Multi unit particulate system:

Conversion of the granules and fine powder of drug as well as excipient into the small,
spherical, free flowing by agglomeration is known as the pelletization techniques. Range
of the pellet is between the 0.5 to 1.5 mm, but other size can also be prepared. By using
many method pellets can be prepared but mostly drug layering and compactions used
widely. Irrespective to the manufacturing process which is used, pellets must have the
following criteria.

(A) It should have spherical and having a smooth surface, this both are considered as
important characteristics for the film coat.

(B) Size of the particle should as much as narrow. But the 600 and 1000µm is consider as
the optimal for the pharmaceutical uses.

(C) To maintain the size of the final formulation form in the limit pellets must have
contain the possible amount of the active ingredients.

Pellets are generally used for the oral controlled release formulations with the gastro
retentive otherwise it should have sustained release properties or it must have the site
specifics delivery. For that pellet with coating are given in the hard gelatin capsules
otherwise it can also be used as disintegrated tablets which releases the drug in the acid
from the pellets.

Development and design of the formulation depends on the role pellets and the role is
based on the novel technique of manufacturing used for the delivery systems. For the
targeted delivery property which offers the flexibility for that formulation must be in
multi unit form like coated and filled capsules otherwise can be in compressed tablet
form. Compare to the other formulation safety and efficacy is much higher. While the oral
formulation higher degree of flexibility provide by the pellets.

Without the formulations, pellets can be separated into proper desired strength;
meanwhile incompatible agents which are bioactive can be blended for the delivery or
those with the different release rate at the different or else at the same site in the
gestrointestinal path.
There are some advantages of the pellets over the single unit like tablet and powders fill
into the capsule. Pellets disperse smoothly in the gastrointestinal path when taken orally,
it also boost the absorption of drug and reduce the irritation of the mucosa with some of
the irritable drug due to less quantity of the drug into the individual pellet, it also reduces
the intrapatient and interpatient variables.

Fig:1.1

Advantage of the pellets:

 Without changing in the processes or the change in the dosage form this
can be divided in the expected dosage forms strengths.
 Significant benefit over the single unit forms can be obtain when active
ingredient with pellets are in the formulation of capsule, suspension
otherwise it can be in disintegrating tablet.
 It can be also used for the delivering the incompatible bioactive agent.For
the delivery in the gastrointestinal path as well as in the different or the
same site pellets can be used for the proper release rate.
 It also helps in the reduction of the irritation in mucosa because of the
irritable drug , it also dissolve freely into the gastro intestianal tracts.
 Coating: Generally coating is done for the stabilizing the active ingredient
in granules and it can also provide the controlled release rate of the drug.
 Easy way of the coating is on the sphere shape because of the not presence
of the edge. It is easy to fill the irregularities on the surface because it is
economical to coat extra coat on of the material.
Density increase: by the spheronization bulk as well tap desity can be increased
this helps to increase the process of packaging.
Improved the flow properties: In which the perfect dose is required or in which
automated process can used in that excellent flow properties is required for that
sphers are used like in tablet, moulding operation, filling of capsule and its
packaging.
Hardness and friability: surface characteristics and internal cohesive force decide
on the basis of friability and hardness. Friability of granules can be decrease and
hardness can be increased by the spheronization. This helps to decrease in the
fines while the handling and transport.

Disadvantages of the pellets:

 Dosing is separated by the volume other than the number and sepreted
single dose is important.
 Changes are observed in formulation to formulation leads to change in the
pellet size but it is in between the 1 to 2 mm.
 Cost increases because of the capsule filling or sometimes tableting
destroys the coat of the pellet.

Properties of the pellets:

Coated pellet:

 It should have proper drug release properties

Uncoated pellet:

 Uniform sizes and shapes

 Flow properties must be good
 Packing must be reproducible
 Higher strengths
  Surface must be smooth
 Coating should be easy
 Less friability

Stage of the pellets growth:

Various steps involves in the pellet formation:

Nucleation

Coalescence

Layering

Abrasion

Transfer

Crushing

Fig 1.2
Methods of preparation:

solution or suspension layering

powder layering

extrusion spehronization

hot melt extrusion

pelletization
technique freeze pelletization

cryopelletization

spray drying

spray congealing

spherical agglomeration

Table 1.1

Solution or suspension layering:

This process involves coalescence of the either suspension or solution which is made up
of the drug substance and binding solution on the seeds this might be inert or granule type
materials. Procedure involves that dissolve the entire component in the perfect quantity to
make the desired viscosity then after it is used for the sparing. The sprayed droplet
coalescence with the pellets and form uniform coat on the surface for this it requires the
proper conditions of drying. This can be done by the drying phase in which material
dissolves and forms the solid bridge this helps to keep the material together on the pellets.
This process won’t finish until the desired weight gain or yield obtained. for this process
size of drug plays versatile role because as the size increases higher quantity of the binder
is used. Because of this viscosity of the solution incenses hence constant stirring required
to prevent the settling of the particles. This may also creates problems like blocking of the
gun settling in the tube. For this technique size of the API must be less than 10-50µm.for
this technique fluid bed centrifugal granulator, conventional pan coat or wurster can be
used.

Powder layring:

In this technique on the nuclei excipient as well as drug or both of them can be deposited
by using the solution. Specialized liquid is used because in this binding solution as well as
the dry powder required for the coating. The primary requirement of the powder layering
method which is the used apparatus must have solid wall for preventing the loss of the
powders before the powder is taken which is wet used for the layering process.

In the initial stage binding liquid and milled powder is added together in the controlled
manner. At the staring stage particle bound themselves and forms the seed after that it
start the forming pellet by using the liquid bridge comes from the spray solution. With the
help of solid bridge this liquid bridge can be replaced by using the binder. Layering wont
finished until the desired size of the pellets achieve. It is most important that powder is
delivered accurately during the whole process as well as it is also important that addition
of the binder liquid rate is must be maintained.

Fig 1.3
If the rate of the powder is high than it may increase the generation of the dust and if the
ratio of addition is higher than the chances of the wetting will be higher it may affect the
quality as well as the yield. Coating pan centrifugal fluid and tangential spray can be used
for the drug layering.

Extrusion spheronization:

For producing the proper size of the pellets in industry mostly this process used. The
main advantage of this process is used to formulate the high capacity loaded drug pellets.
There are various steps involves like:

(A) Dry mixing

(B) Wet granulation

(C) Extrusion

(D) spheronization drying

(E) Drying

(F) Screening

Fig 1.4

Dry mixing is the first step in which drug and excipient are mixed together by using the
wet granulation process in this plastic type of mass generated for the ease of the
extrusion. The mass is then is passed from the cylindrical dies having diameter of the 0.5
to 2.0 mm in the diameter for the cylindrical shape. By cutting and drying cylindrical
shape pellets can be formed. Then these extruders are shift into the spheronizer in which
they are immediately converted by braking to the cylindrical shape because they are
pushed outside as well as at the up side also because of the centrifugal force by the
rotating frictions.

After that they dried at the room temperature or desired temperature to set the size,
hardness and density. For various process screw fed, high sphere mixture, ram,
spheronizer, fluid bed dryer, gravity extruder and oven can be used.

Cryopelletization:

This is the process in which liquid dosage form are converted into the solid sphere shape.
After this pellets are lyophilized or freeze dried for the removal of the oraganic solvent or
water. Amount Liquid nitrogen is selected on the bases of the solid content and the
temperature of liquid dosage forms. This is used for the formulation of the controlled as
well the immediate release dosage forms. In this droplet formation is the most difficult
step for the technique this is based on the viscosity, surface tension, solid content or
equipment design.

Spherical agglomeration:

This is also known as the balling in which powder by mixing with the proper quantity of
the liquid or higher temperature converts particles in spherical by rolling, drums and
mixers.

Hot melt extrusion:

This technique is now a day use for the manufacturing of the spherical shape pellet
without using the solvents or water. This helps to remove the instability variable crates
while the on going process because of the water. Drug release is based on the diffusion
coat hence further coating is not required. It is generally used for the transdermal,
controlled release and for the sustain release formulations.
Fig 1.5

This method consist the following process:

Hot melt extrusion

Melting Shaping soldification

Table 1.2

Spray drying and spray congealing:

This is also known as the globulation process, which involves solution, hot melt
atomizations and suspension formations. Spray drying is the process in which the solution
or suspension is being sprayed along with the drug entities; it may have presence or
absence of the excipients, in the hot air steam generation to dry quickly with spherical
shape.

