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Pharmaceutical Processing A Review on Wet Granulation Technology
Rajesh Agrawal * and Yadav Naveen Modi-Mundipharma Research & Development centre, Modi-Mundipharma Pvt. Limited, Modipuram , Meerut Abstract
Granulation of a powder or mixture of powder is done in order to improve flow, uniformity of contents, better compressibility, improve density and to aid pharmaceutical dosing of the actives. The review article updates about the latest developments in technologies behind most commonly used wet granulation process. Article deals with in depth basic information about granule growth mechanisms during granulation. The article also provides an insight to the in-process variables and factors influencing the granulation end point and its determination when a high shear mixer granulator of laboratory or commercial scale is utilized for industrial production. Keywords: Granulation technology, wet granulation techniques, end point determination, pharmaceutical process, pharmaceutical technology

corresponding author e-mail : ragrawal@modimundipharmaplant.com

INTRODUCTION [1]
Granulation process has been widely used in the pharmaceutical industry for the preparation of material for tabletting. Other process which involves the granule formation includes microencapsulation, multi-particulate system for modified release mechanism and to prepare granules to be used by patient directly. Primarily granules are prepared to improve flow and compression characteristics of the blend but there are many other reasons and some times multiple reasons for granulation such as Improving flow properties of the mix and hence the uniformity of the dose; Increasing the bulk density of a product; Facilitating metering or volumetric dispensing; Controlling the rate of drug release; Decrease dust generation and reduce employee exposure to drug product; Improving product appearance; What is Granulation [1] 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 Technology. Granulation Technology can be broadly classified into 2 types based upon the type of processing involved:
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Dry Granulation Dry granulation involves granule formation without using liquid solution as the product may be sensitive to moisture and heat. In this process dry powder particles may be brought together mechanically by compression into slugs or by roller compression to obtained flakes. 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 compaction [2]. 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. Although the process is most widely used in the pharmaceutical industry, the conventional wet granulation process has following merits and demerits [1]: TABLE 1 Merits and Demerits of conventional Wet Granulation Process Merits Demerits It improves flow property and Process is expensive because of labor, compression characteristics and space, time, special equipment and increases density of granules. energy requirement. Better distribution of color and soluble drugs if added in the binding solution. It reduces dust hazards. Prevents segregation of powders. Makes hydrophobic surfaces more hydrophilic. Multiple processing steps involved in the process add complexity. Loss of material during various stages of processing. Moisture sensitive and thermo labile drugs are poor candidates. Any incompatibility between the formulation components is aggravated during the processing.

Process details: convetional wet granulation Theoretical Aspects According to Iveson [3] there are fundamentally only three stages of process, which determines the wet agglomeration behaviour: Wetting and nucleation; Consolidation and growth and finally Breakage and attrition.

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(Figure 1) illustrates the granule growth phenomenon:

FIGURE 1 Illustration of granule growth by nucleation and by coalescence [4]

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 Hapgood [5] 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 [6] and powder mixing [7]. 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. The addition of granulation liquid to the mass of powder is described by Newitt and Conway Jones[8] and Barlow[9] in a series of four states termed as Pendular, Funicular, Capillary and Droplet or Suspension state which are depicted schematically in (Figure 2).

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FIGURE 2 States of liquid content in an agglomerate during wet granulation [4]. 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. Wet Granulation Techniques Following are the 4 major techniques which are used for wet granulation process. Reviews and details of individual technique are also described in order to provide an understanding of each of technique. High shear mixture granulation[10] 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 rpm [10]. 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:

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1. Dry Powder mixing (Approx 2-5 mins) 2. Liquid binder addition (Approx 1-2 mins) 3. Wet massing After the wet mass is produced, it is further processed to obtain dried grade particle size granules. 1. Wet sieving of granules 2. Drying 3. Dry sieving of granules (Figure 3) Presents details of a typical high shear mixer granulator equipment i.e Rapid Mixer Granulator (RMG)

FIGURE 3 Rapid Mixer Granulator (RMG) 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 [11] and power consumption [12] 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. Advantages 1. Short processing time 2. Lesser amount of liquid binders required compared with fluid bed granulation. 3. Highly cohesive material can be granulated.

