Granulation Technology: Current Status and Recent Advances

 

Poonam Rana* and Himansu Chopra

M. Pharm. 2nd Year Student (Pharmaceutics), Faculty of Pharmacy, GRD (PG) IMT, 214-Rajpur Road, Dehradun-248009

Asst. Prof. (Pharmaceutics), Faculty of Pharmacy, GRD (PG) IMT, 214-Rajpur Road, Dehradun-248009

*Corresponding Author E-mail: ranapoonam505@gmail.com

 

ABSTRACT:

Granulation is performed to a powder or mixture of powder in order to improve flow, uniformity of contents and increasing the compressibility etc. In present review article we summarized the latest developments in granulation technologies behind most commonly used granulation process. Article deals basic information along with advantages and disadvantages of various granulation methods. Granulation step is the first important process which assures the pharmaceutical elegant solid dosage form. Need of large amount of granulating agent and subsequent drying leads to various deteriorating effects which diverted the formulators for newer techniques. The latest technologies includes steam granulation, melt/thermoplastic granulation, moisture activated dry granulation (MADG), moist granulation technique (MGT), thermal adhesion granulation process (TAGP) and foam granulation have their own advantages and these new techniques increases the interest of formulation developers in exploring a highly precise method to overcome the disadvantages of conventional granulation process such as dust generation or deteriorating effect of heat at drying step. Further validation of newer techniques for uniformity of batches is required which assures the quality of finished product. 

 

KEYWORDS: Moisture activated dry granulation (MADG), Moist granulation technique (MGT), Thermal adhesion granulation process (TAGP), Foam granulation.

 


INTRODUCTION:

Granulation may be defined as a size enlargement process which converts fine or coarse particles into physically stronger and larger agglomerates having good flow property, better compression characteristics and uniformity. The art and science for process and production of granules is known as Granulation Technology1.

 

Ideal characteristics of granules:

The ideal characteristics of granules include spherical shape, smaller particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), good flow, good compressibility and sufficient hardness.

 

The effectiveness of granulation depends on the following properties2:

·        Type of binder (strong or weak)

·        Volume of binder (less or more)

·        Wet massing time (less or more)

·        Amount of shear applied

·        Drying rate (Hydrate formation and polymorphism)

·        Particle size of the drug and excipients

 

TYPES OF GRANULATION:

Granulation Technology can be broadly classified into 2 types based upon the type of processing involved:ion

 

DRY GRANULATION-Dry Granulation Techology, the cheapest method of granulation, was suitable for heat and moisture sensitive products that involve least processing steps. In dry Granulation Technology the powder mixture was compressed into a compact mass without utilizing the heat and the solvent followed by milling the compact mass to obtain granules. Compressed mass were obtained with two methods namely slugging and roller compaction. Slugging, the most widely used method, involves pre-compression of the powder to slug with a high duty tablet press while roller compaction involves pre-compression of the powder to flakes with pressure rolls using machines like Chilsonator.  

 

WET GRANULATION - Wet granulation is the most widely used process of granulation in the pharmaceutical industry. It involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction3. The wet mass is dried and then sized to obtained granules. The liquid added binds the moist powder particles by a combination of capillary and viscous forces in the wet state. More permanent bonds are formed during subsequent drying which leads to the formation of agglomerates. 

 

Conventional wet granulation: Theoretical Aspects

According to Iverson4 there are fundamentally only three stages of process, which determines the wet agglomeration behavior:  

·        Wetting and nucleation

·        Consolidation and growth and finally

·        Breakage and attrition.       

 

These phenomena often take place simultaneously in the granulation equipment, making the investigation of the effect of an individual phenomenon on the agglomerate properties difficult. Wetting of the particles is necessary for nucleation, i.e. the formation of initial agglomerates. As per Hapgood5 the nucleation rate is governed by following: 

·        Wetting thermodynamics

·        Drop penetration kinetics and

·        Binder dispersion.

 

The binder dispersion in the powder mass depends on the liquid delivery parameters and powder mixing. Since wet granulation method is the oldest and most convention method of making granules, all components involved in this process forms a three phase system made of:

·        Dispersed solid

·        Granulation liquid and

·        Air

 

Cohesive Force that operates during the moist agglomeration process is mainly due to the liquid bridges that develop between the solid particles, even though intermolecular attractive forces, van-der-waals forces and electrostatic forces also play an initial role. When liquid is added to the drug powder during initial stage, liquid film is formed on powder surface. Discrete liquid bridges are then built at the point of contact. This state is termed as Pendular State, surface tension and the capillary provide the cohesive force during this stage, air is still present between the particles. As the liquid content increases air starts coalesce. The strength of the blend increases. In this so called Funicular State, the air does not built a coherent phase anymore. As water content increases further all inter-particle voids are filled. Capillary pressure and interfacial forces at granule surface hold the particles at this stage called Capillary State. Granules attain its maximum strength at this stage. Further addition of liquid, forms solid particles, completely surrounded by the liquid, resulting in the droplet State. During this stage system consist only two phases, dispersed solid and liquid phase. When the granulation process is finished, the liquid is removed by drying, after that the granule is still kept together by different bonding mechanisms.  

