Wet Granulation Process for Tablet Manufacturing

By: Pharma Tips | Views: 7894 | Date: 29-May-2015

Know about wet granulation process including Types of Wet Granulators, Fluid Bed Dryers, Milling / Screening / Sizing, Preparation of Binder, Granule Lubrication.


Wet Granulation Process for Tablet Manufacturing

Know about wet granulation process including Types of Wet Granulators, Fluid Bed Dryers, Milling / Screening / Sizing, Preparation of Binder, Granule Lubrication.





Wet granulation forms by binding the powders together with an adhesive, instead of by compaction. bridges are developed between the particles and the tensile strength of bonds increases as amount of liquid added is increased. 
Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid.The fluid contains a solvent which can be removed by drying, and should be non-toxic.Typical solvents include water, ethanol and isopropanol and methylene chloride either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved binder / suspension / gelatinized binder. (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry.


Granulating liquids may be used alone or with dissolved binders (glue)
Solvent (e.g. Ethanol, Isopropanol)
-better for moisture sensitive products 
-volatile and so they evaporate / dry more quickly
-can be expensive to purchase
-environmentally responsible disposal can be expensive (solvent recovery plant)
Aqueous (Water)
-cheaper
-safer to handle (non flammable)
-easier to handle and dispose of in an environmentally responsible manner
-can adversely affect stability by hydrolysing susceptible products
-longer drying times (and so longer exposure to heat and abrasion)


Wet granulation (involving wet massing)

Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid (the process of adding a liquid solution to powders). The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry. The density of each granule is increased by increasing the amount of binding solution as well as the mechanical action of the mixer. Therefore, controlling the amounts of solution, binder, and mechanical action allows one to control the strength and density of the granule.

Water is commonly used for economical and ecological reasons (safer to nature and operator). Its disadvantages as a solvent are that it may adversely affect drug stability, causing hydrolysis of susceptible products, and it needs a longer drying time than do organic solvents. This increases the length of the process and again may affect stability because of the extended exposure to heat. The primary advantage of water is that it is non-flammable, which means that expensive safety precautions such as the use of flameproof equipment need not be taken. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required.

Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together. However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold a bond. In such instances, a liquid solution that includes a binder (pharmaceutical glue) is required. Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the most commonly used pharmaceutical binders. PVP is dissolved in water or solvent and added to the process. When PVP and a solvent/water are mixed with powders, PVP forms a bond with the powders during the process, and the solvent/water evaporates (dries). Once the solvent/water has been dried and the powders have formed a more densely held mass, then the granulation is milled. This process results in the formation of granules.

In the traditional wet granulation method, the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can than be recycled. Variations of this traditional method depend on the equipment used, but the general principle of initial particle aggregation using a liquid remains in all of the processes.
A drying process that is too short will produce granules that have entrapped moisture; if the process is too long, then the granules become very dry and friable. If granules that have been dried only on the outside reach the tablet press, then moisture will escape the granules during compression and cause the granules to stick to the tablet-press tooling, a problem called case hardening.

Air flow and temperature control must be uniform. If the dryer has poor air circulation, then the product on the top will become drier than the product on the bottom. Overly dry product breaks apart easily and is no longer in a granular state. When an overly dry granulation is milled, it produces fine dry particles commonly referred to as fines. Fines do not flow well on a tablet press and thereby cause weight variations. In addition, fines do not compress well and can contribute to capping and lamination, which are common tablet defects.On the other hand, compressing the lower-tray granulations, which may contain too much moisture, can cause granules to stick to the tablet-press tooling, another situation that produces defective tablets. The error that is most common to granulation processes is the mixing of overdried granules, overwetted granules, and good granules. Once this mixture is on the tablet press, the full range of the previously described problems ensues: capping, lamination, picking, sticking, and tablet weight and hardness variation.

Criteria for Selecting a Wet Granulation Binder

CriteriaPerformance Impact
High cold water dispersibility and solubilityFast solution preparation when binder is added to solution
Low viscosity solutionsEase of handling and pumping of solution
High binding efficiencyLower use levels. Tablets have higher breaking force and/or require lower compaction force
High water solubilityNo impact on drug dissolution at high use levels



Wet Granulation - the Process


For most products the wet granulation process has three parts
1. Powder Wetting
2. Nucleation
3. Further nucleation or Agglomeration

As the granulation cycle progresses:
-the mean particle size increases
-the particle size distribution narrows
-the granules become more spherical
-density increases
-porosity decreases


1. Powder Wetting
In some formulations this may be up to 80% of the total liquid requirement.


2. Nucleation
Individual particles form small groups of nuclei.


The granule is further constructed by the addition of individual particles or small groups of particles.


3a Further Nucleation




3b Agglomeration
The granule is further constructed by the collision and coalescence nuclei - and is a very rapid process.
Powders
-particle size
-substrate solubility
-wettability
Binder
-added as dry powder or in dissolved in granulating liquid
-amount of binder
-rate of addition and method (sprayed, poured)

Types of Wet Granulators
Granulation carried out using Planetary Mixer
Granulation carried out using Rapid mixer granulator (RMG).
Granulation carried out using single pot processor.
Type of Equipment
-slow speed / high speed mixer / granulator 
-wet mill / dry mill required? screen size?

