spheronization

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Slide 1:

PELLETIZATION & SPHERONIZATION BALADHIYA CHIRAG* Parth Joshi DEPARTMENT OF PHARMACEUTICS SEM.-11 ATMIYA INSTITUTE OF PHARMACY, RAJKOT

INTRODUCTION :

INTRODUCTION WHAT ARE PELLETS ? In the pharmaceutical industry, pellets can be defined as small, free-flowing, spherical particulates manufactured by the agglomeration of fine powders or granules of drug substances and excipients using appropriate processing equipment . Historically, the term pellet has been used by a number of industries to describe a variety of agglomerates produced from raw materials, using different pieces of manufacturing equipment PELLETIZATION AND SPHERONIZATION 2

Advantages Of Pellets:

Advantages Of Pellets Pellets offer a high degree of flexibility in the design and development of oral dosage forms. Pellets as drug delivery systems offer technological advantages, such as better flow properties, less friable dosage form, narrow particle size distribution, ease of coating and uniform packing They can be divided into desired dose strengths without formulation or process changes and also can be blended to deliver incompatible bioactive agents in the gastrointestinal (GI) tract. In addition, pellets, taken orally, disperse freely in the GI tract, maximize drug absorption, minimize local irritation of the mucosa by certain irritant drugs, and reduce inter- and intrapatient variability PELLETIZATION AND SPHERONIZATION 3

Pelletization technique:

Pelletization technique Direct palletization Pelletization by layering Extrusion spheronization Newer technology Melt spheronization Spray drying & spray congealing Cryopelletization Freeze pelletization PELLETIZATION AND SPHERONIZATION 4

Direct palletization:

Direct palletization Powder is mixed and moistened and the powder bed set into centrifugal motion (fluid bed pelletizing in the rotor). The impact and acceleration forces that occur in this process result in the formation of agglomerates, which become rounded out into uniform and dense pellets and are then dried. Another alternative for direct pelletizing is spray granulation. PELLETIZATION AND SPHERONIZATION 5

Direct palletization:

Direct palletization PELLETIZATION AND SPHERONIZATION 6

Pelletizing by Layering:

Pelletizing by Layering PELLETIZATION AND SPHERONIZATION 7 Layer-by-layer pellet build-up - around a given starting core. Process involves the deposition of successive layers of dry powder of drug or excipients or both on preformed nuclei or cores with the help of a binding liquid. Powder layering involves the simultaneous application of the binding liquid and dry powder.

Pelletization by solution/suspension layering process:

Pelletization by solution/suspension layering process PELLETIZATION AND SPHERONIZATION 8 A starting grain or a pellet can be presented as the starting material. The pellet is built up to the required size and active ingredient content on a layer-by-layer basis by spray application of the layering substance. Powder and binders, suspensions or solutions make suitable layering substances. The layers are densely and quickly applied during powder layering in the rotor (fluid bed pelletizing), whereby different types of layers can be formed.

Extruded product spheronization process:

Extruded product spheronization process PELLETIZATION AND SPHERONIZATION 9 The most granulates or extruded products are fed onto the rotating pelletizing plate. The surface is smoothed due to the intensive rolling movement and spherical pellets are produced.

Melt Spheronization:

Melt Spheronization Melt Spheronization is a process whereby a drug substance and excipients are converted into a molten or semi molten state and subsequently shaped using appropriate equipment to provide solid spheres or pellets. PELLETIZATION AND SPHERONIZATION 10

MELT SPHERONIZATION:

MELT SPHERONIZATION PELLETIZATION AND SPHERONIZATION 11 The drug substance is first blended with the appropriate pharmaceutical excipients , such as polymers and waxes, and extruded at a predetermined temperature. The extrusion temperature must be high enough to melt at least one or more of the formulation components. The extrudate is cut into uniform cylindrical segments with a cutter. The segments are spheronized in a jacketed Spheronizer to generate uniformly sized pellets.