 

GRANULATION TECHNIQUES:-

HIGHER SHEAR MIXTURE GRANULATION- High shear mixture has been widely used in Pharmaceutical industries for blending and granulation. In this type of equipment, the particles are set into movement by an impeller rotating at a high speed (Approx 50- 100 rpm). Equipment also contains a chopper which rotates at around 1500 – 4000 rpm6. The primary function of chopper is to cut large lumps into smaller fragments thus increases the binder distribution into the blend. The binder liquid is added by pouring, pumping or spraying from the top. Wet agglomeration in a high-shear mixer involves typically 3 phases: 

·        Dry Powder mixing (Approx 2-5 mins)

·        Liquid binder addition (Approx 1-2 mins)

·        Wet massing

 

After the wet mass is produced, it is further processed to obtain dried grade particle size granules.

·        Wet sieving of granules

·        Drying 

·        Dry sieving of granules

 

First the materials are dry mixed, where after liquid is added during mixing. Then the moist mass is wet massed in order to achieve a narrow particle size distribution. Thereafter the granules are wet sieved, dried and sieved again. The liquid amount is critical, because the process is susceptible for over-wetting, which leads to uncontrollable agglomerate growth. Variations in raw materials may affect the liquid requirement. Impeller torque and power consumption of mixers have been used to monitor the properties of wet masses during agglomeration. The above method of measurement gives a measure of the amount of resistance the impeller experiences to keep a certain rotational speed.

 

Key Input Parameters:-                                                   

·        Impeller Speed

·        Rate of addition of water

·        Mixing (massing) time after addition of water

·        Amount of material in the granulator

·         Feed Material Characteristics.

 

Key Response Factors:-

·        Moisture Content of Granules

·        Particle Size Distribution

·        Intragranular Porosity

·        Bulk/Tap Density

FLUID BED GRANULATION:- Fluidized bed processing, an air suspension technique, of pharmaceuticals was first reported by Wurster to coat tablets that was later used for granulating and drying of pharmaceuticals7,8,9  and particle/granule coating .

 

Fluidized bed granulation process involves spraying of binder solution onto the fluidized powder bed (FPB) to get finer, free flowing and homogeneous granules employing single equipment known as FBP .It contains air-handling unit, product container and air distributor, spray nozzle, disengagement area and process filters, exhaust blower or fan, control system, solution delivery system10, 11, 12.

 

Advantages13:

1. Reduces dust formation during processing,

2. Improves housekeeping and worker safety,

3. Suitable for subsequent coating and controlled release products, and

4. Reduces product loss

 

Disadvantages:

1. Cleaning was labour-intensive and time consuming, and

2. Assuring reproducibility was troublesome.

 

EXTRUSION-SPHERONIZATION:-This process is primarily used as a method to produce multi-particulates for controlled release application. It is a multiple step process involving at least 5 steps capable of making uniform sized spherical particles14.

·        Dry mixing of materials to achieve homogeneous dispersion.

·        Wet granulation of the resulted mixture to form wet mass.

·        Extrusion of wet mass to form rod shaped particles.

·        Rounding off (in spheronizer)

·         Drying these dried rounded particles can be optionally screened to achieve a targeted mean size distribution.

 

Advantages:

1. Ability to incorporate higher levels of active components without producing excessively larger particles

2. Two or more active agents can be easily combined in any ratio in the same unit.

3. Physical characteristics of the active ingredients and excipients can be modified.

4. Particles having high bulk density, low hygroscopicity, high spherocity, dust free, narrow particle size distribution and smoother surface can be produced.

 

Disadvantages This process is more labor and time intensive than other commonly used granulation techniques. 

 

SPRAY DRYING:- Spray Drying as a process has been used to produce microcapsules, food ingredients, flavors, and various biotechnological preparations.It is a continuous process in which a dry granular product is made from a solution or a suspension rather than initially dried the primary powder particles. The solution or suspension may be of drug alone, a mixture of different excipients or a complete formulation. As long as the liquid solution or suspension feed to the drying system, dry powder product continues to be produced15.    

 

Spray drying process involves three fundamental steps-

·        Atomization of a liquid feed into fine droplets.

·        Mixing of these sprays droplets with a heated gas stream, allowing the liquid to evaporate and leave dried solids.

