Principal Investigator a r

1

Pharmaceutical sciences

Product Development 1

GRANULATION TECHNOLOGY

Paper Coordinator

Content Reviewer

Dr. Vijaya Khader

Dr. MC Varadaraj

Principal Investigator

Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University

Content Writer

Prof. Farhan J Ahmad Jamia Hamdard, New Delhi

Paper No: 05 Product Development 1

Module No: 10 Granulation Technology

Development Team

Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi

Prof Roop K. Khar BSAIP, Faridabad

Prof. Dharmendra.C.Saxena

SLIET, Longowal

Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi

2




Introduction

Granulation, a technique of particle enlargement by agglomeration, is one of the most significant unit

operations in the production of solid oral dosage forms particularly tablets and capsules. During

granulation, small fine or coarse particles are converted into large agglomerates called granules. Granules

used in the pharmaceutical industry have particle size preferably in the range of 200 to 500 micrometres.

Usually, granulation commences after initial dry mixing of the necessary excipients along with the active

drug so that a uniform distribution of each ingredient throughout the powder mixture is achieved.

The main purpose of converting powder into granules is:

To enhance the uniformity of the drug in the final product,

To increase the density of the blend so that it occupies less volume per unit weight for better storage

and shipment,

Narrow particle size distribution of the granules facilitate volumetric dispensing and content

uniformity

To improve flow and compaction characteristics of the powder, and

To improve the appearance of the product.

Granulation is an exemplary of particle design and the properties of the granules depend on particle size

of the excipients and drug, the volume, concentration, and type of binder, granulation time, granulation

equipment and drying rate.

The primary methods by which the granules are formed include solid bridges, chemical reaction,

sintering, crystallization and deposition of particles. Besides, binding can also be accomplished through

cohesive and adhesive forces by utilizing high viscous binders. The mechanisms by which granules are

formed from the powder particles encompass wetting and nucleation, coalescence or growth,

consolidation, and attrition or breakage.

3




Blend of powders containing excipients and drug can be compressed into tablets either by direct

compression or after making granules by agglomeration or granulation techniques as described in Fig.

The granulation technique may be categorized in to two types based on the type of method used to

facilitate the agglomeration of powder particles:

(1) Dry granulation: Dry granulation uses mechanical compression or compaction to facilitate the

agglomeration of dry powder particles.

(2) Wet granulation: Wet granulation uses granulation liquid (binder/solvent) to facilitate the

agglomeration by formation of wet mass by adhesion.

Among the two techniques described, wet granulation is widely used granulation technique despite the

fact that it involves complex, time consuming and multiple unit processes compared to dry granulation.

The selection of particular process requires thorough knowledge of physicochemical properties of the

drug and excipients and required flow and release properties. Granulation methodologies like roller

compaction, fluid bed granulation, extrusion/spheronization and spray drying have been used successful

for preparation of various pharmaceutical dosage forms.

4




Granulation technology continues to evolve and various improved, modified, and novel methodologies

now available are described in this module.

DRY GRANULATION

Dry granulation also called as compression granulation is a valuable technique of granulation when the

dose of a drug is too high for direct compaction or when the drug is sensitive to heat, moisture, or both,

which precludes wet granulation. Sensitive drugs like aspirin and vitamins are prepared for tableting by

dry granulation. Dry granulation involves the mechanical compression or compaction of the components

of a tablet formulation by means of a tablet press or specially designed machinery, followed by milling

and screening, prior to final compression into a tablet. Dry granulation could be achieved either by

slugging or by roller compaction.

Slugging involves compaction of blend of powder by means of flat-faced punches. The compacted mass

is called as slug and the process is referred to as slugging. In slugging, large tablets approximately 2 inch

in diameter are made using very heavy-duty machines. These tablets may not have good fill weight

uniformity, but this does not matter, because they are broken up in the next step by coarse milling. The

slugs are then screened or milled to produce granules, which flows more uniformly than the original

powder mixture. When a single slugging process is insufficient to confer the desired granular properties

to the material, the slugs are sometimes screened, slugged again, and screened to obtain the desired

granules.