Spray Drying:

Spray Drying The drug entities in solution or suspension are sprayed, with or without excipients , into a hot air stream to generate dry and highly spherical particles. As the atomized droplets come in contact with hot air, evaporation of the application medium is initiated. This drying process continues through a series of stages whereby the viscosity of the droplets constantly increases until finally almost the entire application medium is driven off and solid particles are formed. Generally, spray-dried pellets tend to be porous. PELLETIZATION AND SPHERONIZATION 12

Spray Congealing:

Spray Congealing This process consists of suspending the particles in a molten coating material and pumping the resultant slurry into a spray dryer in which cold air is circulated. The slurry droplets congeal on contact with the air. The coating agents normally employed are low melting materials such as waxes . The congealing process require higher ratio of coating agents to active material than does the spray drying, because only the molten coating agent constitutes the liquid phase. PELLETIZATION AND SPHERONIZATION 13

CRYOPELLETIZATION:

CRYOPELLETIZATION Cryopelletization is a process whereby droplets of a liquid formulation are converted into solid spherical particles or pellets by using liquid nitrogen as the fixing medium. The technology, which was initially developed for lyophilization of viscous bacterial suspensions, can be used to produce drug-loaded pellets in liquid nitrogen at -1600 º C. PELLETIZATION AND SPHERONIZATION 14

Slide 15:

The procedure permits instantaneous and uniform freezing of the processed material owing to the rapid heat transfer that occurs between the droplets and liquid nitrogen. The amount of liquid nitrogen required for manufacturing a given quantity depends on the solids content and temperature of the solution or suspension being processed. PELLETIZATION AND SPHERONIZATION 15

Application of spheronization & eXtrusion:

Application of spheronization & eXtrusion Controlled release pellets for encapsulation Delayed release enteric coated pellets Sustained release pellets Multi-particulate systems Multi-unit erosion matrix pellets Pellets for special tabletting applications Immediate release pellets for sachets PELLETIZATION AND SPHERONIZATION 16

Spheronization:

Spheronization Spheronization or Maramuerization is a rapid and flexible process where pharmaceutical products are made into small spheres or spheroids. Spheronized products are relatively dense, of a uniform in size and shape and have defined surface characteristics and better flow property. Spheres provide the lowest surface area to volume ratio and thus pharmaceutical compounds can be coated with a minimum of coating material. PELLETIZATION AND SPHERONIZATION 17

advantages of Spheronization :

advantages of Spheronization Optimum Flow and Handling Characteristics More Reporduceable Packing Into Small Containers packing of small sphere into small containers, such as hard gelatine capsules, or larger packages is much more convenient than other dry forms such as powders or granules. Minimum Surface Area/Volume Ratio So,easily coated with a minimum of coating material Easy mixing of non-compatible products Spherical particles are easily mixed PELLETIZATION AND SPHERONIZATION 18

advantages of Spheronization :

advantages of Spheronization Optimum Shape for Coating and for Controlled Release Coating can provide controlled, targeted release at different locations within the body. Elimination of Dust elimination of dust removes the hazards and problems associated with material in this form and Contamination is reduced. PELLETIZATION AND SPHERONIZATION 19

advantages of Spheronization :

Improved Hardness and Friability Spheronization increases the hardness and reduces friability of granules dependant upon adhesive forces and surface characteristics Improved Packing of Beds and Columns In some chemical processes porous beds or packed columns are used as chemicals reactors and catalysts Spherical surfaces allow the reproduction of beds with always the same volume of void spaces advantages of Spheronization PELLETIZATION AND SPHERONIZATION 20

Method for spheronization :

Method for spheronization PELLETIZATION AND SPHERONIZATION 21

Mixing :

Mixing The pre-mixed dry ingedients , mostly composed of the API and Avicel , are wetted with water or organic solvent and mixed in a high shear granulator or double planetary mixer to form a homogeneous wet mass suitable for wet extrusion. PELLETIZATION AND SPHERONIZATION 22

Extrusion :

Extrusion The wet mass is metered by a special feeder into the extruder where it is continuously formed into cylindrical extrudates of uniform shape and size. PELLETIZATION AND SPHERONIZATION 23

Spheronization :

Spheronization The wet extrudates are placed in a spheronizer where a gridded, fast spinning disc, breaks them into smaller particles and rounds them to form spheres. PELLETIZATION AND SPHERONIZATION 24

spheronizer:

spheronizer Laboratory Spheronizer 250 Pilot plant or production Spheronizer 380 Continuous production twin drum spheronizer PELLETIZATION AND SPHERONIZATION 25

Key Spheronization Factors:

Key Spheronization Factors Disc speed and load Disc groove geometry Disc diameter and speed Retention time Product paramaters Other factors - Rheology -Binders: -Moisture content -Lubricants PELLETIZATION AND SPHERONIZATION 26

Disc speed :

Disc speed Momentum too low Extrudate not densified sufficiently No spheres formed Momentum too high Too much force on the granules Compression of particles within the granules Minimum porosity Granules fracturing PELLETIZATION AND SPHERONIZATION 27

