Granulation, Generally, all of the particles are distributed in irregular manner, when particles create bond between them then granules are formed. To create bond between the particles is not automatic process, mechanical forces are applied to the particles or various types of binding agents are used to create granules. Granulation is simply a particle collecting process where particles are particles create bond between them by compression or with the help of binding agent.
List of binding agent used in pharmaceutical company in granulation process of different material-Various types of binders use in pharmaceutical industry such as-
Natural Binders
- Alginic Acid
- Acacia
- Cellulose
- Gelatin
- Pregelatinized Starch
- Starch Paste
- Tragacanth
Synthetic/Semisynthetic Polymer
- Ethyl Cellulose
- Hydroxy Propyl Methyl Cellulose (HPMC)
- Hydroxy Propyl Cellulose
- Methyl Cellulose
- Microcrystalline Cellulose
- Polyvinyl Pyrrolidone (PVP)
- Polyvinylcaprolactam
- Polyethylene Glycol (PEG)
- Polyvinyl Alcohols
- Polymethacrylates
- Sodium Carboxy Methyl Cellulose
Top Binder Manufacturer
- BASF Company
- Colorcon
- Dow Chemicals
- FMC Corporation
- Natural Starch and Chemical Company
- Penwest Pharmaceutical
- Quest International Group
- Wolff-Cellulosics
Most of the granules size distribute from 0.2 to 4.0mm and this size may be change based on their mode of use. Granulation process refers to the activity where particles are adhere to form larger and this repeated procedure create multiple particle entities called granules. Granules are formed from series of primary particle, after completion of the process the identity of the primary particle is no longer available.
Objective of Granulation:
1. To produce quality product is the top most priority of the granulation process.
2. To avoid segregation of the ingredients in the powder mix.
-Different size of particle presents in particle mix, segregation mainly occur for the different size of particle with irregular ratio in power mix. Normally two types of particle present in a mix. Normally smaller and coarser particle tend to settle down in the bottom of the container and comparatively large particle store on the top of the container. If granulation process conducted standard way then no particle settle down on the container.
If segregation of the powder mix occur then, tablet compression leads to irregular pattern. Physical criteria didn’t match as per set parameter then directly affect the product quality. To avoid this problem, granulation process to be conduct by using suitable binding agent from appropriate source. Correct proportion of particle mix prevent settle down of the granules.
3. To increase the flow properties of the powder mix.
-Powder contains small size particle, irregular shape or surface characteristics denote poor flow property as the cohesive forces are not dominant here. Cohesive forces to be increase to get better flow property of powder. If cohesive forces is not dominant, particles are generally settle down to the bottom of the container.
4. To produce even mixtures.
5. To control powder density.
6. To produce dust free preparation.
7. To remove poor content uniformity.
8. To increase the compaction characteristics of the Mix.
9. To seizure and fuse small quantities of active material.
Mechanism of Granulation: How granules are formed
In pharmaceutical industry, granulation is the key step to prepare any type of tablets, pellets, powder for suspension and related powder products. So this is very important to know how to develop gangues from powder. How granules quantity may be develop and how we can overcome associate problem during granulation.
This is very important to form bond between powder particles as they adhere between them form particle-particle bond. The bond formation to be adequately strong so that they can overcome the breakdown tendency during subsequent handling.
Type of bonding mechanism: Five Types
- Solid bridges
- Mobile liquid films
- Immobile liquid films
- Mechanical interlocking
- Attractive forces between solid particles
Methods of Granulation
Wet Granulation
Dry Granulation
1. Adhesion and cohesion forces in immobile films
In the presence of sufficient liquid in powder mix to form thin and immobile layer then inter-particulate distance will be reparably decrease and subsequently contact area between the particles will be increase.
Due to more surface availability bond strength between the particles will be increase, as per Van Der Waals force of Attraction, the forces are proportion to the particle diameter and inversely proportional to the separation distance.
During Dry Granulation, the pressure will increase the contact surface between the layers and subsequently decrease inter-particulate distance in the result; this will contribute the granule strength.
In the presence of highly viscus solution of adhesive, the thin, immobile layer form which will strengthen the bond between the particles compare to mobile films.
2.Interfacial forces in mobile liquid films
In the time of wet granulation, sufficient liquid is added to the powder and this liquid distributed around and between the particles. Sufficient liquid help to exceed the immobile layer to convert into the mobile film. Several types of water distribution systems which has been demonstrate here-
Pendular Phase:
During this phase, lens shaped rings of liquid hold particles where as this phase generally occur low moisture condition in the powder mix. Surface tension forces in the liquid-air interface and the hydrostatic suction pressure in the liquid bridge cause adhesion.