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Disadvantages 1. Mechanical degradation could take place in case of fragile particles. 2. Due to increase in temperature chemical degradation of thermolabile material could be resulted. 3. Over wetting of granules can leads to large size lumps formation. Fluid bed granulation [13] Fluidization is the operation by which fine solids are transformed into a fluid like state through contact with a gas. At certain gas velocity, the fluid will support the particles giving them free mobility without entrapment. Fluid bed granulation is a process by which granules are produced in single equipment by spraying a binder solution onto a fluidized powder bed. The material processed by fluid bed granulation are finer, free flowing and homogeneous. The system involves the heating of air and then directing it through the material to be processed. Later, the same air exit through the voids of the product. [13] Fluid bed processing of pharmaceuticals was first reported by Wurster, by using air suspension technique to coat tablets later used this technique in granulating and drying of pharmaceuticals [14-15], for the preparation of compressed tablets. Fluidized bed system contains various components such as Air-Handling Unit (AHU) Product Container and Air Distributor Spray Nozzle Disengagement Area and Process Filters Exhaust Blower or Fan Control System Solution Delivery System.

(Figure 4) presents a typical fluid bed granulator (Glatt Type)

FIGURE 4 Fludised Bed Granulator (Glatt)

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Advantages 1. It reduces dust formation during processing, thus improves housekeeping; 2. It reduces product loss; 3. It improves worker safety. Disadvantages 1. The Fluid Bed cleaning is labor-intensive and time consuming. 2. Difficulty of assuring reproducibility. Extrusion-Spheronization [16] 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 particles. 1. Dry mixing of materials to achieve homogeneous dispersion. 2. Wet granulation of the resulted mixture to form wet mass. 3. Extrusion of wet mass to form rod shaped particles. 4. Rounding off (in spheronizer) 5. Drying These dried rounded particles can be optionally screened to achieve a targeted mean size distribution. (Figure 5) describes schematically the steps involved in the extrusion spheronization process.

FIGURE 5 Different steps involved in the Extrusion- Spheronization process

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FIGURE 6 Extrusion Spheronizer (Glatt Type) 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 [17] Spray Drying as a process has been used to produce microcapsules, food ingredients, flavors, and various biotechnological preparations. This process differs from the methods discussed above in that 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 produced. Figure [6] represents the configuration of spray dryer of open-mode design with single point powder discharge.

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FIGURE 7 Spray dryer configurations (from GEA Niro) The spray drying process involves three fundamental steps1. Atomization of a liquid feed into fine droplets. 2. Mixing of these sprays droplets with a heated gas stream, allowing the liquid to evaporate and leave dried solids. 3. 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. OTC products are good candidates. 5. Suitable for heat sensitive product Advanced Granulation Techniques [17] 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

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i) Steam Granulation Pure steam is a transparent gas. At standard temperature and pressure, pure steam (unmixed with air, but in equilibrium with liquid water) occupies about 1,600 times the volume of an equal mass of liquid water. [18] (www.wikipedia.com) This process is simply a modification of conventional wet granulation method. Here steam is used as a binder instead of water. Process offers several advantages and disadvantages [17] over other conventional granulation methods such asAdvantages 1. Uniformly distributed in the powder particles 2. Higher diffusion rate 3. Results in more spherical granule formation 4. Thermally aids in drying process 5. Higher dissolution rate of granules because of larger surface area generated 6. Time efficient 7. Environment friendly 8. No health hazards to operator 9. Regulatory compliance 10. Maintain sterility Disadvantages 1. Requires special equipment for steam generation and transportation 2. Requires high energy inputs. 3. Thermolabile materials are poor candidates 4. More safety measure required 5. Not suitable for all the binders. ii) Melt Granulation [19] 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 tablets. This process has also been widely accepted for the enhancement of dissolution profile and bioavailability of poorly water soluble drugs by forming solid dispersion.
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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 [20]. 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 temperature. This process offers various advantages such asAdvantages 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. Various hydrophilic and hydrophobic binders used in the preparation of pharmaceutical formulation are mentioned in the table-2 and table-3. TABLE 2 Hydrophilic Meltable Binders used in the Melt Granulation Technique [21]

Hydrophilic Meltable Binder Gelucire50/13 Poloxamer 188 Polyethylene glycols : PEG 2000 PEG 3000 PEG 6000 PEG 8000

Typical Melting Range (C) 44 50 50.9

42 53 48 63 49 63 54 63

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TABLE 3 Hydrophobic Meltable Binders used in the Melt Granulation Technique [21]