·        Separation of the dried powder from the gas stream.

 

Advantages

1. Rapid and continuous process.

2. Reduces overall cost by avoiding labor intensive drying and granulation steps.

3. Offers minimal product handling and operator exposure to dust.

4. Suitable for heat sensitive product.

 

AVANCED GRANULATION TECHNIQUES

Over a period of time, due to technological advancements and in an urge to improve commercial output various, newer granulation technologies have been evolved such as-

·        Steam Granulation

·        Melt/Thermoplastic Granulation

·        Moisture Activated Dry Granulation (MADG)

·        Moist Granulation Technique (MGT)

·        Thermal Adhesion Granulation Process (TAGP)

·        Foam Granulation

 

STREAM GRANULATION

·        It is modification of wet granulation. Here steam is used as a binder instead of water.

·        In this method of granulating particles involves the injection of the required amount of liquid in the form of steam.

·        This steam injection method, which employs steam at a temperature of about 150° C., tends to produce local overheating and excessive wetting of the particles in the vicinity of the steam nozzles, thereby causing the formation of lumps in the granulated product16

 

Advantage:

·        Higher distribution uniformity,

·        Higher diffusion rate into powders,

·        Steam granules are more spherical,

·        Have large surface area hence increased dissolution rate of the drug from granules.

 

MELT GRANUALTION TECHNOLOGY

Melt Granulation process has been widely used in the pharmaceutical industry for the preparation of both immediate and controlled release formulations such as pellets, granules, and tablets17. This process has also been widely accepted for the enhancement of dissolution profile and bioavailability of poorly water soluble drugs by forming solid dispersion. Melt Granulation is also known as “Thermoplastic Granulation” as the granulation is achieved by adding a meltable binder which is in solid state at room temperature but preferably melts in the temperature range of 50oC – 80oC .No further addition of liquid binder or water is required in the process as the binder in the melted state itself act as granulating liquid and dried granules can be easily obtained by simple cooling at room temperature18. This process offers various advantages such as-

 

Advantages

1. Time and cost effective, as it eliminates the liquid addition and drying steps.

2. Water sensitive drugs are good candidates.

3. Controlling and modifying the release of drugs.

4. Regulatory compliance

 

Disadvantages

1. Heat sensitive materials are poor candidates.

2. Binders having melting point in the specific range can only be utilized in the process.

 

MOISTURE ACTIVATED DRY GRANULATION (MADG)

·        In this method moisture is used to activate the granules formation but the granules drying step is not necessary due to moisture absorbing material such as MCC19.

·        The moisture-activated dry granulation process consists of two steps, wet agglomeration of the powder mixture followed by moisture absorption stages.

·        A small amount of water (1–4%) is added first to agglomerate the mixture of the API, a binder, and excipients. Moisture absorbing material such as MCC and potato starch is then added to absorb any excessive moisture20.

·        After mixing with a lubricant, the resulting mixture can then be compressed directly into tablets. Hence, this process offers the advantage of wet granulation is that eliminates the need for a drying step.

·        MCC, potato starch, or a mixture of 50% of each was used as moisture absorbing material. 

 

Advantages 21

1. Applicable to more than 90% of the granulation need for pharmaceutical, food and nutritional industry. 

2. Very few variables involved in the process.

3. Suitable for continuous processing

4. Less energy involved during processing.

 

MOIST GRANULATION TECHNIQUES (MGT)

MGT works on the same principle as Moisture Activated Dry Granulation (MADG) described earlier. It involves binder activation by adding a minimum amount of liquid. Then, excess of moisture present in the blend is removed by adding moisture absorbing material like Microcrystalline Cellulose (MCC) which eliminates the drying step. It is applicable for developing a controlled release formulation22

 

THERMAL ADHESION GRANULATION PROCESS (TAGP)

TAG was a novel GT, patented by Wei-Ming Pharmaceutical Company (Taipei, Taiwan) that involves granulation by adding very less amount of water or solvent. In this process the binder/diluent mixture was first moisturized by spraying water or ethanol (2.0–3.6%, by weight of the total mixture). Then the blend was placed in a pre-warmed glass bottle, sealed, and heated by an infrared lamp to raise surface temperature of the vessel to 900C –1050C (in case of water) or 700C–900C (in case of ethanol) and mixed under tumble rotation for 3–20 min until granules had formed. Resulted granules were immediately sifted with proper sieve23.