Funicular Phase:
This is the intermediate stage between the pendular and capillary phase when air start to displace between the particles then the particles arrange funicular phase. After completion of the intermediate phase- Funicular Phase then capillary phase visible where air completely displace/remove between the particles.
Capillary Phase:
As all the air remove between the particles, the Capillary Phase arrive and the entire particle held by the help of capillary suction in liquid-air interface at the granule surface. Tensile strength increases almost three times in moist granule in capillary and pendular phase.
The total moisture content plays a vital role in the phase of the power bed where total moisture content is the key factor, if separation of the particle can be decrease capillary phase may be reached easily which is the most desirable phase in granulation.
Droplet Phase:
This is the most undesirable phase in granulation. This phase is important in granulation at spray drying of suspension.
Mechanism
During the wetting and mechanical handling of particulates, the Agglomeration, granulation and pelletizing processes is greatly involved. If we increase the wetting and mixing, then open and porous agglomerate structure changes into more close and grain like granule structure. The control of moisture is the main factor in particle engineering, energy input require achieving desired structure of the granules.
Generally wet bridges considered as temporary structure as the moist granule will be dried in the certain period of time. This phase is measured prerequisite for the creation of solid bridges which is created by adhesive present the liquid.
3. Formation of Solid Bridge after Evaporation:
Solid bridges:
First, solid bridges formed by the help of adhesives present in the liquid or dissolving materials present in the granulating liquid. This can be formed in several ways-
- Partial melting
- Hardening binders
- Crystallization of dissolved substances
Partial melting
Most of the low melting substances present in granulation process melt down by applying of pressure in the dry granulating process. Particles are readily bind with one after another and crystallization develop as the applying of pressure.
Hardening binders
By the help of adhesive which add to the granulating solvent, the liquid form liquid bridges, and upon drying the adhesive harden the phase and form solid bridges and bind the particles together. Common uses binders like PVP[ Polyvinylpyrrolidone], CMC[Carboxymethylcellulose], starch etc. plays the vital role.
Crystallization of dissolved substances
The powdered ingredients use in the solvent use in wet granulation may partially dissolve the powdered ingredients. At time of drying of granules, crystallization of powder material occur and act as hardening binder.
Drying rate of the granules are greatly hampered by the size of the crystals create in the bridges, larger the particle size will require more drying time and vice-versa.
4. Attractive forces between solid particles
There are two types of attractive forced which can operate between particle in pharmaceutical system beside the liquids and solid bridges formed by binding agents, demonstrate here-
•Van der Waals forces
•Electrostatic forces
This to me mention here that the Electrostatic forces don’t contribute to the final strength of the granules moreover this is important in the powder cohesion and initial formation of agglomerates e.g. during mixing. This force may be increase during when grain sizes decrease.
Van der Waals forces having four orders of magnitude which consider the greater compare to electrostatic and add great strength to the granules. When the distance between adjacent surfaces decreases then the magnitude of these forces increase. Dry graduation process is achieved by applying the forces to the particles.
5. Mechanical Interlocking:
mechanical interlocking phases that the adhesion occurs when adhesive properly penetrates into the holes, crevices and pores, and other loopholes of the adhered surface of a substrate and which locks mechanically of the substrate and must have the right rheological properties which will help to penetrate pores and other opening in due time.
Adhesion
Besides adsorption, there are Four other mechanisms of adhesion has been projected. The first mechanism is mechanical interlocking, which occur when adhesive drifts into the pores in the adhered surface. The second mechanism is interdiffusion, result when liquid adhesives are subject to dissolve and diffuse in the adhered materials. Adsorption and surface reaction projected to third reaction.
Mechanisms of Granule Formation:
a)Nucleation
Particle with particle[Particle-particle] contact and adhesion for liquid bridges is the key factor in the Granulation process. Particles are joined together to form pendular phase. Application of agitation, desifies the pendular forms and form the capillary phase and this form act as nuclei for granule growth and the next phase.
b) Transition
Nuclei can grow in two ways e.g. Single particle can be added to the respective nuclei with the help of pendular bridges, another possible ways, where two or more nuclei combine and form big nuclei. After completion of the phase, upon application of agitation to the bed the combined nuclei reshape and this phase can defined as a condition where large number of small granule present in greater range of distribution.
c) Ball Growth
When agitation continued, granule coalescence continue produce unusable, over-massed system where this phase greatly depend on the liquid quantity and material properties.
Coalescence
In this stage, two or more granule join and form large granule.
Breakage
Granules subject to break into fragments and this fragments adhere/join with other granule form a layer to the persisting/living granule.
