is quite different to other extruders. The product is allowed to fall between two rotating gears. The base of the gear form has holes so that the product is pushed through the base of each gear tooth into the hollow centre of the gear and falls out of the front of the gear. A small film of how gear extruders operate http://www.youtube.com/watch?v=o7_cqrIYhjQ This process is the type of extrusion that generates the least possible amount of heat. This low generation of heat is principally for three reasons;
1. Very little work is done to the product before it enters the extrusion teeth and the actual moment when the product is pushed through the holes in the die.
2. The product moves through the extrusion holes very quickly and emerges into the centre of the gear. Because the extrusion is very quick and the time the product is under pressure is short very little heat is generated.
3. Finally because the gears themselves are significantly large and solid lumps of steel any small amount of heat generated is easily transferred away. The point of extrusion in both screw fed and screen extruders is much less solid and therefor the transfer of heat away from the product is significantly slower.
Step 3: Spheronization
Spheronization is a batch process. Extrudates are charged to the spheronizer and falls on the spinning plate. During the first contact of the cylindrical granules with the friction plate, the extrudates are cut into segments with a length ranging from 1 to 1.2 times their diameter. These segments then collide with the bowl wall and they are thrown back to the inside of the friction plate. Centrifugal force sends the material to the outside of the disc. The action of the material being moved causes the extrudate to be broken down into pieces of approximately equal length related to the diameter of the extrudate. These cylindrical segments are gradually rounded by the collisions with the bowl wall and the plate and each other. The ongoing action of particles colliding with the wall and being thrown back to the inside of the plate creates a “twisting rope movement” of product along the bowl wall. The continuous collision of the particles with the wall and with the friction plate gradually converts the cylindrical segments into spheres, provided that the extrudates are plastic (pliable) enough to allow the deformation without being destroyed or sticking together. It is essential that this rope movement is present for an optimal spheronization. When the particles have reached the desired level of sphericity, they are then discharged from the spheronizer.
Step 4: Drying/Coating
Wet pellets are collected and dried in a vertical fluid bed drier (FBD) or in some instances a tray hot with a flow of hot air covering the pellets. The FBD can also be used to coat the pellets (using a Wurster insert) if so desired.
Machine Parameters
In principle the basic machine consists of a round disc with rotating drive shaft, spinning at high speed at the bottom of a cylindrical bowl. The spinning friction plate has a carefully designed pattern to the base. This is most often cross-hatched, several sizes and other types available. These discs are designed to increase the friction with the product. Spheronization equipment is available from several manufacturers.
Friction plate pattern.
The most common groove pattern used for spheroniser discs is the “waffle-iron” or cross-hatch design, where the friction plate is like a chessboard of chopped-off pyramids. The choice of which disc type and size to use is rather empirical. Discs with a radial design are also used, as these are considered gentler on the material being spheronised.
Friction plate speed.
The typical rotation speed of a 700 mm diameter disc ranges from 400 to 500 rpm. The higher the speed, the more energy is put into the particle during a collision. The optimum speed depends on the characteristics of the product being used and the particle size. In general, smaller discs require a high speed while bigger discs require lower speeds. In practice the optimum speed can be determined from experience and systematic testing. For some products it might be recommendable to start at a high speed and to lower the speed in the final stage of the process. But again this can be determined by simple practical tests. The process allows a high degree of flexibility for most materials.
Retention time.
Typical spheronization retention times to obtain spheres range from 2 to 6 minutes (it can be as little as 30 seconds or as much as 14 minutes). As with speed this is relatively easy to determine and best obtained by simple trials with specific products. For some products, the strong cohesive forces in the extrudate prevent the extrudate from breaking up into smaller pieces. If the objective is to reduce dust and not necessarily obtain perfect spheres than the short contact with the friction plate is sufficient to break the long extrudate into small segments and round the edges. The edges of cylindrical granules are the most fragile part and they will generate dust during handling and transportation. Spheronisation with a short retention time can help to reduce this amount of dust significantly.
The charge volume
The optimum level depends upon the machine size and the product characteristics; there is an optimum quantity of product to be charged per batch into the spheroniser chamber that will produce the most narrow particle distribution and the best spheres. Increasing the load per batch increases the hardness of the spheres and smooths the granule surface.
Product parameters
The result obtained in the spheroniser depends on the rheology of the product. The particles must have enough plasticity to allow deformation under the impact they receive during the spheronization process, but also must be strong enough to withstand the collisions with the friction plate, each other and bowl wall without being broken up and destroyed.
- The rheology of the product can be changed (and measured using a Mixer Torque Rheometer) by varying the formulation (excipients, API level, moisture), or physically (mixing time, type of mixer, intensity of mixing).
- Binders can be used to increase the strength of the granules and reduce the amount of fines generated during the spheronisation. If too much binder is added and the granules can become too hard, it will be difficult to obtain good spheres.
- Lubricants will increase the plasticity but may also increase the amount of fines generated during spheronisation.
- Water can also be used as a lubricant. If too much water is used, sticking can occur on the friction plate and bowl wall. It can also happen that the granules will stick together, forming big lumps. If the extrudate are too dry, a high amount of fines will be generated.
- The optimum moisture content for spheronization is slightly less than for extrusion only or for making tablets by compression.
Auxiliary Equipment
There is various auxiliary equipment that can help to improve the efficiency and ease of the spheronisation process.
Water jacket.
Warm or cooling water can be introduced in a jacket. Warm water can be particularly useful on the chamber wall to drive off moisture that would cause product sticking on that wall. Cooling the wall will avoid temperature rises in heat sensitive products, although, the average temperature rise in a spheroniser is generally rather small (normally about 4°C).
Air introduction (Fines air).
A slight flow of air can be introduced in the chamber from under the friction plate this not only prevents dust from getting between the rotating plate and the wall of the chamber but also can help to remove moisture from the granule’s surface, improving the friction forces and the process efficiency.
Non-Stick Coatings
For some products, the chamber wall and the spheronisation plate can be coated with non-stick materials if this is necessary for ease of use with sticky materials or cleaning.
References
- Extrusion-spheronisation - A literature review.,Chris Vervaet, Lieven Baert and Jean Paul Remon. International Journal of Pharmaceutics; Volume 116, Issue 2, 28 March 1995, Pages 131-146
http://www.sphinxsai.com/Oct_dec_2010_vol2_no.4/PharmTech_vol2_no.4_1_pdf/PT=44%20(2429-2433).pdf