Slide 28:

The speed of spheronization plate should be kept constant during the whole process. Speed affects the size, hardness, sphericity and density of the pellet. high speed has been reported to give higher sphericity lower friability smooth surface and higher crushing strenght.the speed of the plate was found to have a major influence on the overall dissolution rate which is linked to pellet size PELLETIZATION AND SPHERONIZATION 28

The Spheronizer Drum Charge Volume:

The Spheronizer Drum Charge Volume The optimum charging volume depends upon the machine size and the product characteristics A typical charge volume for a machine with a 380 mm diameter disc is about disc is 4 liters , depending on the density of the material. Increasing the batch size increases the hardness of the spheres and smoothens the granule surface PELLETIZATION AND SPHERONIZATION 29

Disc Groove Geometry:

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 Generally, extrudates up to 0.8 mm in diameter are normally processed on a 2 mm pitch plate with a 3 mm pitch plate is used for extrudates up to 3 mm in diameter. PELLETIZATION AND SPHERONIZATION 30

Disc Diameter:

Disc Diameter Loads from 0.5 to 25 kg can be compared One plane critical stability (OPCS) can be expressed as a function of number of revolutions of the plate Number of revolutions can be used to predict scale-up PELLETIZATION AND SPHERONIZATION 31

Binders :

Binders Binders can be used to increase the strength of the granules and reduce the amount of fine dust generated during the spheronisation . If too much binder is added and the granules become too hard, it will be difficult to obtain good spheres. PELLETIZATION AND SPHERONIZATION 32

Lubricants:

Lubricants Lubricants will increase the plasticity but also increase the amount of fine dust 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 extrudates are dry, a high amount of fine dust will be generated. PELLETIZATION AND SPHERONIZATION 33

Recent innovation :

Recent innovation The Micro Px ™ Technology consists of a continuous fluid bed process. After liquid spraying and coating of APIs, generated micropellets are classified by applying a vertical online air sifting system. The entire process constitutes of a well balanced system of spray drying and consecutive drug layering. The Micro Px ™ Technology process results in manufacturing of high drug loaded matrix-type micropellets . Drug loadings of produced pellets can be up to 95%. Micro Px ™ Technology process can be also applied for taste masking, which usually have an ideal particle size distribution between 200 to 400 µm. PELLETIZATION AND SPHERONIZATION 34

Micro Px™ Technology process:

Micro Px ™ Technology process PELLETIZATION AND SPHERONIZATION 35

CELLETS:

CELLETS Homogenous distribution of the active agent and the controlled release are two fundamental advantages of this dosage form. Due to the uniform concentration of highly active agents more reliable formulations can be achieved. As an inert, odorless and tasteless excipient , microcrystalline cellulose is extremely versatile. Therefore our Cellets ® are made from certified MCC and water only. Allowing combining the benefits of neutral pellets with the unique properties of cellulose. PELLETIZATION AND SPHERONIZATION 36

Fast Dissolving Pellets :

Fast Dissolving Pellets Fast dissolving products are designed as multiple-unit systems , which consist of several thousand spherical particles. Fast Dissolving Pellets are manufactured using proprietary pelletisation techniques . Fast Dissolving Pellets consist entirely of very water soluble and/or swellable excipients and can be compressed into orally dispersible tablets (ODTs). PELLETIZATION AND SPHERONIZATION 37

CHARACTERISTICS Fast Dissolving Pellets :

CHARACTERISTICS Fast Dissolving Pellets Narrow particle size distribution, e.g. 100 - 400 µm Smooth mouth feel Highly water soluble & swellable pharmacopoeial constituents with low hygroscopic behaviour Addition of flavoring agents possible Spherical pellets with porous structure; porosity facilitates disintegration and dissolution Mechanically very stable; easy product handling Packaging into conventional stick packs feasible PELLETIZATION AND SPHERONIZATION 38

REFERENCES :

REFERENCES Influence of process variables on physical properties of pellets using extruder spheronizer . Drug development industrial pharmacy, 25 (!) , 45-61 (1999). Physical characteristics of HPMC and HEC and investigation of their use as pelletization aids, R. Catlapalli , B.D. Rohera , International Journal of Pharmaceutics, 161(1998)179-193. www.spheronizer.com PELLETIZATION AND SPHERONIZATION 39

THANK YOU:

THANK YOU 40 PELLETIZATION AND SPHERONIZATION