This is mostly used for the increasing the dissolution rate. This is the process in which
drug melts and dissolves in the gum, waxes or fatty acids, then after is being sprayed in
the chamber in that temperature is under the melting points of the ingredients for the
manufacturing of the spherical shape.
Freeze pelletization:

This is the new technique for the manufacturing of the spherical shaped pellet having the
API. This method involves, solid carrier and API are being molten and then introduced
into the immiscible and inert column of the solutions. They can be moved only either
upward or the downward this is also happen on the bases of the liquid density inside the
column. In this method less variables are affecting which have many advantages over the
many techniques like quality and cost of the product. It give the product with the narrow
distribution size. This method do not require the drying because pellets solidifies at the
room temperature.

Compression:

It is the one type of manufacturing process for pellet. Different size of the pellets can be
prepared using compacting mixture or he API under the pressure. Process variable
controlling and formulation are same as the tablet preparations.

Introduction

Fluidized bed coater:

FBD is widely used since last few decade because it provides the higher energy and mass
transfers. This process involves drying, agglomeration, cooling, coating, and granulations
this can be used for both heat resistant as well as heat sensitive. This is the process in
which coating occur inside the FBP, in that coating is being done for the desired release
or to change the behaviours. There are three basic machines involved for the fluid bed
technology.

(A) Top spray

(B) Bottom spray

(C) Tangential spray

Fig 1.6

(A) Top spray:

Lengthened chamber allow the pellet to stay in the fluidization for long time that travels
with the higher velocity it helps to reduce the agglomeration. Conical shape allows the
decelerations of streamed air uniformly. Larger filter housing is present in it. The
arrangement provides proper shaking that help the fines to come back into the bed
without the fluidization interruption this helps to reduce the agglomerations. Nozzle is
kept lower into the expansion chambers it helps to coat the materials coalescence on the
surface of the pellet particle from the short distances; it also provides longer drying of the
coated pallets

This is used for organic as well as aqueous film coating, hot melt small particle and
granules, and control release coat.

(B) Bottom spray:

This method contains cylindrical container with plate which is perforated. In this the
second cylinder is present which is fitted above the perforated plates. For the dispensing
of the coating liquid the nozzle is fitted in the middle of the plate. The design of the plate
consist larger holes in the area below the coating panel. This method is widely used for
the sustain release pellets because it give arranged flow of the particle and highly
reproducible films. By using this method aqueous, oraganic, suspension, solvents,
emulation, hot melts and films can be operated. It mostly used for the mini tablets, pellets,
and small particles having the size of the 100 to 600 kg.

(C) Tangential spray:

This is the wet granulated based method used since last 19080s. In this the nozzle is
preented in the side of the container. The basic function is spinning the variable disk.
While the ongoing process three main forces are involved mechanical force which helps
in the particles moment, granulation and mixings (A) spinning disk which creates the
centrifugal forces. (B) The lifting forces created by the air which is travels from the disk.
(C) Gravitational force because of that particles fall on the disks. This create the spiralling
kind of the helical structure give the best mixing chance and give proper granules having
the content uniformity.

What is wruster coating?

It is the technology which is used for the formation of proper film on the powder, and
pellets. It is also used for drying and coating.

Film formation process required volatilization of aqueous or non aqueous solvent for the
file formation on pellets. File formation occur based on the drying of the pellets. This
system have more drying temperature than the other system.

Mechanism of coating in wruster.

Wruster apparatus generally use in the industry for powder and pellet coating. The size of
the container is 100 to 500 gm to 800 kg can be used. Mainly this is used for coating 100
micronn size tablets. The chamber of wruster apparatus is conical & cylindrical partition
is having half the diameter at the bottom at the coating site. In the bottom site orifice plate
which is known as the air distribution plate (ADP). This plate divided into two region .
one area which is open it is under the wruster apparatus column is highly permeable to
pass more air volume and velocity. Inlet air as pass upside pellets or particles passes from
nozzle which is in the between the air distribution plate. Nozzle which mounted between
the Air distribution plate having two type of properties (A) one part of it is for the passing
of the solution and one part of nozzle is for the atomized air in fixed pressure and volume.
The pattern of the spry is droplet which is like solid cone, the angle of spray is around the
30-50 which is known as the zone of coating. one region is known as down bed part that
is in the outer part of the division. Selection of the ADP (air distribution plate) is
depending on the density as well as the size of used material.

Role of the down bed part or region is to keep the materials into the suspended type and
strained horizontal to site which is in base of the partition. Role of the columns height
helps to maintain the flow of the solution parallel into the zone of the coating. While
coating process was continuous size of the batch was increased meanwhile so at the same
time height need to be adjusted for achieving the flow of the pellet. Expansion region is
up site part of the products container the role of this is to maintain and to reduce the air as
well as the velocity of the particles.

Fig 1.7

Each and every technique of the fluidized bed coating is known as the higher rates of
mass as well heat transfers but in all this wurster is much effective techniques. Material
having higher water solubility that is coated by using wruster without any kind of
problem of penetration of core. Droplets which are applied on the outer layer of the core
that will spared and it generate film that is continuous and constant drying was also
simultaneously carried out. As the initially coat applied then after spray rate can be
increased. The high quality of the films are generated by using the organic solvents, in
this generated droplet that impose on the core fast to decreases the potential of drying of
film.

Varibles of wruster caoting

There are main five mostly affecting process factors which affects the quality. (a)
equipment variables (b) solution (c) preheating (d) spraying and (f) drying.

Solution
Solid content
Solution
Delivery pump
Equipment
Equipment Preheating
Wruster column diameter Inlet air point
Air distribution plate Shaking interval
Column height from ADP Inlet temp
Nozzle tip Product temp
Air volume
Nozzle tip diameter
Atomization air pressure
Number of nozzle Variables Preheat time
Filter bags type of wruster
coating

Spraying
Drying
Inlet air dew point
Inlet air temp
Shaking interval
Inlet air volume
Inlet air temp
Exhaust temp
Product temp
Inlet air temp
Air volume
Atomization air pressure
Spray rate nozzle
Drying time
Atomization air pressure

Table 1.3

Air distribution plates (ADP)

To reduce the attrition and to obtain the perfect consistency fluidization proper air
distribution plate need to be selected. The rate of the fluidization affect the velocities of
the particles as the smaller the particles it require the less the air volume than the bigger
particle. the velocity of air as well as the pressure difference must be same at the ADP.
Hence while using small particles, having lesser opening are plates used for generating
resistances at plate for the good distribution of air. There are different type of the plates
used depending on the pellet size.

Types of plate based on the size.

Equipment Pellet size in micron Plate combination

6'' Wurster < 500 Micron A
250 << 1200 Micron B
600 << 1800 Micron C
> 1200 Micron and D
Tablets
For < 300 Micron A- I
commercial 150 << 800 Micron B- I
models 500 << 1200 Micron B-H
700 << 1400 Micron C-H
800 << 1800 Micron C-G
> 1500 Micron and D-G
Tablets
Table 1.4

Column heights:

Proper circulation of the pellets can be obtained by the adjusting the gap of partition from
the spray zones and up bed partitions columns. On the basis of the flow, shape, density
and size column height is being adjusted. This is also considered as the critical parameters
for coating of the small subtract and it was found that it changes the drug releasing of
pellet. this problem was generated because of the pellet flow in the columns and
exposures of the subtract to coating solution droplet into the spraying zone.

The slugged like form and slow flows of the pellets from the columns creats the
agglomerations in which gap of column is more and in that less pressures of generated to
take particles into the column. If the column’s gap is too less than very less amount of
pellets comes in column because of that loss of material may be happened and over
wetted pellets may also be generated. So proper height of the columns need to be adjusted
so that proper amount of pellets comes into columns. Frequent changes of the column are
not required. The column gap for wurster is about to 6ˈˈ and in wurster of 40 to 50mm
about to 18ˈˈ is recommended.

Filter bag.

Filter begs use to prevent the defeat of the materials and to permit air to passes through. If
the porosity is higher it leads to higher loss. And if the lower will be the porosity than the
optimal it leads to the filter stuck and the process will be interrupted which leads to affect
the product’s yield. Selection of the is on the bases of the past experiences and size of the
materials. With the help of differential pressure porosity of filter begs can be examine
while the coating.