Hydrophobic Meltable Binder Bees wax Carnauba wax Cetyl Palmitate Glyceryl stearate Hydrogenated castor oil Microcrystalline wax Paraffin wax Stearic acid Stearic alcohol

Typical Melting Range (C) 56 60 75 83 47 50 54 63 62 86 58 72 47 65 46 69 56 60

iii) Moisture Activated Dry Granulation (MADG) [22] MADG is a process in which moisture is used to activate granule formation, without the need to apply heat to dry the granules. There are two main stages in MADG: Agglomeration Moisture distribution/ Absorption

During agglomeration, drug is blended with diluent(s) and binder in the powder form, to obtain a uniform mixture. This blend constitutes approximately 50-80% of formula weight. While mixing, a small amount of water (1-4%) is sprayed as small droplets onto the powder blend, which moistens the binder and makes it tacky. The binder facilitates the binding of the drug and excipients as they move in a circular motion forced by the mixer blades. The process does not results in larger lumps formation as the amount of water used in this process is very small as compared to the other conventional wet granulation techniques. The particle size of the agglomerates generally falls in the range of 150500 m. In moisture distribution/absorption, moisture absorbents, such as microcrystalline cellulose or silicon dioxide, are added while mixing continues. When they come into contact, the moisture absorbents pick up moisture from the moist agglomerates, resulting in moisture redistribution within the mixture. When this happens, the entire mixture becomes relatively dry. While some of the moisture is removed from the wet agglomerates, some of these agglomerates remain almost intact and some usually the larger particles may break up. This process results in granulation with more uniform particle size distribution.
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Advantages 1. Applicable to more than 90% of the granulation need for pharmaceutical, food and nutritional industry. 2. Time efficient 3. Very few variables involved in the process. 4. Suitable for continuous processing 5. Less energy involved during processing. Disadvantages 1. Moisture sensitive and high moisture absorbing API are poor candidates. 2. Formulations with high drug loading are difficult to develop. iv) Moist Granulation Technique (MGT) [17] 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 formulation. v) Thermal Adhesion Granulation Process (TAGP) [23] TGAP involves granulation by adding very less amount of water or solvent as compared to the traditional wet granulation methods. In this process drug and excipient mixture heated at a temperature range from 30oC to about 130oC in a closed system under mixing by tumble rotation until the formation of granules take place. Drying step is not required in most instances due to low amount of moisture added in the process. Granules of required particles size can be obtained after cooling and screening. It provides granules with good flow properties and binding capacity to form tablets of low friability, adequate hardness and have a high uptake capacity for active substances whose tableting is poor. vi) Foam Granulation[24] Foam granulation technique involves addition of liquid binders as aqueous foam. The advantages of foamed binder addition conventional binder addition method includes1. No spray nozzle is used 2. Improve process robustness 3. Less water required for granulation 4. Time efficient drying
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5. Cost effective 6. Uniform distribution of binder 7. No over wetting 8. Applicable for water sensitive formulation End -point determination in wet granulation Most challenging task while performing wet granulation in high-shear mixers, is the detection of end point and reproducibility of same end point by controlling various process variables. End-point can be defined by the formulator as a target particle size mean or distribution. It has been shown that once you have reached the desired end-point, the granule properties and the subsequent tablet properties are very similar regardless of the granulation processing factors, such as impeller or chopper speed or binder addition rate. This is called the principle of equifinality. The ultimate goal of any measurement in a granulation process is to estimate viscosity and density of the granules, and, perhaps, to obtain an indication of the particle size mean and distribution. These factors may be monitored and controlled by use of suitable measuring devices to achieve reproducibility in the process. Various primary independent factors in different granulation processes which can affect the granulation end point are presented in (Table 4). TABLE 4 Factors affecting high-shear wet granulation process [25] PROCESS VARIABLES Impeller Speed Chopper Speed Liquid Flow rate Impeller Load Liquid addition method Mixing time PRODUCT VARIABLES Amount of liquid binder Type of binder Surface tension Viscosity Adhesiveness Particle size distribution Solubility Wettability APPARATUS VARIABLES Size and shape of mixing chamber Size and shape of impeller Size and shape of chopper

