Factors Affecting Disintegration Process In Tablet 2f603z

Factors affecting Disintegration Process in Tablet Bioavailability of a drug depends in absorption of the drug, which is affected by solubility of the drug in gastrointestinal fluid and permeability of the drug across gastrointestinal membrane. The drugs solubility mainly depends on physical – chemical characteristics of the drug. However, the rate of drug dissolution is greatly influenced by disintegration of the tablet. Disintegrants used to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet. However, There are several factors affecting disintegration process in tablet, they are : 1. Effect of Fillers 2. Effect of Binder 3. Effect of Lubricants 4. Effect of Surfactant Effect of fillers The solubility and compression characteristics of fillers affect the rate and mechanism of disintegration of tablet. If soluble fillers are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants. Effect of binder As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid disintegration. Even the concentration of the binder can also affect the disintegration time of tablet. Effect of lubricants Mostly lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This hydrophobic coating inhibits the wetting and consequently tablet disintegration. Lubricant has a strong negative effect on the water uptake if tablet contains no disintegrants or even high concentration of slightly swelling disintegrants. The disintegration time is hardly affected if there is some strongly swelling disintegrants are present in the tablet. There is one exception, sodium starch glycolate effect remains unaffected in the presence of hydrophobic lubricant. Effect of surfactants

Surfactant Sodium lauryl sulfate

Remarks Good-various drugs Poor - various drugs

Polysorbate 20

Good

Polysorbate 40 & 60

Poor

Polysorbate 80

Good

Tweens

Poor

Poly ethylene glycol

Poor

(Good – decrease in disintegration time, Poor – increase in disintegration time) Sodium lauryl sulphate increased absorption of water by starch or had a variable effect on water penetration in tablets. Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time.

Factors Affecting Granulation Process Wet granulation is the process by which powders are converted to granules with the desired properties to ensure good tablet production. Important consideration are : 1. Type and quantity of Binder 2. Compatibility 3. Characteristics of drugs and other excipients 4. Spreading of Binder 5. Temperature and Viscosity 6. Method of Addition of Binder 7. Mixing Time 8. Material of Construction of Granulator 9. Type of Granulator 10. Process Variables 11. Apparatus Variables 12. Impeller Movement Type and quantity of Binder Criteria

Performance Impact

High cold water dispersibility and solubility

Fast solution preparation when binder is added to solution

Low viscosity solutions

Ease of handling and pumping of solution

High binding efficiency

Lower use levels. Tablets have higher breaking force and/or require lower compaction force

High water solubility

No impact on drug dissolution at high use levels

The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation. As for example hard granulations results due to stronger binder or a highly concentrated binder solution which require excessive compression force during tableting. On the other hand, fragile granulations results due to insufficient quantity of binder which segregates easily. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore the optimum quantity of liquid needed to get a given particle size should be known in order to keep a batch to batch variations to a minimum.

Compatibility The primary criteria is the compatibility of binder with the API & other tablet components. This is traditionally found by choosing appropriate stability study design. Characteristics of drugs and other excipients The drugs characteristics like its compressibility, particle size, surface area, porosity, hydrophobicity, solubility in binder are important in granulation process. Strong binder such as liquid glucose and sucrose need to be added to drug that exhibits poor compressibility while the drugs that exhibit good compressibility can be using a weak binder such as starch paste. Fine and porous particles requires higher amount of liquid binder as compared to coarse particles. Hydrophilic drug/excipients exhibiting absorption characteristics require higher volume of binder as compared to hydrophobic drug/excipients. The granule quality (size , friability) is governed by the solubility of the drug in the granulation solution. Spreading of Binder A binder that spreads easilyon particles is superior as compared to that which shows poor wetting quality. For example HPMC is a superior binder for paracetamol as compared to PVP. Temperature and Viscosity Fluid (less viscous) binder exhibit good spreading behavior. Method of Addition of Binder The method of addition of binder is also important. PVP can be used as solution as a binder or it may be dry blended with powders and later activated by adding water. Distribution of binder is favored if it is dispersed instead of pouring it. Mixing Time The mixing time also determines quality of granules. If the wet massing time is higher (resulting into hard granules), the tablets may fail the dissolution test in certain cases since drug release from hard granules is altered. Material of Construction of Granulator The material of construction of granulator determines the volume of binder required and also granule size distribution. Higher volume of binder is needed if vessel wall are wetted easily by binder. Vessel wall made up of Stainless Steel require higher volume of binder as compared to vessel made up of plastics (PMMA/Polymethylmethacrylate and PTFE/Polytetrafluoroethylene/Teflon). In case of PMMA and PTFE due to high