Nozzle tip size or diameter

Selection is carried out on the basis of the size of the nozzle, as the smaller nozzle is
inserted more the spray will be but nozzle choking is also observed mostly with the
smaller nozzle. To prevent the agglomeration in pellet coating more atomization fluid
need to be generated as compare to the pan coater. It is most important that used nozzle is
enough able to atomized the solution which is used for the coating it should also work as
at the high spray rate also. Sometimes larger droplet of the coating solution was also
generated because of the poor performances of the used nozzle this problem occur nozzle
cannot distribute properly droplets on the core pellets which are going to be coated and it
also causes that it may not dry quickly as compare to the smaller droplet. Small droplet
quickly dries. Some of the droplets might be dried before they come in contact with
pellets or tablet that may leads to inappropriate coating on the pellet surface. For proper
and uniform atomization, in which spray rate increases above the capacities of nozzle
larger spray droplets have seen with the smaller droplet, as the larger droplet generated
leads to agglomerates. To prevent agglomeration multi unit nozzle can be used.

Coating solutions or nature of suspensions:

it must have sufficient solid contents for the ease of spraying. As the viscosity is higher
the droplet size of the coating solutions is affected and this may leads to the change in the
surface of pellets. If the solution is more viscous and tacky in nature then spray rate need
to be reduced. Mostly with the higher solid contents will increase the process time.
Meanwhile in HPMC and ethyl cellulose it is completely opposite specially they are in
the solution form.

Dew point:

Drying of the coated pellets is also affected by the temperature and humidity inlet air.
With the help of psychometric charts the relationship can be determine between
temperature and humidity. Humidity changes as the season changes or it also changes day
today. Evaporating capacity of air changes with the change in the dew points of the air.
Though the temperature is low but drying capacity of the air can be increased by the
lower humidity but that will create higher static charge in products.fir the removal of this
variable at the initial level specific and absolute level need to be same compulsorily at the
starting stage of the developments.

Higher humidity (absolute) will create depression in the air temperature below the dew
point, this will causes the condensations of the water either in the machine or on the
products surfaces. At the initial stage for the water soluble drug higher moisture content is
not suitable. Once the initial coat is generated than after humidity can increased as the
static charge generated once on the pellet are coated by the polymers. To create similar
environment in the wurster chambers while the coating lab scale or the pilot scale batch, it
is required to be run the process at the dew point value. This factor is scale independent.

Inlet and products temperature:

To increase evaporation of the coating solutions sprayed on the pellets the inlet air must
be heated. Air temperature controlling is very important because it affects qualities of the
coat formation. Mostly higher temperature produces dry environments generate spray
dried powder and over wetting leads to agglomeration while attrition. The proper
temperature produced proper evaporation of the coating liquids which produced slowly
and proper sprayed film of coating solution on the pellets by coalescence of polymeric
particle and it also avoid agglomerations and drug migrations in the layer of liquid.
Higher temperature leads to the drying of the droplets quickly and don’t coalesces when
come in contact with the core particle. This will create discontinuous coat which is porous
and uneven and this will not give desired release of drug.

Higher temperature may also lead to the spray drying of the atomized droplet of the
coating material before impinged on the pellets this will leads to the loss of coating
material and leads to thinner coat. Spray drying of droplet produces embedded into the
film coats and it disturb the continuity.

On the other side if the temperature less then comparatively longer time requires for the
coating this will leads to the migration of the soluble drug from the core to the moistened
coat layers. Soluble drug reduce the surface tensions of liquid’s layer it also lower the
capillary forces which is important to produce the deformations and the coalescence of
the sprayed droplets. Drug embedded in final coat might be dissolves on come in contact
with the dissolutions media leads to porous as well as permeable coats.

If temperature is too much lower than the minimum film formation temperatures it will
also create problem that coalescence not occur it will leads to discontinue and
inappropriate film.

Spray rate:

Binary nozzles are used in the wurster apparatus. During the process spreading,
formation, coalescences and evaporations happen almost simultaneously while the
process. The spray rate is depended on the core particle and the solution’s properties. The
evaporation happen by the atomization air which us used for the development of the sprat
mist that helps to increase the viscosity of the droplet. In solvent based coating, excessive
atomization pressure leads to spray drying effect of the spray.

Based on the drying efficiency and tackiness nature of the solution spray rate is being
adjusted. For the coating of the smaller particles the droplet size is being kept as small by
increasing atomization or by decreasing the spray rate to prevent the formation of the
agglomerations. At the starting of the coating spray rate required to be kept less to prevent
the solubilisation of the core. After the formation of the initial coat spray rate can be
increase afterwards.
It is shown that as the size of the particle is too big it should take the more droplet without
any agglomeration. As the particle enlargement become higher it is important to increase
the spray rate at specific time interval. As the spray rate is higher it increases the
possibility of the agglomeration and leads to the less proper coating, whereas lesser the
spray rate produces the small droplet and it avoid the agglomerations, specially at that
time when smaller core pellets used.

Though the spray rate is less and faster drying of the droplet avoid the colescence of the
polymers leads to the poor formation of the coat.

Air volume:

It is important for the proper fluidization and proper drying of the pellets while the
coating. Less air flows might not provide proper drying to the air in the circulations of
pellets and might not remove the moisture from the settled droplets while the coating and
it leads to the more agglomerations.

Though higher airflow can produces the higher attrition and it creates erosion of the core
or cracks and may also augments spray drying. This also creates the loss of the release
property of the functional coating.

Rate of air flow is different for the all equipment and it also depend on the characteristics
of the products such as particle size, density and shape. Bubbling type of fluidization used
for the non aqueous coating because it reduces the generation of the static charge and
friction between particle, but in aqueous coating process more precise fluidization is
required for more drying capacity.

Atomization air pressure:

Pneumatic nozzle is used for generally for the spraying of the coating solution. Thish
nozzle use air pressure used to convert coating materials in the droplet forms. Higher the
atomization of generates small spray droplet and it is important to avoid agglomeration,
specially at that time when coating is carried out on the smaller pellets.
If the atomization pressure is higher than droplet of spray may propelled away quickly
this will not help in droplet and core contact. High atomizations also crats the attriation of
the core and leads to fines.

If the atomization is low it will creates coarse droplet, this are dried slowly and support in
the formation of the liquid bridge between the core, leads to agglomeration of the pellets.
In larger capacity equipment the is one consideration is that it may have sufficient drying
capacity, and rate limiting factor is the incapability of the nozzle to atomize the liquid at
the speed at which process air removes the generated water vapours. The only option for
taking advantage of higher drying capacity is to increase the nozzle that is use the more
compress air at the same pressures.

A process in which drying capacity is too high with limited droplets size will generate
unnecessarily delayed productivity. Change the nozzle to the HS nozzle, it uses the higher
compressed air with the similar atomization of air pressure, this will leads to the sudden
change in the drying capacity uses.

Drying/curing time:

Solution viscosity increased as the polymer dissolves in the organic solvents. While the
film form at that time gel like phase generate by solvent evaporation and polymeric film
formed. Meanwhile for aqueous dispersion film generation is much difficult.

Anti tacking agents and surfactant are used in the aqueous dispersions for the formation
of good film and process coating. Plasticizer can be used for the reduction in the
minimum film formation temperature of the polymer with the higher glass TG(transition
temperature). Coating which is based on the aqueous dispersion in which when polymer
and particle comes in contact with each other that will generate coalescence while the
drying.
Fig 1.8

(a) Image shows film formation of organic solution. (b) Image shows the film formation
of aqueous polymeric dispersion

Scale up process:

Process parameter in the fluid bed process can be controllable, which give easy
optimizations and reproducible product. There is relation between spray rate, process time
and spray rate spraying time increasingly at different interval in each scale over 5 various
sized chamber with two multiple and single nozzle. Coating which is applied that also
shows that time of process also increases in the multiplication of 5 and 3.1 for two of the
various products from small scale to higher scale.

Before the manufacturing of the scale up batch important variables and their outcome on
the yield should be known while the manufacturing of the lab scale. While the
formulation is the scale up activities starts than it is for the scale up and scale out the
manufacturing. Many of them are very easy to set up like batch size, spray solution
viscosity, batch size, base plate, batch size, concentration, apparatus assembly, dew point,
and column height.

There are various parameter can be set by taking trials those are known as dependent
variables such as air pressure, air volume, atomization, spray rate and products
temperature. These are very to recognize at the small scales formulations it needs lesser
time and costs. Than after DOE(design of experiments) for the settle the most critical
parameter as per the regulatory guidelines. To decrease the trial for that different software
used like design expert.