While performing wet granulation in a high-shear mixer, formulation scientist is in regular concern with few variables which plays leading role in determining the end product properties, brief description of these variables are given below: Power Consumption Measurements of Power Consumption of the mixer motor have been widely used for end point determination because measurement is economical and well co-related with the growth of granules [26-27]. Power consumption can also be co-related with mean particle size of the granules although it is not linear in the entire range [28]. Intra granular porosity also shows 2011 International Journal of Pharmaceutical Frontier Research 78

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some co-relation with power consumption [29]. Pharmaceutical high-shear mixers are generally equipped with one or more device for such measurements. Significant drawback of the power consumption measurement is that it reflects load on the motor rather than load on the impeller where actual action is being performed and can vary with time regardless of the load. Lindberg [30] co-relate the power consumption and the saturation level S of the granules as shown in eq.-1 below.

S = H (1- ) / * P

(eq-1)

The saturation level S of an agglomerate is defined as the ratio of pore volume occupied by liquid to the total volume of pores available in the agglomerate. Where H is the mass ratio of liquid to solid, is the intra-granular porosity and P is the density of the particle relative to the density of the liquid [31]. Impeller Load Load on the main impeller can be estimated by measuring current in DC motor because torque generated by the impeller is proportional to the current applied. Current meter (ammeter can be used for small scale DC motors. In case of AC motor impeller load does not vary linearly with the current applied therefore current is completely in-effective as a measurement of impeller load in AC motor [32]. Power ~ Torque * Speed Impeller power consumption can be calculated as a product of the direct torque, rotational impeller speed, and a coefficient (usually equal to 2 times a unit conversion factor, if required). Impeller torque, on the other hand, is directly related to the load on the impeller. It was observed that when the end-point region of a granulation is reached, the frequency distribution of a power consumption signal reaches a steady state [33]. Impeller Torque In wet granulation process change in impeller torque and power consumption of the impeller occurs as a result of change in the cohesive force or the tensile strength of the granules in the powder bed. Therefore impeller torque is an excellent in-line measurement of the load on the main impeller [34]. Torque rheometer has been extensively used for the off- line measurement of torque required to rotate the blade of the device and this torque has been used to access rheological properties of the granules and the end point of the granulation process [35]. The torque value thus obtained was termed as measurement of wet mass consistency which describes the rheological properties of the wet mass [36]. Liquid/ Binder solution Addition Both moisture content and rate of addition of binding solvent is important in successful attainment of granulation end point. Mean granule size is strongly dependent on the specific surface area of the excipients, as well as the moisture content and liquid saturation of the agglomerate. During the wet massing stage, granules may increase in size to a certain degree while the intragranular porosity goes down. Binder addition rate controls granule density, while impeller and chopper speed control granule size and granulation rate. There are
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conflicting reports on preferred method addition to the granulating mixture. Some recommend not to add dry binder to the blend because homogeneous binder distribution cannot be assured, other recommend dry binder addition [37]. However, slow addition of solvent or binder solution to the blend is a preferred method of choice to avoid local over wetting. Mixing Time Chalmers and Elworthy [38] explored the effect of wet mixing-time on various oxytetracycline granules and tablet properties. An increase in wet-mixing time resulted in a decrease in intragranular porosity, as measured with mercury intrusion, an increase in mean granular size, and an increase in bulk density. The strength of granules was also inversely related to the intragranular porosity. Impeller or Motor Shaft Speed Rate of impeller rotation could be used as some indication of the work being done on the material. Since the motor or impeller power consumption is proportional to the product of torque and speed, the latter is an important factor in evaluating the corresponding load [39]. Other factors that may affect the granules quality includes spray position, spray nozzle type and the product composition. Variables such as mixing time and bowl or product temperature are not independent factors in the process but rather are responses of the primary factors listed above. Various articles have been published regarding end point detection in high shear wet granulation using sound and vibration signals [40] and using Infra-red (IR) sensors [41]. Emerging technologies for the detection of end point in wet granulation process are 1. Acoustic Emission Sensors Technology 2. Near Infra-Red (NIR) 3. Focused Beam Reflectance Measurement (FBRM) End Point in a wet granulation process is characterized by rheological properties of the wet mass such as density, viscosity etc which are in turn a function of particle size, shape and other physical properties. End Point can be quantified with the help of dimensionless numbers such as Newton Power Number (Np), Froud Number (Fr), and Reynolds Number (Re) that will assume a certain numeric value for every state (condition) of granulate. For eg under fixed processing conditions Np will be proportional to the Net Power Consumption P for any end point. Thus, in order to reproduce an end-point, it is sometimes sufficient to monitor power of the impeller (or the motor) and stop when a predefined net level of the signal is reached. Np = P / ( n d) (Power Number) Fr = n d / g (Froude Number) Re = d n / (Reynolds Number) P = Power required by the impeller or motor = Specific density of particles (kg / m3)
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n = Impeller speed (revolutions / s) d = Impeller (blade) diameter or radius (m)] g = Gravitational constant (m / s2)