Layering
Addition of the new powder mix with the existing granules, the powder mix adhere with the existing granules and form a layer over the existing granule and increase the granule size.
Abrasion Transfer
If agitation applied to the granules bed, then agitated granule leave abraded materials, which further add to the other granules and accelerate the granules growth.
Factors Affecting Granulation Methods
Liquid Requirement
In high shear mixers, the liquid requirement margin is narrow to granule growth and produce over wetted mas. For the intensive wet mass and densification of the granule less liquid requirement assume compare to low share mixers. Impeller rotation speed is another factor for liquid requirements and resulting evaporation of the solvent specially water in the binder solution. In high-shear mixers, intense agitation results temperature rise and subsequently loss of solvent for evaporation.
Theory of granule formation in general
At the early stage of studies near at 1950’s, it was stated that the granules growth by coalescence and limiting moisture content and further mechanical agitation modifies granule shape.
The modern science has divided the process in four major class for granulation process such as-
- Powder wetting and nucleation
- Granule coalescence or growth
- Granule consolidation
- Granule attrition or breakage
- Granulation is a complex combination of these subsequent processes.
Pharmaceutical Granulation Technology
The word “granulated” derived from Latin Word ‘‘granulatum,’’ denote “grained”. Granulated materials come from two way, by “size enlargement” of primary particles and “size reduction” of dry compacted materials. Now a day’s granulation technology has been widely applicate at mining, agrochemical and coal industry.
In these industries, agglomeration techniques mainly used to reduce dust and this technique provide easy handling and boost the material’s decisive effectiveness.
In the year of 1843, W. rockedon invent the tablet press and subsequent modification and patent was done by J. A. McFerran[1874], T. J. Young (1874), and J. Dunton (1876) in USA which tremendously hit the granulation technology in pharmaceutical technology. The granulation technology was further reshuffle at 1970 when high speed tablet and capsule filling machine with PLC was invented.
The regulatory bindings such as content uniformity/blend uniformity facilitate to produce desired granule characteristics for pharmaceutical company. On the other hand, continuous uniform materials/granule flow must be ensure for high-speed compression and capsule filling machines. Granulation is the best example of particle design. The attributes of the granules controlled by formulation and the process respectively.
Granulation method can be divided into two major group as Wet granulation where liquid use to bind primary particles and Dry Granulation where no liquid is used.
The reasons for granulating a pharmaceutical compound are demonstrated as follows:
- To decrease dust.
- To densify the materials.
- To increase the appearance of the product.
- To simplify metering or volumetric dispensing.
- To improve the flow rates and rate of uniformity.
- To escalation the uniformity of drug dissemination in the product.
Processing steps of drug substance can be easily achieved avoiding granulation steps. By using a direct compressible excipients like MCC[Microcrystalline Cellulose] which was introduce in 1970s in a blender then compress tablets or filled hard gelatin capsule. This is very efficient method for cost effective method, faster process time and simple process steps.
In this technique, low dose of drug substance show reverse criteria, uniformity of drug substance is not possible/ accurate result may not found. The sample need to collect from the blender and time require performing the test to get satisfactory result. A newly introduce PAT[Process Analytical Technology], online measurement of ingredients made possible. FDA also release latest guideline about PAT.
Beside content uniformity, there are numerous cause to avoid direct compression technique for wide range of products where drugs substance need to densified to reduce size and physical criteria such as disintegration, hardness, friability need to meet.
Another approach like traditional spray-drying process become popular in day to day to produce drum to hopper granulation avoiding conventional granulation process. This is very suitable for OTC drug which generally produce large amounts.
In pharmaceutical company, some of the products/drug substances are moisture sensitive which can’t subject to direct compression, then roller compaction is the best method to compress this product.
Before introduce of high shear-mixer, low-shear mixer was the first priority, shear-mixer generally use in in wet granulation their efficient, reproducible and modern process control capability. High-shear mixers enhanced with new technologies as one-pot processing and subsequent drying using gas stripping/vacuum or microwave.
The most versatile featured Fluid-bed processors has been using in the pharmaceutical industry over the last 35 years though initially it was introduce with single dryer, now enhanced with multiprocessor to coat particles, pelletize, granulate and drying. Now combination of high-shear mixer for granulate and fluid bed as dryer is the most popular method in granulation technology.
Theory of Granulation
Wet granulation technology is especially considered in size enlargement where small particles are compacted; agglomerated or else brought together to form larger particle comparatively permanent structure though the original particle can be distinguished. Size-enlargement and Granulation technology has the wide range of application in various industries like pharmaceutical, fertilizer and detergent production factory.