On large scale compression granulation is performed using a specially designed machine called as Roller

compactor. Roller compactors, utilize two rollers that revolve toward each other. Powdered material is

fed between the rollers by a screw conveyor system. The rollers exert known fixed pressures on the

powdered material that flows between the rollers. After passing through the rollers, the compacted mass

resembles a thin wide ribbon that has fallen apart into large segments. These are equivalent to the slugs

produced by the slugging process. The segments are then screened or milled for the production of

granules. One such roller compactor equipment which is widely utilized for preparation of granules in

pharmaceutical industry is Chilsonator.

5




FIG. 11 Schematic diagram of a Chilsonator roller compactor

Since the invent of roller compactor, there has not been much progress in the dry granulation technology

in comparison to wet granulation, except for one important innovation known as pneumatic dry

granulation.

. Pneumatic Dry Granulation

Pneumatic dry granulation is an innovative proprietary technology developed by Atacama LabsOy

(Helsinki, Finland). It utilizes roller compaction together with air classification method to produce

granules with extraordinary combination of flowability and compressibility. In this method, initially a

compacted mass comprising a mixture of fine particles and granules are produced by roller compactor.

The smaller granules and/or fine particles are separated from the intended size granules in a fractioning

Formatted: Font: (Default) Times New Roman, 12 pt

Formatted: Font: (Default) Times New Roman, 12 pt, Bold

6




chamber by entraining in a gas stream and are returned to the roller compactor for re-compression. On

the other hand the intended size granules pass through the fractioning chamber to be compressed into

tablets. The primary advantage of this technology is that it provides good flowability even with high

drug loads up to 70-100%. Further the technology offers high processing speed, little wastage of material,

low dust exposure and low cost of production. However the influence of recycling on the quality of

granules and friability problem remains a major issues regarding this technology.

(Courtesy of the Fitzpatrick Company, Elmhurst, IL.)Roller compactors, utilize two rollers that revolve

toward each other (Fig. 1112-13). By means of a hydraulic ram forcing one of the rollers against the

other, the machine is capable of exerting known fixed pressures on any powdered material that flows

between the rollers. Powdered material is fed between the rollers by a screw conveyor system. After

passing through the rollers, the compacted mass resembles a thin wide ribbon that has fallen apart into

7




large segments. These are equivalent to the slugs produced by the slugging process. The segments are

then screened or milled for the production

8




WET GRANULATION

Wet granulation is the widely used technique for preparation of granules by wet massing of the excipients

and drug with granulation liquid with or without binder. In wet granulation the powders are bind together

due to adhesive interactions instead of compaction. Addition of a granulating liquid to a mass of powder

may be characterized in a series of stages described by Newitt and Conway-Jones; these are as illustrated

in the Figure12.

FIG.-12. Stages in the development of granules (After Newitt and Conway-Jones.12)

At initial stage, addition of granulating liquid causes wetting of powder particles. Liquid film formed on

surface of powder particles may combine to produce discrete liquid bridges at points of contact. The

surface tension and negative capillary pressure in such bridges provide the cohesive force and result in

a condition called as the pendular state. At this moment the granules has low mechanical strength.

As the liquid content increases, several bridges may coalesce, giving rise to the funicular state and a

further modest increase in the strength of the moist granule.

Eventually, as more liquid is added and the mass is kneaded to bring particles into closer proximity, the

void spaces within the granule are entirely eliminated. At this point, bonding is affected by interfacial

forces at the granule surface and by a negative capillary pressure throughout the interior liquid-filled

space, a condition referred to as the capillary state.

9




Further addition of liquid results in droplet formation in which the particles are still held together by

surface tension, but without intragranular forces. The capillary state represents the stage with the

maximum strength of the wet granules and optimization of many granulation processes involves ensuring

that this state has been achieved.