= Dynamic viscosity Newton (power) number Np, which relates the drag force acting on a unit area of the impeller and the inertial stress, represents a measure of power requirement to overcome friction in fluid flow in a stirred reactor. In mixer-granulation applications, this number can be calculated from the power consumption of the impeller or estimated from the power consumption of the motor. Froude Number [42] has been described for powder blending and was suggested as a criterion for dynamic similarity and a scale-up parameter in wet granulation. The mechanics of the phenomenon was described as interplay of the centrifugal force (pushing the particles against the mixer wall) and the centripetal force produced by the wall, creating a compaction zone. Reynolds numbers relate the inertial force to the viscous force. They are frequently used to describe mixing processes and viscous flow, especially in chemical engineering [43].

CONCLUSION
This article provides a review of wet granulation technologies which are existing in the pharmaceutical industry. A judicial selection of appropriate technology for carrying out the granulation process is the key to achieve a targeted granulation and final product parameters. In depth knowledge of the processing techniques and their merits and demerits is required to adopt during development stage of product. A systematic approach should be followed for selecting the suitable granulation process. The above review article aims to provide comprehensive information in this regard, which will be useful for the researchers and scientists involved at the product development stage.

REFERENCES
1. Dilip M. Parikh, Theory of Granulation, Handbook of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York, 1997: 7-13. 2. Leon Lachman, Herbert A. Liberman, Joseph L. Kanig, Tablets, The Theory and Practice of Industrial Pharmacy, 3rd edition, Varghese publishing house, Bombay, 1991: 320-321. 3. Iveson SM, Litster JD, Hapgood K, Ennis BJ. Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review. Powder Technol. 2001;117: 3-39 4. Kristensen HG , Schaefer T. Granulation, a review on wet granulation, Drug Dev. Ind. Pharm. 1987; 13(4&5): 803-872. 5. Hapgood KP, Litster JD, Biggs SR, Howes T. 2002. Drop Penetration into Porous Powder Beds. J.Colloid Interf.Sci. 2002; 253: 353-366. 6. Knight PC, Instone T, Pearson JMK, Hounslow MJ. An investigation into the kinetics of liquid distribution and growth in high shear mixer agglomeration. Powder Technol. 1998; 97: 246-257.
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Litster, J.D., Hapgood, K.P., Michaels, J.N., Sims, A., Roberts, M., Kameneni, S.K., and Hsu, T., 2001. Liquid distribution in wet granulation: dimensionless spray flux. Powder Technol. 114 (1-3) 32-39. 8. Newitt DM, Conway-Jones JM. A contribution to the theory and practice of granulation, Trans. Inst. Chem. Engrs., London, 1958; 36: 422. 9. Barlow CG, Chem. Engr. London, (No.220), CE 196, 1968. 10. Dilip M. Parikh, High Shear Mixer Granulators, Handbook of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York, 1997:152-154. 11. Lindberg NO. Studies on granulation in a small planetary mixer. II. Granulation of lactose and an antacid mixture. Acta Pharm.Suec. 1977; 14 :197-204. 12. Leuenberger H, Bier HP, Sucker H. Theory of the granulating-liquid requirement in the conventional granulation process. Pharm.Technol. 1979; 3 (6): 60-68. 13. Dilip MP. Batch Fluid Bed Granulation, Handbook of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York, 1997: 228-237. 14. DE Wurster. J AM Pharm Assoc Sci 1960; 49:82. 15. DE Wurster. J AM Pharm Assoc Sci 1959; 48:451-454. 16. Dilip M. Parikh, Extrusion Spheronization as a Granulation Technique, Handbook of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York, 1997:334337. 17. http://www.pharmaprdia.com/Tablet:manufacturing method/Granulation 18. www.wikipedia.com 19. Chaudhari PD. Melt Granulation Technique: A Review. Pharmainfo.net. 2006; 4 (1). 20. www.pharmainfo.net , Manufacturing methods of tablets, 2009. 21. Eliasen H, Kristensen HG, Schafer T. Growth mechanism in melt agglomeration with low viscosity binder, Int J Pharm. 1999; 186: 149-159 22. Ismat U, Jennifer W. Moisture-activated dry granulation: The one pot process.Pharma Tech Eur 2010; 22(3). 23. Yeh TS , Sheu MT , Chen SJ, Tseng CB, Yeh DH, Ming W. Pharmaceutical Mfg. Co., Ltd., Taipei Medical University Application of Thermal Adhesion Granulation a Novel Low-Moisture Granulation Method for the Production of Direct-Tabletting Formulations and Aids. 24. Keary CM, Sheskey PJ. Priliminary Report of the Discovery of a New Pharmaceutical Granulation Process Using Foamed Aqueous Binder. Drug Dev. Ind. Pharm 2004; 30(8): 831- 845. 25. Gohel M, Parikh R. Granulation with Rapid Mixer Granulator (RMG): A Review. Pharmainfo.net, 2008. 26. Schwartz JB, Szymczak CE. Power consumption measurements and the mechanism of granule growth in a wet granulation study. AAPS Meeting November, 1997 27. Holm P, Jungersen O, Schfer T, Kristensen HG. Granulation in high speed mixers. Part I: Effect of process variables during kneading. Pharm Ind 1983;45:806-811. 28. Holm P, Schaefer T, Kristensen HG. Granulation in high-speed mixers. Part IV. Effects of process conditions on power consumption and granule growth. Powder Technol 1985; 43:225. 29. Ritala M, Holm P, Schaefer T, Kristensen HG. Influence of liquid bonding strength on power consumption during granulation in a high shear mixer. Drug Dev Ind Pharm 1988; 14:1041. 30. Lindberg NO, Leander L, Reenstierna B. Instrumentation of a Kenwood major domestic-type mixer for studies of a granulation, Drug Dev Ind Pharm1982; 8 (5) : 775782. 31. Faure A, York P, Rowe RC, Eur J Pharma Biopharm 2001; 52: 269-277.
2011 International Journal of Pharmaceutical Frontier Research