Based on the statistical results range can be set for the parameters and based on that
process validation carried out for the freezing the parameters. After the variable is fixed
only one may be remain but mass effect because of increasing the weight of in the
commercial scale. After studying all he parameters it is easy for the compensates the mass
effects by small changes in the approximate parameters of the pilot scale and the scale up
batch. After the fixing the parameters at the lab scale further step is to predict the
parameters for the scale up batch.

After the three successful reproducible batches manufacturing further step is to generate
the parameters for the pilot scale batch having single wurster. The formulation of
products is generally carried in 6ˈˈ wurster having the batch load of the 0.5 to 2 kg. Spray
nozzle and wurster column are small. 18ˈˈ wurster is appropriate for the pilot batch in
which base plate and wurster column are too large.

Single spray nozzle used in lab to pilot batches but size of the nozzle is larger and allow
higher spray rates. Density of mass flow and batch depth increases. From the lab to pilot
scale batches coating zone increase. In pilot and commercial batches coating zone will
remain the same only change observed is that wurster column.

That’s why role of the wurster column base area is important in uniform coating. Every
parameter must be proportional to the wurster column base area in comparison with the
lab scale batch. In scale up batch it was found that all the process variable are important
after understanding the process variables at the scale down model it will be much easier
to analyze.
Same controlled process will apply, all the variables remain same in the pilot scale batch.
The mass effect will be only affected by the unknown factor. Stepwise approach needs to
be followed to adjust the parameter for scale up.

From the lab to pilot scale occupancy must be same and meanwhile the distribution plate
needs to be same geometrically in each part of the apparatus. Ratio of the air volume to
the plate areas and spray rates to the air volumes must be maintained. The factor for the
scale up from the GPCG 1.1to the FBE 125C is normally 9 time depended on the
supplier. Scale up factors is applicable to the spray rate, atomization air pressures and air
volume.

Some of the variables are discussed below:

Air volume:

Fluidization is based on the air volume during the process. This can be decided based on
the scale up batch optimization from the small to large scale the velocity kept same. To
same velocity can be obtained by the base plates which are below the columns of lab as
well the pilot equipments. This is also known as the fluidization air volumes.

Below equation can applied for the calculation of the airflow.

V2=V1*A2/A1

V1= Air flow at lab scale model

V2= Air flow in the scale up trial

A1= Base area of the column for lab scale

A2= Base area of column in pilot model

Batch size:

“Batch size means first of all generates the pilot scale up and after that decide the
equipment” The parameters changes a little based on the size of the batch because of the
mass effects. First of all fix and process validation is carried out for the batch size change.
It is important to kept the batch size in the appropriate occupancy.
Example: in pam glatt GPCG 1.1, the working capcity(volume) is 2.4 lit, meanwhile in
the Pam FBE 125 is 84 lit, means PAM 125 is 35 times more bigger than the GPCG 1.1.
It means if the batch planned for the PAM 125 than it must be 35 times higher than the
GPCG 1.1. For the non functional coating working volume can be 20-100 % and for the
non functional 20-80% can be set.

Spray rate and Atomization air pressure:

Spray rate can be increases by increasing the drying efficiency it is not based on the batch
size. Sometime it also becomes the critical variable for various perspectives. First of all it
is economically time consuming process leads to increasing the cost. Longer the process,
it will create the many problems while the on going process like clogging of the nozzle.
As the inlet increases in relation to that only spray rate can be increase.

During the scale up trials drying capacity is considered as the critical parameter. There
are various rate limiting steps like batch size, capacity of drying, and droplets size of the
coating solution into the coating area and core materials. Temperature and humidity
remain constant in the scale up batch, only on the bases of air volumes the drying
capacity can be can be increase.

With respect to inlet air volume only the spray rate can increase. Over the conventional
coating gun spray nozzle with the HS wurster have several advantages. Agglomeration
generates near to the spray gun because bigger the droplets are generated there whereas hs
wruster compliant, in that coating gun and martial do not come in contact with each other
and that’s why spray rate can be also increased higher.

Below equation shows calculation for the spray rate for the pilot scale batches.

S2=S1*V2/V1

V1= air flow of lab trial

V2= air flow of scale up trial

S1= spray rates of the lab trial

S2=spray rate in the pilot trial

To maintain the droplets size, increasing in air atomization and spray rate must equal than
only process can be maintain. For same droplet size for the lab trial and pilot trial air
atomization air volumes and spray rate must be same.

Maximum 4 to 5 bar range pressure can be used for the atomization air volumes.
Mechanical stress on the core is higher because of high velocity this occur because of the
higher atomization air pressures. Though at the lab scale if high pressure was used then
also in scale up trial either spray gun having the bigger capacity used such as HS guns or
spray rate must be slow.

By any how spray rate need to be maintained by reducing or increasing inlet air
temperature.

Mass effect:

Based on the lab scale equipment’s batches performance mass effect cannot be predicted.
6ˈˈis considered as best for the lab sale models and 18ˈˈ is considered as the best for the
large scale models. Fluidization of material adjusted 125 cm or lesser height, and height
of bed 200 mm, it should not be more than that, for the 6ˈˈ wurster this need to be set. For
the 18ˈˈ wurster approximately 600mm heoght of bed and 2 meter height for fluidization
is being set.
Literature survey:

Literature survey of MPUS:

Bharkatiya M. et al 2012:

Reported that the importance of the Multi unit particulate system over the conventional
system and the advantages over the single unit formulation. Manufacturing of the pellets
by using various techniques known as the pelletization like suspension or solution
layering, extrusion spheronization, powder layerings, freeze pelletization spray drying,
cryopelletization, spray agglomeration, and spray congalings.

Khan A. et al 2014

Reported that multi unit particulate system provides good therapeutic actions and helps to
achieve controlled as well as delayed release pellets without the risk of dose dumping
blending flexibility, for the various pattern release, it also provides the little gastric
residence times and reproducibility. Pellatization is the method for manufacturing of the
pellets, this also helps to manufacture beads as well.

Ramu S. et al 2013

Study show that the advantages of the multi unit particulate system, pellets over the
conventional or single unit forms the manufacturing techniques shows how to
manufacture pellets from the fines. Studies show the advantages and disadvantages along
with the applications of the manufacturing technique also show the evaluation and factor.

Fluidized bed coater:

Chauhan J. et al 2011

Study shows that description about the coating process on the pellets in fluidized bed
coating. It gives the idea about the coating of the pellet by using the solution droplets. It
show that the drying granulation agglomeration coating and drying are involved in the
process of fluidization. It is mostly used for the products like heat resistance and heat
sensitive products. this study shows the different types of the coating like top spray,
bottom spray and tangential spray and the factors involves in the coating process.
Shrevastava S. et al 2010

Study shows that importance of the fluid bed coating for the formulation of the novel
dosage forms with the high therapeutically efficiency. It shows the application of the fluid
bed coating for coating, agglomeration, drug layering and granulation of the verity of the
pellets. It is also used for the drying process as well. It shows that the types of the spray
used for the coating and they are mainly different on the basis of the nozzle locations.
Study also reviewed that the novel technologies used for the pelletization techniques like
MicroPx, Procell, and CPS and shows the applications advantage and disadvantage.

Puspati R et al 2014

Study show that the importance of the fluid bed process for the development of the new
dosage forms. Study reviewed the principle involve in the process that is material which
is to be coated is in the suspension form with help of the air stream. This 3 principle those
are top sprays, bottom sprays and tangential sprays are discussed in detailed. Study show
the advantage disadvantage and new technologies used in the FBP. It also shows the
problem solutions of the parameters observed during the process.

Sonar G.et al 2015

Study show that importance of the wurster coating over the other pelletization techniques
and it also provides many advantages in the single process. It shows that wurster is the
constantly working continuous, less interruption as well as provides the high degrees of
the reproducibility are main benefits of this technique. It shows that the many factors
affect the process during the process they are called as the process variables. Basically,
five types which affects the process like coating liquid variables, equipment variables,
spraying variable, drying and preheating variables which affect the coating process. Study
shows the detailed description of the all the variables and there sub parts. It also shows
that many of them are having the medium or low risk. All the risk are required to study at
the small scale batch while the developing the qulity by designs as well experimental
designs by various software. Study shows that how to control the variable at the lab scale
to prevent their effect at the scale up batch. Wurster based methods scale up is totally on
the bases of the optimization of the all process variable as well identify the risk of the
variables and carrying out in the scale up factor which is provided by the vendors are
required to be calculated. Lab scale as well as the commercial batch of the wurster must
be liner and almost similar while the manufacturing this is the important key for the
proper carrying out of the scale up factors.