 

Advantages24

1. Utilizes less amount of water or solvent,

2. Granules with good flow properties and binding capacity were obtained even with substances having poor tabletting properties, and

3. Minimizes the dust generation during powder processing.

 

FOAM GRANULATION

Foam granulation technique involves addition of liquid binders as aqueous foam25. The advantages of foamed binder addition conventional binder addition method includes-

·        No spray nozzle is used

·        Improve process robustness

·        Less water required for granulation

·        Time efficient drying

·        Cost effective

·        Uniform distribution of binder

·        No over wetting

·        Applicable for water sensitive formulation

 

PNEUMATIC DRY GRANULATION (PDG)

PDG was a novel dry granulation method developed by Atacama Labs (Helsinki, Finland) following standard roller compaction method to compact material at very low compaction force with subsequent milling and fractionating milled material employing a newly innovated fractionating device that separates the granules and recycles rejected fraction. PDG was suitable for automatic or semi-automatic production of granules that enables flexible modification of drug loading, disintegration time and tablet hardness26.

 

Pneumatic Dry Granulation Replaces Wet Granulation

Today, wet granulation is the most commonly used granulation method. Formulation teams will usually target a direct compression or dry granulation formulation where possible but in approximately 80% of the cases they end up with a wet granulation formulation due to processing issues. Wet granulation is also unsuitable for moisture sensitive and heat sensitive drugs, it is more expensive than dry granulation, it is relatively labour intensive and can take a long time.  There are a large number of process steps and each step requires qualification, cleaning, and cleaning validation, high material losses can be incurred because of the transfer between stages, there is the need for long drying times (Figure 1). Scale up is usually an issue, and there are considerable capital requirements27.

 

PDG Technology granules have excellent properties compared to wet granulation, dry granulation and direct compression. At the same time, the granules show both high compressibility and flow ability.  The results can be archived without using exotic and expensive excipients28.

 

Figure 1: PDG Technology and wet granulation comparison

 

Advantages of PDG Technology

The PDG Technology has a number of advantages to support the above claims including the following: 

1.      Good granulation results even at high drug loading have been achieved even with materials known to be historically difficult to handle,

2.      Faster speed of manufacturing compared with wet granulation,

3.      Lower cost of manufacturing compared with wet granulation,

4.      The system is closed offering safety advantages due to low dust levels and potential for sterile production or handling of toxic materials,

5.      The end products are very stable - shelf life may be enhanced,

6.      Little or no waste of material,

7.      Scale-up is straight forward,

8.      The granules and tablets produced show fast disintegration properties, offering the potential for fast release dosage forms, and

9.      Release time can be tailored to requirements.

 

FREEZE GRANULATION TECHNOLOGY

Swedish Ceramic Institute (SCI) has adopted and developed an alternative technique – freeze granulation (FG) – which enables preservation of the homogeneity from suspension to dry granules29, 30. By spraying a powder suspension into liquid nitrogen, the drops (granules) are instantaneously frozen. In a subsequent freeze-drying the granules are dried by sublimation of the ice without any segregation effects as in the case of conventional drying in air (Figure 2). The result will be spherical, free flowing granules, with optimal homogeneity 31, 32.

 

Figure 2: Freeze granulation

 

FG provides optimized condition for the subsequent processing of the granules, for example easy crushing to homogeneous and dense powder compacts in a pressing operation. High degree of compact homogeneity will then support the following sintering with minimal risks for granule defects.

Besides, high degree of granule homogeneity, FG offers several other advantages:

1.      Control of granule density by the solids content of the suspension.

2.      Mild drying prevents serious oxidation of non-oxides and metals.

3.      No cavities in the granules.

4.      Low material waste (high yield).

5.      Small (50–100 ml suspension) as well as large granule quantities can be produced to equal quality.

6.      Easy clean of the equipment (latex binder can be used).

7.      Possibility to recycle organic solvents. 

 

CONCLUSION:

The recent advancement in granulation techniques overcome various disadvantages and pave the way for getting new precise methods which assures the uniformity and desirable particle size of granules. Further low dust, low wastage of material and good flow properties achieved by newer techniques created interest in development of such methods.

 

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15.     United States Patent 4489504 - Steam granulation apparatus and method.

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18.     www.vectorcorporation.com/news/papers.asp, Optimization of Binder Level in Moisture Activated Dry Granulation (MADG) Using Absorbent Starch to Distribute Moisture.

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20.     Ismat Ullah, Jennifer Wang, Shih-Ying Chang, Hang Guo, San Kiang, Nemichand B. Jain, Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes, Pharmaceutical Technology, 2009; 33(12).42-51.

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23.     Yeh TS and Yeh DH. Process for the preparation of direct tabletting formulations and aids. United States Patent 6,761,905.2004.

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Received on 23.05.2014                Modified on 05.06.2014

Accepted on 24.06.2014                © RJPT All right reserved

Research J. Pharm. and Tech. 7(8): August  2014  Page 946-951