angle, all granulating liquid is forced immediately into the powder bed and gives narrow particle size distribution. While in case of steel, due to less angle liquid layer formed on the wall surface which in turn causes inhomogeneous distribution of liquid over the powder bed resulting into broader granule size. Type of Granulator Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators. Process Variables Higher degree of densification of the granules results due to higher impeller speed as well as longer wet massing time. If liquid saturation increases tendency of agglomeration may occurs. Consequently, impeller speed and wet massing time affect the granule size. Apparatus Variables The apparatus variables in High Shear Mixer have a larger effect on granule growth than in FBD because the shear forces are dependent on the mixer construction. The size and shape of the mixing chamber, impeller and chopper vary in different High Shear Mixers. Impeller Movement If impeller movement is helical adhesion of wetted mass to the vessel is less. This gives a narrower granule size and few lumps. In case of High Shear Mixers, adhesion of wetted mass to the vessel is a problem which can be reduced by proper construction of the impeller or by coating the vessel with Polytetrafluoroethylene i.e. Teflon. High Shear Granulator In Granulators by Calistus OziokoJanuary 11, 20160 Comments A high shear granulator consists of a cylindrical or conical mixing bowl, a three bladed impeller, a chopper, an auxiliary chopper, a motor to drive the blades and a discharge pot. By either circulating hot or cool liquid or steam through the jacket, the mixing bowl is jacketed for heating or cooling the contents of the bowl as the case may be. The high shear wet granulation process using high-shear granulator can be divided into 5 stages and they included; 1.

Powder mixing

2.

Binder addition or addition of granulating liquid.

3.

Wetting of powder and nucleation

4.

Growth of granules and densification of the powder.

5.

Granule attrition and breakage.

The impeller which is employed in mixing of the dry powder and spreading of the granulating fluid in high shear granulator, normally rotates at a speed ranging from 100rpm to 500rpm. The chopper forms part of high shear granulator and is used to break down the wet lump to produce granules. The chopper rotates at a speed of 1000 to 3000rpm. Powder densification and/or agglomeration are by the in cooperation of a granulation fluid into the powder with high-power-per-unit mass, through rotating highshear forces. High-shear granulators can be sub classified into vertical high-shear granulator and horizontal high-shear granulator. These sub-classes are primarily distinguished by the geometric positioning and orientation of the primary impellers. A vertical high-shear granulator is where the impeller shaft rotates in the vertical plane and the impellers are bladelike. The vertical high-shear granulator could be either a topdriven (example Colleter-Gral granulator) or a bottom-driven unit (example Diosna or Powrex granulators).

In the horizontal high-shear granulator, the impeller shaft rotates in the horizontal plane (or is said to be side driven). Factors affecting the granulation process and granule properties of a high-shear granulator include; 

Formulation variables; that is the type and quantities of excipients used



The physical properties of the materials to be granulated



The type and amount of binder solution used in the process

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Process variables which includes; 1.

Load of the granulator bowl.

2.

Impeller speed

3.

Granulating solution addition method

4.

Granulating solution addition rate

5.

Chopper speed

6.

Wet-massing tire

7.

Granulator design.

Pharmaceutical uses of high-shear granulator 

Granulation of highly cohesive material containing hydrophilic polymers which is not achievable with low-shear granulation

Advantages of High-shear granulators 

Granulation process requires less binder solution.



Granulation is achieved within a short time.



Greater densification and production of less friable granules.



The granulator produces reproducible less friable granules with a uniform particle size distribution.



High-shear granulator minimizes the exposure of drug dust to workers due to reduced process dust generation.



Granulation end point is predictable while using high-shear granulator.



Requires short drying times.

Disadvantages of high-shear granulator 

High-shear granulator produces less compressible granules when compared to low-shear granulator.



It has a narrow range of operating conditions.



Over wetting of the granules may lead to formation of large sized lumps.



Thermolabile materials could be chemically degraded due to increase in temperature.

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Mechanical degradation can take place in case of fragile particles.      