Asija R. et al 2012

Study shows the development of the wruster coating. It also show the applicability of the
wurster apparatus like it can be used for the non aqueous as well as aqueous solution
based coating. It reviewed that the high quality of the film can be developed by using this
method it shows that this can be used for the suspension, solvent, aqueous, emulations
films. This can be used for the coating of the tablets, pellets and capsules having batch
size from the 100g to 600kg. This can be used for the controlled as well as the extended
release or enteric coating pellet. Study shows the detailed description of the all parameters
as well.

Pulgamwar G. et al 2015

Study show that the fluid bed is important for the manufacturing of the novel formulation
with the higher therapeutic efficiency. Study reviewed that it is used for the improvement
of the powder properties for tablet compression. High quality granules can be obtain by
the controlling the process parameter by well measured. It shows that it is used for the
granulations, coating or layering of the various range of the particle size. It is also used
for drying process based on the location of the nozzle that is spray, bottom and tangential
detail description shown in the study. Study reviewed that advance pelletization method
efor the manufacturing of the new dosage form which are based on the “Multiunit
particulate system” having good therapeutic efficacy discussed in details.

Excipients

Eudragit

Singh S. et al

Study shows that the ideal property for the drug delivery system (A) it must be in single
dosage form in all while the entire treatment. (B It must have fewer side effects. (C) It
must release the active ingredient the specific site. This can be achieved by the specific
polymer. This study shows that the importance of the eudragit and their details. It also
shows that use of the eudragit for the different drug delivery system and give detail
description of the physicochemical properties.

Sonje A. et al. 2013

Study shows that polymer selection based on the release of the drug. Polymer has
basically two types of the properties (A) stability of the polymer in the acidic pH (B) it
must dissolve slowly to for the proper release rate. The study shows the role of eudragit in
different drug delivery mechanism and their physicochemical properties.

HPMC

Phadtare D. et al. 2014

Study shows that importance of the hypromellose in drug release in effective manner.
This review shows that the details of the HPMC and use. It shows the thermal, chemical
as well as mechanical properties, hydration from the matrix, and mechanism of the drug
release from the polymeric matrix of HPMC. This also shows the maximum value used
for the different type of dosage forms.

Huichao W. et al 2014

Study shows the details about the application of the HPMC in pharmaceutical
formulations. Based on the induction application of liquid, solid, controlled gel and
capsule preparation. The review shows the role of HPMC in pharmaceutical preparations.
General procedure:

In pellet prapration, there were 3 basic steps involved (A) drug layering (B) seal coating
(C) entric coating.optimization of coating solution was done for that different
concentration of IPA/WATER mixture was prepared and used for drug layered pellets. In
drug layering solution was prepared and sprayed on the sugar spheres and drying was
carried out for 30 min and after that pellets were passsed through the 30 mesh sieve.

Required quntity was taken for the further process on pellet.before that otimization of seal
coating was carried out and then seal coating was done. Coating solution was prepraed
and sprayed on the drug layered pellets after that 30 min drying was done.

Entric coating was done on the seal coated pellets which is the last step. In enatric coating
different parameter were observed which are criticle and design was applied on those
paramter and after that sacle up batch was taken by fixing the parameters and using
factors provided by the vendor to obtain the same result as scale down.

Optimization of coationg solution concentration (IPA/WATER)

Drug layering on core pellets

Optimizaation of percentage coating of seal coated

Seal coating on drug layered pellets

Optimization of the percentage of entric coating

Entric coating on seal coated pellets

Sacle up batch

Table 4.1
List of material and equipment used:

Table 4.2.1

Material name Supplier

SUGAR SPHERE Signet chemical
HPMC E5 LV Colorcon, dow chemical
HPC LF International speciality
TALC LUZINAC Signet chemical
PEG 400 Monochem
IPA Phener
EUDRAGIT L 100 Evonic
TEC s.javari
FERRIC OXIDE RED Signet chemical
Table 4.3

Equipment Company
Weighing machine Essae teraoka ltd
Model- DS-862 (10gm-6kg)
Weighing machine Metter toledo Switzerland
Model- MS 2045 01(0.1mg-220gm)
GPCG 1.1 Pam glatt
Stirrer REMI lab

Materials:

Table 4.4

Sugar sphere
Category Capsule/tablet diluents
Description It is genrally used as the inert core for the tablet as well as the
capsule mainly for the malty particulates sustained release
dosage forms. They are generally generated based on the drug
coat mostly done with the help of the polymeric coat.
 Meanwhile drug as well as the matrix coat is applied on the core
pellets. The API released from the coat via diffusion process
otherwise it may release from the polymer by controlled
erosions. Various mixture of the drug in the one single
formulation can be formulated by the coating process of the drug
and different polymer on the core pellets.
They are available in various sizes. They are differentiated on
the bases of the diameter.

HPMC E5
Category Polymer
Description It solubilises into both organic as well as aqueous media and it is
used for the fill coating.
There are two grade used for the formulations.
(a) Lower viscosity: This can be used for aqueous film coating
liquids.
(b) Higher viscosity: This can be used for the oraganic solvents.
The main function the HPMC E5, it is also used for the thicknig
agent and helps to increase the tensile strength as well as flexural
strength. It slso helps for increasing the surface coat.

HPC
category Polymer/binder
Description It solubilises into both water as well as alcohol the film of HPC
is tacky and leads to restraints on the coats. It is used in the
combination which provides adhesion to pellets.
Mixture of HPC(non ionic polymer) and HPMC helps to form
stronger gel of the final matrix, it also helps to decreases the
diffusion as well as erosion rates. Molecular weight of the HPC
is generally in between 100000 to 7000000 Da for faster water
dissolving polymer.
 This mixture is generally used for the slow drug release
mechanism.

Talc
Category Antiadhering agent
Description It is generally used in the range between 1-5% as anti
adhering agent.
Tackiness is considered as the important parameter while
the coating process this may become tacky based on the
glasss transition temperature. So to avoid this problem anti
adhering agent is added.
Generally talc is widely used to avoid this problem. But it
was found that use of talc leads to sedimentation of the
material while the spraying of the solution, clogging of the
spraying nozzles as well as leads to incompatibility
sometimes with the solution. Sphericirty and agglomeration
capacity are considered as the critical parameters when the
talc is used for the inert core for the layering of the drug.
For decreasing the poor strength problems and for giving the
sphericity to granule the used talc must be Wet Spherical
Agglomeration(WSA) was used for the pellet coating. Talc
have good agglomerating and micrometric is excellent
properties and it is good as compare to the sugar sphere.
Combination of the talc and sugar sphere used in pan coating
which shows good drug layering as well as coating
efficiency and good drug release path in in vitro studies,
that’s why talc is used for the coating. It also have
deformable like properties which helps to generate
disintegration matrix it also have benefits of the pellet. Talc
particles avoid fracture while the compressions.
As comparing to the sugar sphere talc having less strength.
PEG
Category Plasticizer
Description Solid grades of the PEG used for the film coatings as well as the
hydrophilic polishing materials. For the plasticizer solid grades are
used. These grades are also used for the film forming polymers.
Liquid grade generally used for the film coating. It also helps to
increase water permeability and also helps for the protection
against lower pH of the enteric coating.
It is generally used for the microencapsulated product in that it
helps as plasticizer in that it also helps to prevent the destruction
of the film coat while the compression in the capsule.
For improving the mechanical strength for the coating in the
formulations plasticizer are added in the dosage forms.
For the good and continuous film Plasticizer and film forming are
compatible with each other.
Plasticizers are mandatory to be mixed with the polymer having
less film formation capability and for coalescence of the particles.
It helps to reduce the glass transition temperature and reduces the
minimum film forming temperature for the coating process.
Plasticizer generate channel for the drug to diffuse for coated
pellet through insoluble film.
For good solubility less molecular weight glycol is added.
Molecular weight up to 600 PEG is selected for easy solubilisation
in water.

TEC
Category Plasticizer
Description Some ester like TEC, tributyl citrate acetyl tributyl and
 acetyltriethyl are genrally used as the plasticizer. It is generally
used for the coating of the capsule, tablets, granules and beads
used for immerdate release, eantric coating, taste masking and
sustained release.