While some tablets are still made in the traditional manner, newer equipment has been developed that

can accomplish both dry mixing and wet granulation efficiently and in much less time. New

mixer/granulators such as Lodige, Diosna and Gral, allow several processes of wet granulation to be

conducted in rapid succession or to be combined in one piece of equipment. These new mixers are

classified as highspeed mixer/granulatorsThese high speed mixer/granulators are provided with

secondary chopper blades which function as a lump and agglomerate breaker so that sieving is no longer

an essential prerequisite of powder blending.

The method of introducing the binder depends on its solubility and on the components of the mixture.

Since, in general, the mass should merely be moist rather than wet or pasty, there is a limit to the amount

of solvent that may be employed. Therefore, when only a small quantity is permissible, the binder is

blended in with the dry powders initially; when a large quantity is required, the binder is usually

dissolved in the liquid.

The principle of wet granulation is to add the binder by some means so that it will form bridges between

the particles to form granules (Fig.).

Formatted: Font: (Default) Times New Roman, 12 pt

10




The liquid plays a key role in the granulation process. Liquid bridges are developed between particles,

and the tensile strength of these bonds increases as the amount of liquid added is increased. These surface

tension forces and capillary pressure are primarily responsible for initial granule formation and strength.

Once the granulating liquid has been added, mixing continues until a uniform dispersion is attained and

all the binder has been activated. During granulation, particles and agglomerates are subjected to

consolidating forces in large blenders for 15 min to an hour. The length of time depends on the wetting

properties of the powder mixture and the granulating fluid, and upon the efficiency of the mixer. A rough

way of determining the end point is to press a portion of the mass in the palm of the hand; if the ball

crumbles under moderate pressure, the mixture is ready for the next stage in processing, which is wet

screening. The wet screening process involves converting the moist mass into coarse, granular aggregates

by passage through a hammer mill or oscillating granulator, equipped with screens having large

perforations. Overly wet material dries slowly and forms hard aggregates, which tend to turn to powder

during subsequent dry milling.

A drying process is required in all wet granulation procedures to remove the solvent that was used in

forming the aggregates and to reduce the moisture content to an optimum level of concentration within

the granules. After drying, the granulation is screened again. The size of the screen depends upon the

grinding equipment used and the size of the tablet to be made.

Wet granulation has witnessed various technical and technological innovations which are further

described in this module.

Reverse Wet Granulation

Formatted: Font: (Default) Times New Roman, 12 pt, Italic

11




Reverse wet granulation involves the immersion of the dry powder into the binder liquid followed by

controlled breakage to form granules. According to this technology the drug was mixed with a solution

of binder to form a drug-binder slurry as a granulating fluid. Granules were then formed by immersing

a mixture of other dry excipients into the drug-binder slurry. Advantage of this method is that it give

better dissolution results specially with poorly water soluble drugs. Additionally tablets formed from

these granules eroded more uniformly during dissolution compared to usual wet granulation technique.

This process produced granules with lower intragranular porosity and a greater mass mean diameter at

lower binder concentrations when compared to the conventional wet granulation.

Steam Granulation

12




In steam granulation, steam is used as a binder instead of liquid water. The advantage of using steam as

binder is that it provides uniform distribution and higher diffusion rate into the powder particles resulting

in production of spherical granules with larger surface area, and shorter processing time. Another

advantage is that it has a more favorable thermal balance during the drying. Upon condensation, steam

forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its

elimination, and evaporates more easily. An equipment such as high-shear mixer coupled with a steam

generator would be enough for this technique. Although the granules produced by this process have

higher dissolution rate due to increased surface area but this process is not suitable for thermolabile drugs

and is not processed with all types of binders.

13




Moisture-Activated Dry Granulation

This technique also known as moist granulation technique uses very little amount of water to activate a

binder and initiate agglomeration. The first step of the technique is wet agglomeration of the powder

particles followed by next step where moisture absorption or distribution occurs.