Drying:
Tray Drying Ovens (several hours)
-Older technology (similar to baker’s ovens) with a lot of manual manipulation
-liquid can only be lost from the upper surface of the granule packed in the tray.

Fluid Bed Dryers (tens of minutes)
-fine mesh at the base  and cloth filter bags at the top prevent granule escaping
-warm, dehumidified air is passed up through the base at such a force that it fluidises the granules
-the liquid can be lost from a much greater surface area and so drying times are shortened
movement of granules may lead to attrition
Microwave / Vacuum Dryers (tens of minutes)
-often used in “single pot” equipment (granulate and dry in the same vessel)
-maximum batch size is limited to allow penetration of the radiation
-gives rapid drying with relatively low temperatures
-granule is stationary so less attrition The milling used during the granulation stages can be defined as:

Milling / Screening / Sizing
Wet Milling - directly after the mixer granulator and before the dryer
Dry Milling - directly after the dryer
The mills used are to break down lumps or agglomerates by screening and not for high energy size reduction
This helps to give a more uniform granule size
A typical mill for wet or dry milling would be a Comil (pictured). The impeller blade is not in contact with the screen but it “pushes” the granule through when it rotates.

Preparation of Binder
-Steam kettle must  be cleaned as per the relevant cleaning SOP.
-Cleanliness must be checked and recorded by the Production Officer on batch manufacturing record.  
-Line clearance must be done and documented as per relevant SOP.
-Binder material of only one lot should be brought to the binder preparation area.
-The Steam kettle should be operated as per relevant SOP.
-SS accessories  should be cleaned as per relevant SOP.
-Code No. of  SS sieve to be recorded in BMR
-The  steam kettle must have status label at all times.
-Exhaust of binder area must be kept `ON' during the preparation of binder.
-Calibration of steam kettle pressure gauges and pressure testing should be done every year.
-Whenever stirrer is used for binder preparation, ensure that it is not touching to the bottom of steam kettle.

Planetary Mixer
Planetary mixer is used for wet mixing of the powders, Powder mixing usually has to be performed as a separate operation using suitable mixing equipment. The mixed powders are fed into the bowl of the planetary mixer and granulating liquid is added as the paddle of the mixer is responsible for wet mixing and kneading action required to form the granules. The paddle of planetary mixer has planetary motion. Design of mixer is such that there is a bare minimum clearance between wall of mixer and blades and devoid of any void spaces.

Granule Lubrication
-After drying and before compression a lubricant is added and the granule is blended for a short time (the lubrication blend).
-The lubricant forms low strength bonds on the surface for the granules which helps flow and prevents the granules sticking to the compression punches.
-It also helps prevent the tablet sticking in the die and assists in tablet ejection.
-The most common lubricant is Magnesium stearate.
                                                               

High Speed Mixer-Granulator
The machines have a stainless steel mixing bowl containing a main impeller, which revolves in the horizontal
plane, and a auxiliary chopper (breaker blade) which revolves either in the vertical or the horizontal plane.                                                            Roller Compactors
The mixer utilize a bowl mounted in vertical position. A high speed mixer blade revolves around the bottom of the bowl. The impeller assembly fit over a shaft at the bottom of the mixing bowl. The impeller assembly is specially constructed to discharge the material from getting under it.The mixer also contains a high speed chopper blade which functions as lump or agglomerate breaker.
Safety precautions to be taken during operation and machine changeover. 
-Compressed air must not be less than 1.5 kg/cm2
-Before scrapping the material ensure that the agitator blade and chopper are not in motion.
-During changeover the electrical panel board, PLC and electrical motor for chopper, motor for lifting and positioning device must be covered with polybag.
-During washing and scrapping of the equipment main switch must be off.
-Operator should not insert hand in discharge port during unloading of wet granules.
-Nuts and bolts must be checked before starting the operation.
-During manual checking of end point during granulation ensure that motion of agitator and chopper are stopped completely.
-Never bypass any safety interlock to operate the machine.
-Never touch the moving parts of machine.
-Do not hold the saizoner lid without locking rod.
-Check for any unwanted material inside the bowl.
-Do not insert hand in discharge port during unloading the granules.
-5 m filter of the respective product to be fixed to the air vent of saizoner mixer.
-Calibration of agitator and chopper should be done once in  six  months.
-Calibration of pressure gauge should be done every year.


Fluid Bed Dryer
Advantage of Fluid bed Granulator.
-Rapid wet massing, agglomeration and drying is carried out in within one unit.
-Granulation operation are less laborious and time consuming as compared to other types of wet granulators.
Disadvantages of Fluid bed Granulator.
-No adequate mixing of powder components.
-There is tendency of demixing especially when there is disparities in particle size and density in the material being processed.
-Particles under granulation has tendency to stick to the equipment filters this reduces effective filter surface area. This also cause product loss and increase in cleanup difficulties.


High Speed Mixer-Granulator
Fluidized-bed granulators have a similar design and operation to fluidized-bed driers. The powder particles are fluidized in a stream of air, but in addition granulation fluid is sprayed from a nozzle to the bed of powder. Granulating fluid is heated and filtered air is blown or sucked through the bed of unmixed powder to fluidize the particles and mix the powder; fluidization is actually a very efficient mixing process. pumped from a reservoir through a spray nozzle positioned over the bed of particles.The fluid causes the primary powder particles to adhere when the droplets and powders collide.



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