Eudragit L 100
Category Polymer
Description Various types of eudargit used for the film formation on the
pellets it is based on the pH value like at pH >6 eudragit L is
used, at pH>7 eudragit S & FS.
This is amorphous polymers having the 9 to > 150°c glass
transition temperature. This polymer is nontoxic, biodegradable
nonabsorbable, and biodegradable. Anionic eudragit L genrally
dissolves at the ph grter than 6 that is mostly used for the enatric
coating, whereas for colon target drug delivery eudargit S is used
which is soluble at above pH 7.
Eudragit L 100 55 used for release into duodenum whereas
eudragit L 30D 55 aqueous dispersion used for the pH 5.5.
For release into jejunum or ileum at pH 6 eudragit L 100. And the
mixture of the eudragit S 100 and L 100 used for the release into
pH 6.0-6.5.
Eudragit L as well as S are the anionic polymer they are
differnciate on the basis of the methacrylic acid ester the formed
film is insoluble less under pH 5 this helps to produce resistance
in gastric fluid.in intestine at pH 5.5 based on the several
mechanism like salt generation in netural or alkaline medium
helps to dissolve the films step by steps.

Ferric oxide red

Category Vendor
Description It is generally used for the protection against the light. This
 compounds are inorganic in nature having the on or more than one
or some time s combination of the iron oxides.

IPA
Category Solvent or vehicle
Description It is generally used for the film coating of both tablet as well as for
pellets. It can be removed by the evaporation.
Sometime to avoid static charge and for reducing the cost some
time along with IPA water is used.

Evaluation parameters:

Dissolution:

Dissolution was checked by using Paddle apparatus at 100 RPM in two media buffer 6.8
and in acidic pH 1.2 (0.1N HCL).

In acidic pH release must be less than 1% to prevent the drug release enteric coating was
done. In intestine at 20 min 85 % and at 30 min more than 95% drug released must be
required to pass the test.

Total impurity:

“Some part of the novel drug molecules which is not chemical part is known as the new
drug substance”

There are three typed of the impurities.

(A) Organic: Intermediates, staring material, by products, reagents and degraded products

(B) Inorganic: heavy metal, reagents, inorganic salt

(C) Residual solvents: inorganic or oraganic liquid used as the solvents for the
preparation of the coating solution.

Total impurity must be less than 1 % to pass the test.

Stability condition:

The rationale behind this test is to give information about the quality of the API as well as
how the different environment affect to the product that leads to the degradation like light
temperature and humidity. It helps to create the storage condition of the formulations.

There are 4 climatic zones for the stability test.

Zone 1: Temperature

Zone 2: Subtropical and may be high humidity

Zone 3: dry and hot

Zone 4: humid and hot

Accelerated stability testing: it helps for the identification of the shelf life of the
formulation by increasing the decomposition rate for that temperature of the reaction need
to be increased. Self life can be identified in month with the help of the accelerated
stability.

Stability condition for formulation: 40ºc/75% RH ±2ºc ±5% RH for 3months.

Loss on drying:

It can be expressed as the loss of the mass in percentage (% w/w) because of the loss of
the volatile and water based solvents that can remove by the special conditions. This
method helps to measure the amount of the water or volatile substance in the
formulations.

Limit for the LOD: Not more than 3%.

% yield:

This can be calculated based on the ratio of the theoretical total amount used for the
formulation and practical yield that is obtain after the trial.

%yield= theoretical yield *100/ practical yield.

General Procedure for drug layering on core pellets:

All the ingredients were weighed accurately. IPA and water mixture were prepared in one
beaker. Mixture was divided into two halves in separate beaker then drug was added in
beaker (A) and mix them till API is completely soluble.

The solution of HPMC (Hydroxypropyl MethylCellulose), HPC(Hydroxypropyl

cellulose) and PEG(polyethylene glycol) was prepared in other beaker (B) mix them
properly. The prepared solution of beaker B was transferred into beaker A. Talc was
added in the beaker and continues stirring was carried out for 45 min.

Sugar sphere was loaded into the FBP and the prepared solution was sprayed on the sugar
spheres by using bottom spray method.

All the parameters were noted and maintained. The coated pellet sifted from the 40 mesh
sieve for removing the aggregates. % yield was calculated.

Procedure for the seal coating on the drug layered pellets:

All the ingredients were weighed accurately. HPMC and HPC were added in water and
IPA mixture mix it for 30 min. TEC and talc were mixed in the above mixture.
Continuous stirring was carried out for 45min.

The prepared solution was sprayed on the drug coated pellets. All the parameters were
maintained and recorded. The coated pellets were passed through 40 mesh sieve. %yield
was calculated.

Procedure for enteric coating seal coated pellets:

All the ingredients were weighed properly and Eudragit L 100 was dissolved in acetone
completely. Talc, TEC and ferric oxide red were dissolved in IPA/water and mix the
prepared solution with the eudragit solution.

Sprayed the above solution on the seal coated pellets and passed through the 30 mesh
sieve maintained and record all the parameter. Calculate the % yield.

Preliminary batches (drug layering)

Table 4.5.1 Drug coating

Composition Category Weight

Sugar sphere core pellets 100 mg
API API 20 mg
HPMC E5 Binder 9.90 mg
HPC-LF Binder 9.90 mg
TALC LUGINAC Anti tacking 5.90 mg
PEG 400 Plasticizer 3.89 mg
IPA/WATER(70:30) Coating solution Q.S

Table 4.5.
Seal coating

Composition Category Weight

Drug layered pellets Core pellets 149.59 mg
HPMC E5 Binder 4.9 mg
HPC –LF Binder 4.9 mg
TEC Plasticizer 2.0 mg
TALC LUGINAC Anti tacking 3.0 mg
IPA/WATER Coating solution q.s
Table 4.5.3 Enteric coating

Composition Category Weight

Seal coated pellets 165 mg
Eudragit L100 Polymer 12 mg
TEC Plasticizer 2.5 mg
TALC LUGINAC Anti tacking agent 5.4 mg
FERRIC OXIDE RED Colour 0.1 mg
IPA/WATER/ACETONE Coating solution Q.S

Preliminary trials:
Table 4.6

Trial 01:

Composition Trial 01(enteric coating)

Weight of drug coated pellets(gm) 818.19

%yield (gm) 932.85 (99.2%)

Note: trial one was carried out to check the effect of enteric coating on the drug layering.

Procedure:

Same as above.

Result and Conclusion

Results show that Batch (trial 1) was failed in RS (related substance) in trial 1 and it was
found that the dissolution was near to the criteria.

The batch was failed in trial 1 in which direct enteric coating was applied. The drug was
found to be incompatible with the enteric coating material. Results show that seal coating
is compulsorily required between the drug layering and enteric coating. Result also shows
that dissolution was not much affected by direct enteric coating. So in trial 2 different
percentage of the seal coating was carried out.

Table 4.7

Preliminary trial 2,3and 4

Composition Trial 2 Trial 3 Trial 4

Percentage of seal 8% 10% 12%
coating
Initial weight of pellets 818.25 818.20 818.15
%yield(gm) 880.56(99.5%) 894.3(99.3%) 910.44(99.3%)

Results and conclusion

Results show that all the batches were passed in RS.

In trial 2, 3, and 4, different percentage of seal coating was carried out but the batch with
10% was selected for further process. 8% coating was carried out in trial 2 in which coat
was thin but the results show the dissolution near to the criteria but RS was comparatively
higher so in next trial 4% of coat was decided to increase hence in next trial 10% coat was
applied. Result of trial 3 with 10% coat was found to be desired so batch was passed the
test. Trial 4 was taken with further with 4%, hence in next trial was taken with 12%. The
results of trial 4 show that the batch was passed.

But trial 3 with 10% coating show desired result, it was selected because if 2% percentage
more or less coat applied in further trials still there were not significant changes observed.

Table 4.7.1 result table

Results Trial 2 Trial 3 Trial 4

Related substance % 0.87 0.54 0.52

Table 4.8 Preliminary trials 5 and 6

parameters Trial 5 Trial 6

product temperature (°c) 28-33

temperature(°c) 29-35 30 35

Exhaust temp (°c) 26-30

Atomization (bar) 1.2

Column height (mm) 17

Spray pump RPM

2-8 8 8

Blower % 50

Inlet RH(%) 20-30 25 20

Note: effect of spray rate was checked while enteric coating process.

Procedure: same as enteric coating.

Result and conclusion of trial 5:

Results show that trial 5 was failed in because of agglomeration and batch was failed in
RS also.