Agglomeration is enabled by adding a small amount of water, usually less than 5%, to the mixture of

drug, excipients and binder. Agglomeration takes place when the granulating fluid activates the binder.

Once the agglomeration is achieved, moisture absorbents such as silicon dioxide or microcrystalline

cellulose is added to facilitate the absorption of excess moisture. Addition of moisture absorbents results

in moisture redistribution within the powder mixture, leading to relatively dry granule mixture. During

the moisture redistribution process, some of the agglomerates remain intact in size, while some larger

agglomerates may break leading to more uniform particle size distribution. This process avoids

expensive drying step. The process does not lead to larger lumps formation and particle size of the

agglomerates usually range from 150-500 microns since the amount of water used is very small

compared to usual wet granulation.

The granules prepared via this technique has increased particle size, better flow and compressibility.

Additional advantages include time efficiency, less energy input, involvement of few process variables

and wide applicability. However, this technique could not be used for processing when dose of drug is

high or when drug is moisture sensitive or hygroscopic owing to stability and processing problems

associated with these types of drugs. A high-shear mixer coupled with a sprayer would be a suitable

equipment for the moist granulation process.

14




Thermal Adhesion Granulation

Thermal adhesion granulation utilizes addition of a small amount of granulation liquid and heat for

agglomeration. Unlike moist granulation which uses water alone as granulation liquid, this process uses

both water and solvent as granulation liquid. In addition to this, heat is used to facilitate the granulation

process. In this process, the drug and excipients are heated at about 30–130 °C in a closed system under

tumble rotation to facilitate the agglomeration of the powder particles. The use of limited amount of

solvent eliminates the drying process. Granules of the required particle size can be obtained after cooling

and sieving. This technique is quite simple and easy to use with low moisture and binder contents for

preparing highly compressible materials or for modifying the poor characteristics of excipients. Besides,

this technique provides granules with better particle size, good flow properties and high tensile strength

that could be directly compressed into tablets with adequate hardness and low friability. High energy

inputs and requirement of special equipment for heat generation and regulation are few of the limitations

of this technique.

15




Melt granulation

Melt granulation also called as thermoplastic granulation is a technique that facilitates the agglomeration

of powder particles using binders, which melts or softens at low temperature range of about 50 to 90°C

followed by cooling and the consequent solidification of the molten binder to complete the granulation

process.

Low melting binders can be added to the granulation process either as a solid that melt during the process

a process called as in situ melt granulation or in the form of molten liquid as a spray-on. Optionally,

drugs can be dispersed in the molten liquid binder. The in situ melt granulation includes heating a mixture

of drug, binder and other excipients to a temperature within or above the melting range of the binder. In

contrast, the spray-on procedure encompasses spraying of a molten binder onto the heated blends. Melt

granulation is suitable alternative to other wet granulation techniques which are used for water sensitive

materials. The biggest advantage of this method is that the aqueous or organic solvents are not demanded

16




and hence the environmental requirements of solvent capture and recycling are eliminated, while the

absence of water excludes the wetting and drying phases, making the entire process less time- and

energy-consuming. Melt granulation method could be efficiently applied in order to to improve the poor

physical properties of the drug substance and further to enhance the stability of moisture sensitive drug.

The major drawback of this process is the need of high temperature during the process, which can cause

degradation of the thermo labile drugs. The binders used for this process could be either hydrophilic or

hydrophobic. However, the selection of a meltable binder with a hydrophilic/hydrophobic feature is

critical factor for the dissolution behavior of the drugs. Owing to the numerous advantages of this

technique over conventional wet granulation process the interest in melt granulation has increased.

Freeze granulation

Freeze granulation technology also called as spray freezing involves spraying droplets of a liquid slurry

or suspension into liquid nitrogen followed by freeze-drying of the frozen droplets. By spraying a powder

suspension into liquid nitrogen, the drops are instantly frozen as granules, and in the subsequent freeze

drying process, the granules are dried by sublimation of ice without any segregation effects. The main

advantage of this process is that it yields spherical free-flowing granules that could be formed by using

both water and organic solvent.