82

IJPFR, April-June 2011; 1(1):65-83

Invited Review

Agrawal et al.

32. Cliff MJ. Granulation end point and automated process control of mixer-granulators: Part 2. Pharm Tech 1990; 5:38-44. 33. Terashita K, Watano S, Miyanami K. Determination of end-point by frequency analysis of power consumption in agitation granulation. Chem Pharm Bull 1990; 38(11):31203123. 34. Ghanta SR, Srinivas R, Rhodes CT. Use of mixer-torque measurements as an aid to optimizing wet granulation process. Drug Dev Ind Pharm 1984; 10(2):305-311. 35. Rowe RC, Sadeghnejad GR. The rheological properties of microcrystalline cellulose powder/water mixes - measurement using a mixer torque rheometer. Int J Pharm 1987; 38:227-229. 36. Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixergranulators. Eur J Pharm Sci 1999; 8(2):85-93. 37. Laicher A, Profitlich T, Schwitzer K, Ahlert D. A modified signal analysis system for end-point control during granulation. Eur J Pharm Sci 1997; 5:7-14. 38. AA Chalmers, PH Elworthy. Oxytetracycline tablet formulations: the effect of wet mixing time, particle size and batch variation on granule and tablet properties. J Pharm Pharmacol 1976; 82:239. 39. Alderborn G. Granule properties of importance to tableting. Acta Pharm Seuc 1988; 25:229-238. 40. Daniher D, Briens L, Tallevi A. End point detection in high-shear granulation using sound and vibration signal analysis. Powder Tech 2008; 181 :130-136. 41. Miwa A, Yajima T, Itai S. Prediction of suitable amount of water addition for wet granulation. Int J Pharm 2000; 195:81-92. 42. Zlokarnik M. Dimensional analysis and scale-up in chemical engineering. Springer Verlag, 1991 43. Zlokarnik M. Dimensional analysis and scale-up in chemical engineering. Springer Verlag, 1991

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