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IJPFR, April-June 2011; 1(1):65-83 Invited Review Agrawal et al. © 2011 International Journal of Pharmaceutical Frontier Research 79some co-relation with power consumption [29]. Pharmaceutical high-shear mixers aregenerally equipped with one or more device for such measurements. Significant drawback ofthe power consumption measurement is that it reflects load on the motor rather than load on theimpeller 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 asshown in eq.-1 below. S =H( 1 ε )/ ε *P (eq-1)The saturation level

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S of an agglomerate is defined as the ratio of pore volume occupied byliquid to the total volume of pores available in the agglomerate. Where H is the mass ratio ofliquid to solid, ε is the intra-granular porosity and P is the density of the particle relative to thedensity of the liquid [31]. Impeller Load Load on the main impeller can be estimated by measuring current in DC motor because torquegenerated by the impeller is proportional to the current applied. Current meter (ammeter can beused for small scale DC motors. In case of AC motor impeller load does not vary linearly withthe current applied therefore current is completely in-effective as a measurement of impellerload in AC motor [32].Power ~ Torque * SpeedImpeller power consumption can be calculated as a product of the direct torque, rotationalimpeller speed, and a coefficient (usually equal to 2 π times a unit conversion factor, ifrequired). Impeller torque, on the other hand, is directly related to the load on the impeller. Itwas observed that when the end-point region of a granulation is reached, the frequencydistribution 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 impelleroccurs as a result of change in the cohesive force or the tensile strength of the granules in thepowder bed. Therefore impeller torque is an excellent in-line measurement of the load on themain impeller [34]. Torque rheometer has been extensively used for the off- line measurementof torque required to rotate the blade of the device and this torque has been used to accessrheological properties of the granules and the end point of the granulation process [35]. Thetorque value thus obtained was termed as “measurement of wet mass consistency” whichdescribes 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 successfulattainment of granulation end point. Mean granule size is strongly dependent on the specificsurface area of the excipients, as well as the moisture content and liquid saturation of theagglomerate. During the wet massing stage, granules may increase in size to a certain degreewhile 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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IJPFR, April-June 2011; 1(1):65-83 Invited Review Agrawal et al. © 2011 International Journal of Pharmaceutical Frontier Research 80 conflicting reports on preferred method addition to the granulating mixture. Some recommendnot 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 bindersolution 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 oxytetracyclinegranules and tablet properties. An increase in wet-mixing time resulted in a decrease inintragranular 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 theintragranular porosity. Impeller or Motor Shaft Speed Rate of impeller rotation could be used as some indication of the work being done on thematerial. Since the motor or impeller power consumption is proportional to the product oftorque 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 typeand the product composition. Variables such as mixing time and bowl or product temperatureare not independent factors in the process but rather are responses of the primary factors listedabove.Various articles have been published regarding end point detection in high shear wetgranulation 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 Technology2. Near Infra-Red (NIR)3. Focused Beam Reflectance Measurement (FBRM)End Point in a wet granulation process is characterized by rheological properties of the wetmass such as density, viscosity etc which are in turn a function of particle size, shape and otherphysical properties. End Point can be quantified with the help of dimensionless numbers suchas Newton Power Number (Np), Froud Number (Fr), and Reynolds Number (Re) that willassume a certain numeric value for every state (condition) of granulate. For eg under fixedprocessing conditions Np will be proportional to the Net Power Consumption ∆

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P for any endpoint. Thus, in order to reproduce an end-point, it is sometimes sufficient to monitor power ofthe impeller (or the motor) and stop when a predefined net level of the signal is reached.N p = ∆ P/( ρ n d) (Power Number) Fr =n d / g (Froude Number) Re =d n ρ / η (Reynolds Number)P = Power required by the impeller or motor ρ = Specific density of particles (kg / m3) IJPFR, April-June 2011; 1(1):65-83 Invited Review Agrawal et al. © 2011 International Journal of Pharmaceutical Frontier Research 81 n = Impeller speed (revolutions / s)d = Impeller (blade) diameter or radius (m)]g = Gravitational constant (m / s2) η = Dynamic viscosityNewton (power) number Np, which relates the drag force acting on a unit area of the impellerand the inertial stress, represents a measure of power requirement to overcome friction in fluidflow in a stirred reactor. In mixer-granulation applications, this number can be calculated fromthe 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 criterionfor dynamic similarity and a scale-up parameter in wet granulation. The mechanics of thephenomenon was described as interplay of the centrifugal force (pushing the particles againstthe 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 todescribe mixing processes and viscous flow, especially in chemical engineering [43].   

CONCLUSION This article provides a review of wet granulation technologies which are existing in thepharmaceutical industry. A judicial selection of appropriate technology for carrying out thegranulation 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 toadopt during development stage of product. A systematic approach should be followed forselecting the suitable granulation process. The above review article aims to providecomprehensive information in this regard, which will be useful for the researchers andscientists involved at the product development stage.