In trial 5 effect of higher temperature and RH were checked but batch was failed because
of agglomeration reason behind this was found that higher temperature leads to sticking
and this produced lumps of the pellets and higher RS increases the degradation and leads
to increase in total impurity So in trial 6 it was decided to take with higher the
temperature and lower RH

Result and conclusion of trial 6:

Result shows that the batch was passed

Trial 6 was carried out with the high spray rate and higher temperature so higher
temperature prevent sticking and it was found the inlet RH was less helps to prevent
degradation.

Conclusion: As the temperature increases RH decreases higher temperature helps to

prevent sticking and lower RH helps to prevent the degradation of the product.

Table 4.9

OPTIMIZATION OF COATING SOLUTION:

Trial 7 Trial 8 Trial 9

100% IPA 50:50 (IPA/water) 70:30(IPA/water)

Result and conclusion:

Result shows that trial 9 was passed and used for further batches.
It was found that in trial 7 with 100% IPA highly static charged was observed during the
process. Because of higher static charge flow pattern was not proper and good surface
morphology was not achieved. So based on result of trial 7 water was used in next trial to
prevent static charge.

Trial 8 was taken by using 50:50 (IPA:water). It was found that there was not static
charge observed because of water, but during the process higher temperature was required
because of water. Less yield was obtained. Hence further trial was taken with less amount
water decreased.

Trial 9 was carried out with 70:30(IPA:water). It was found that comparatively less
temperature required. Results show that % yield was higher and loss was also less. So for
further trial 70:30 was used.

Table 4.10

OPTIMIZATION OF THE ENTERIC COATING Trial 10,11 and12:

Enteric coating TRIAL: 10 TRIAL:11 TRIAL: 12

percentage 8% 12% 16%
Initial weight (gm) 894.7 894.5 894.6
yield (gm) 961.4 997.2 1032.8

Table 4.10.1 parameters

Inlet Product Exhaust Atomization Colum Spray Blower Inlet

temperature temperat temp (bar) n pump
% RH(%)
(°c) ure (°c) height
(°c) RPM
(mm)

Set actual

31-33 29-32 29-31 26-30 1.2 17 2-5 50 20-25

Results

Results show that trial 11 gave good dissolution than other trial.

Result of trial 10 show that it was failed in dissolution it was found that thin coat was
formed on the seal coated pallet and dissolution in acid was found higher and batch was
failed so in next trial it was decided to take batch with 4% extra coat.

In trial 11 and 12 it was observed that both give good yield and good dissolution but it
was found that trial 10 with 12% gave good dissolution compare to the trial 11. It was
observed that trial having 16% enteric coating forms thick coat due to which slow
dissolution was obtained compare to the trial 12 so for further trial 12% enteric coating
was used.

86.50% enteric coating

86.00%
85.50%
% drug release

85.00%
84.50%
84.00%
83.50%
83.00%
12% 16%
% drug coating

Fig 4.1
Design expert trial

2³ full factorial Design was applied by using design expert on the most critical parameters
(A) inlet RH (B) Temperature (C) spray rate

Table 4.11

Trial Run Factor 1 Factor 2 Factor 3

Inlet RH Temperature Spray rate
% °C gm/ml
Trial 13 1 35 34 2
Trial 14 2 25 30 5
Trail 15 3 25 30 5
Trail 16 4 35 26 8
Trail 17 5 15 26 2
Trail 18 6 15 34 8
Trail 19 7 15 34 2
Trail 20 8 15 26 8
Trail 21 9 35 26 2
Trail 22 10 25 30 5
Trail 23 11 25 30 5
Trail 24 12 35 34 8

Table 4.12 Result table

Trial Run Dissolution at Dissolution at Dissolution at Total

10 min 15 min 20 min impurity
Trial 13 1 35.5 57.1 80.2 0.78
Trial 14 2 34.7 66.1 87.8 0.73
Trail 15 3 38.2 66.4 88.1 0.72
Trail 16 4 43.3 70.1 92.2 0.81
Trail 17 5 37.1 59.3 82.9 0.61
Trail 18 6 41.2 68.3 90.8 0.54
Trail 19 7 36.4 57.3 80.4 0.63
Trail 20 8 44.2 70.2 92.4 0.64
Trail 21 9 36.5 59.4 83.0 0.80
Trail 22 10 37.7 65.9 86.5 0.74
Trail 23 11 35.2 66.7 87.6 0.70
Trail 24 12 41.6 68.4 89.9 0.81
Effect of slow spray rate, temperature and RH

Trial RH Temperature Spray Dissolutio Dissolution Dissolutio RS

rate n 10 min 15 min n 20min
1 35 34 2 35.5 57.1 80.2 0.78
5 15 26 2 37.1 59.3 82.9 0.61
7 15 34 2 36.2 57.3 80.4 0.63
9 35 26 2 36.9 59.4 83.0 0.80

It can be seen that at the slow spray rate and high temperature causes to decrease in the
dissolution. It was found that higher spray rate form spray drying effect and reduces the
yield and it forms uneven coat on the surface of the pellets so it decreased the dissolution.

It was found that as the RH increases, total impurity also increases because of the higher
water content in the air so it may causes degradation by hydrolysis or oxidation whereas
at lower RH this was not observed and RS was less though it was within the criteria.

Medium spray rate, temperature and RH

Trial RH Temperature Spray Dissolution Dissolutio Dissolution RS

rate 10 min n 15 min 20min
2 25 30 5 34.7 66.1 87.8 0.73
3 25 30 5 38.2 66.4 88.1 0.72
10 25 30 5 37.7 65.9 86.5 0.74
11 25 30 5 35.2 66.7 87.6 0.70

It can be seen that batch show good result. It was found that all the parameters not
affected much on the result. Dissolution was also within the criteria. RS was also less
because of the less water content in the air helps to prevent the degradation.

High spray rate, temperature and RH

Trial RH Temperature Spray Dissolution Dissolution Dissolution RS

rate 10 min 15 min 20min
4 35 26 8 43.3 70.1 92.2 0.81
6 15 34 8 41.2 68.3 90.8 0.54
8 15 26 8 44.2 70.2 92.4 0.57
12 35 34 8 41.6 68.4 89.9 0.79

It was found that at the higher temperature dissolution decreases and it also produced the
spray drying effect and also decreased the %yield it was observed that at higher
temperature proper film was not formed. At lower temperature dissolution was higher
because in that film was properly formed.

It was found that as the RH increases total impurity also increases because of the higher
water content in the air so it may causes degradation by hydrolysis or oxidation whereas
at lower RH this was not observed and RS was less though it was within the criteria.
 100
comarative study of design trials trail 1
trail 2
90
trail 3
80 trail 4
trail 5
70 trail 6
persentage drug release

trail 7
60 trail 8
trail 9
50
trail
10
40
trail
11
30
trail
12
20

10

0
1 2 3 4 5
responce

Fig 4.2

Drug release at T10 min:

Drug release of the all the batches were separately taken as shown in above table. Value
was obtained in the range of 34 to 47%. On the basis of that polynomial equation was
generated.

Y1=+27.02+0.38X1+0.23X2+6.03X3-0.012X1X2-0.18X1X3-0.14X2X3+0.005X1X2X3

Here X1=Inlet RH

X2=Product temperature

X3=spray rate

Based on the polynomal equation it can be identified that the individual

parameter(X2,X3) have positive efffect on the dependent variable and it was observed
that intrection of paramter have negligible effct on the dependent varible. So it was
concluded that as the value of independent variable increases the value of Y3 increases.
Fig 4.3

The above figure show that the relation between the product temperature, spray rate and
dissolution.

Based on the response following approaches can be used.

 To obtain the desired drug release proper spray rate must be maintained for higher
spray rate higher the temperature required for proper drying of the film.
 Less temperature and less spray rate it also helps to causes the above condition.

Dissolution at T15 min:

Drug release of the all the batches were separately taken as shown in above table. Value
was obtained in the range of 56 to 71 %. On the basis of that polynomial equation was
generated.

Y2=+61.79+0.052X1+0.23X2+1.83X3-0.0018X1X2-00.0089X1X3-
0.000521X2X3+0.000312X1X2X3

Here X1=Inlet RH

X2=Product temperature

X3=spray rate
Based on the polynomal equation it can be identified that the individual
parameter(X2,X3) affect on the depedent variable, it was observed that all the
independent factors have positive effect. It was found that interacation of the independent
varible have negligible effect. So it was concluded that as the value of independent (X2,
X3) variable increases the value of Y2 increases.