The suspension quality always determines and reflects the granule quality in terms of homogeneity.

Using this process the structure and homogeneity of the particles in the slurry or suspension are retained

in the granules. This technology is particularly useful for the preparation of granules that needs to be

prepared from suspensions whose particle size and homogeneity need to be preserved. Although variety

17




of material in dispersed form can be granulated using this technology, it is suitable for the preparation of

fine powder mixes. The powders prepare using this technology possess superior aerosol performance

due to favorable aerodynamic properties.

The major advantages of this technology include (a) preparation of granules with no cavities, (b) ability

to control the granule density through the solid content of the suspension, (c) use of heat sensitive

compounds due to mild drying procedure, (d) high product yield due to low waste of material, (e) high

degree of granule homogeneity due to the absence of migration of small particles, and (f) possibility of

recycling organic solvents.

Given the ability of this technology to maintain size and homogeneity, sooner or later it will benefit the

formulation of re-dispersible parenteral formulations, nanoparticles, self-emulsifying drug delivery

systems and liposomes. Although organic solvents with suitable freezing point (-25 to +10 °C) can be

used, water as medium is preferred in this process, which could be a limiting criteria given the poor

solubility of various drugs and processing excipients.

Foam granulation

18




Foam granulation analogous to spray agglomeration, involves the addition of binder solution as foam

instead of spraying or pouring liquid onto the powder particles. Adding the binder solution as a foam

rather than a spray alleviates the problems of unpredictable and inconsistent binder distribution that can

affect tablet hardness and drug release. This technology exploits the characteristics of the foamed binder

to successfully improve the distribution of binder onto the powder particles, even at a binder amount

lower than that required in the conventional spray granulation method. This is due to the fact that the

surface area and volume of the foamed binder solution is remarkably high compared to the sprayed water.

Most importantly, the sprayed liquid droplets have a low spread-to-soak ratio, which means they tend to

soak into powders and cause over wetting rather than spreading on the surface of the powder particles,

requiring high levels of water and binder, and eventually long drying rates to remove excess water. In

contrast, foamed binders have a high spread- to-soak ratio, and because of this the binders are coated

onto the particles rather than soaked, leading to less amount of binder and more consistent binder

distribution. These factors improve the reproducibility and shorten the processing time.

Due to the involvement of low amount of water and short process time, water sensitive drugs could also

be processed using this technology. Additionally, this technology would prove useful for potent drugs

due to its ability to distribute drugs evenly. Further, this technology eliminates the use of spray nozzles

and its related clogging problems and processing variables.

Standard equipment such as shear mixer or fluid bed granulator could be used for this technology in

association with a foam generator. A foam generator can be installed in the binder solution tank to

introduce the binder as foam onto the moving powder particles.

19




Although this technology merits in countless ways, further understanding of process parameters, foam

quality, etc. needs to be explored.

Conclusion

Technological innovations that improve and ease existing processes could contribute to improved

process ability and quality of the formulations in addition to a considerable impact on the product

development, time and economy.

Obviously, the pharmaceutical granulation techniques have improved over the years. Nevertheless,

efficient and cost-effective processes have always been the keen interest of the pharmaceutical industries.

Each technique has its own merits and limitations, and the type of technique and technology selection

requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and

release properties, etc. in addition to the granulation techniques and technologies itself. During the

formulation development, each drug substance poses a unique challenge that must be taken into

consideration at the process selection stage by the formulation development scientists.

In the pharmaceutical industry, although various technologies have been introduced from time to time,

only few have emerged as successful for real time utilization due to different kinds of hurdles such as

manufacturing efficiency, economy, regulatory issues, etc. The new technologies discussed in this

module would need enhancements in terms of equipment, process, etc. before being industrialized

successfully. Nevertheless, these could provide a platform for further technological innovation.

Principal Investigator a r

Documents

Transcript of Principal Investigator a r