Fig 4.4

The above figure show that the relation between the product temperature and spray rate.

It was observed that dissolution increases as the spray rate increase with respect to the
temperature. From the above graph it was observed that for desired release, spray rate
must be low and temperature should be sufficient for proper drying.

For T20 Min:

Drug release of the all the batches were separately taken as shown in above table. Value
was obtained in the range of 81 to 93%. On the basis of that polynomial equation was
generated.
Y3=+74.21+0.59X1+0.13X2+3.78X3-0.019X1X2-0.0104X1X3-
0.068X2X3+0.0033X1X2X3

Here X1=Inlet RH

X2=Product temperature

X3=spray rate

Based on the polynomal equation it can be identified that the individual parameter affect
on the depedent variable, it was observed that all the independent factors have positive
effect. It was found that interacation of the independent varible have negligible effect. So
it was concluded that as the value of independent variable increases the value of Y3
increases.

Fig 4.5

The above figure show that the relation between the product temperature and spray rate.
It was observed that dissolution increases as the spray rate increase with respect to the
temperature. From the above graph it was observed that for desired release spray rate
must be low and temperature should be sufficient for proper drying.

Effect on impurity:

Total impurity was checked for the individual trial the above table shown the results of
the total impurities. The range of the impurity was found between 5 and 8.this shows that
total impurity was affected by the product temperature and RH. Based on that polynomial
equation was generated.

Y4=-0.066+0.29X1+0.019X2+0.14X3-0.00070X1X2-0.0046X1X3-
0.0052X2X3+0.00016X1X2X3

Where X1=Inlet RH

X2=Product temperature

X3=Spray rate

The polynomial equation shows that independent variable(X1) has positive effect on the
dependent variable. So it was concluded that as the value of independent variable(X)
increases the value of Y4 increases.
Fig:4.6 shows effect of product temperature and RH on the total impurity

It was observed that total impurity increases as the RH increases. It was found that as the
increases in RH leads to degradation of the product because of the hydrolysis or oxidation
this happened because it contained more water.

Table 4.13 Conformational batch trail 25

Condition RH Product Spray rate Dissolution at 20 Impurity

temperature min
Design 15 30 8 92 0.605
condition
And result
Trial condition 15-17 29-31 8 91.73 0.584
And result
Result and conclusion:

At 20 min similar result was observed as shown in the software and impurity was also
similar. At 20min 91.73 % drug release was obtained and impurity was 0.584 %. Hence
the trial passed.

Formulation of Optimized batch:

On the basis of the preliminary trial and based on the factorial design, range of the RH
was decided and product temperature was fixed. Based on the design expert software
following area was obtain which shows the optimized batch.

Overlay plot

Fig 4.7
Table 4.14.1

Composition of Optimized batch (trial 26)

Drug layering

Composition Category For 5500 capsule

Sugar sphere core pellets 550 gm
API API 110 gm
HPMC E5 Binder 54.45 gm
HPC-LF Binder 54.45 gm
TALC LUGINAC Anti tacking 32.59 gm
PEG 400 Plasticizer 21.39 gm
IPA/WATER(70:30) Coating solution Q.S
Table 4.14.2 Seal coating

Composition Category For 5500 capsule

Drug layered pellets Core pellets 818.25(822.88) gm
HPMC E5 Binder 26.95 gm
HPC –LF Binder 26.95 gm
TEC Plasticizer 11 gm
TALC LUGINAC Anti tacking 16.5 gm
IPA/WATER Coating solution Q.S
Table4.14.3 Film coating

Composition Category For 5500 capsule

Seal coated pellets Core pellets 894.70(899.72) gm
Eudragit L100 Polymer 66 gm
TEC Plasticizer 19.7 gm
Talc Luginac Anti tacking agent 29.7 gm
Ferric oxide red Colour 0.55 gm
IPA/Water/Acetone Coating solution Q.S

Table 4.14.3A parameters

Inlet Product Exhaust Atomization Colum Spray Blower Inlet

temperature temperat temp (bar) n pump
% RH(%)
ure (°c) height
(°c) (°c) RPM
(mm)

Set actual

31-35 30-33 29-32 26-30 1.2 17 2-8 50 18-25

Result and conclusion:

The prepared trail of the optimized batch was passed.

It was found that Weight of final pellets was 1004.2gm after all process and % yield was
99.37%. Result shows that %assay was within the limit 97-110%. LOD was found 1.8%.
The results shows that Dissolution F2 (similarity index) was more than 50 and the % drug
release was obtain same as the innovator’s results. The trial was also passed in RS and
was 0.64 % (limit less than 1).
 %Drug release of optimized batch
100
90
80
70
% drug release

60
50 %Drug release of trial
batch
40
30
20
10
0
0 5 10 15 20 25 30 35
time(min)

Fig 4.8

comparision of optimized batch and

inovator
120
100
%drug release

80 % drug release of innovator

60 %Drug release of trial batch
40
20
0
0 5 10 15 20 25 30 35
time(min)

Fig 4.9

Table 4.15.1 drug coating

Scale up batch trial 27:

Composition Category Weight

Sugar sphere core pellets 19.25 kg
API API 3.85 kg
HPMC E5 Binder 1.925 kg
HPC-LF Binder 1.925 kg
TALC LUGINAC Anti tacking 1.55 kg
PEG 400 Plasticizer 0.77 kg
IPA/WATER(70:30) Coating solution Q.S
Table 4.15.2 seal coating

Composition Category Weight

Drug layered pellets Core pellets 29.08 kg
HPMC E5 Binder 0.9625 kg
HPC –LF Binder 0.9625 kg
TEC Plasticizer 0.385 kg
TALC LUGINAC Anti tacking 0.5775 kg
IPA/WATER Coating solution Q.s

Table 4.15.3 enteric coating

Composition Category Weight

Seal coated pellets Core pellets 31.710 kg
Eudragit L100 Polymer 2.31 kg
TEC Plasticizer 0.479 kg
TALC LUGINAC Anti tacking agent 1.039 kg
FERRIC OXIDE RED Colour 19.25 mg
IPA/WATER/ACETONE Coating solution Q.S
Note: In scale up batch factor was used which was provided by the vendor.

Result and conclusion:

Results show that batch was passed in dissolution as well as RS it was found that results
were obtain same as the scale down.

• Total weight of the final pellets was 35.29 kg was obtained.

• %yield=99.33% was obtained

• LOD = 1.87%
Factor 35 was used for scale up, and it was observed that the occupancy was similar to
scale down batch. Factor 10 was used for spray rate study in the scale up batch and the
spray rate was found that the process worked smoothly without the formation of
agglomerates and sticking of pellets was avoided. Factor 10 demonstrates that working
within the limit of 18-85 will give good results. Also, when the limit was crossed beyond
85, sticking was observed.

Table 4.15.3A parameters

Parameters Range during process

Inlet temperature (°c) 31-35

Set temperature

Actual 36-30

Product temperature (°c) 29-33

Exhaust temperature(°c) 26-30

Atomization (bar) 2.5

Column height(mm) 40-45

Spray pump RPM 18-72(80)

Inlet RH(%) 18-25

Stability:

Description:

White opaque body and white opaque cap, size “2” hard gelatin capsule filled with red
coloured pellets.
Table 4.16

description Standard Initial 1M 3M

Net content 1846 mg 1850 mg 1846 mg 1844 mg

(±3)

LOD NMT 3.0% 1.8% 1.7% 1.9%

Related NMT 1 % 0.53 % 0.61% 0.66%

substance

Dissolution Acid – NMT 1.2 1.4 1.2

10% at 60 min

Buffer- NLT 95.2 95.4 96.2

95% at 30 min

Stability criteria : 40°C/75% RH, ±2°C/±5% RH

UPTO 3 MONTHS

PACK : 30 Count in normal HDPE bottle 100 cc

 % drug release of scale up batch
120
100
80
% drug release

60 % drug release
40
20
0
0 5 10 15 20 25 30 35
time

Fig 4.10

comparision of scale up and inovator

120

100

80
%drug release

% drug release of innova-

60 tor
%drug release of scaleup
40 batch

20

0
0 5 10 15 20 25 30 35
time(min40

Fig 4.11
 comparision of inovator,optimized and scale up batch
120

100

80
% drug release

% drug release of innova-

tor
60
%Drug release of trial batch
40 %drug release of scaleup
batch
20

0
0 5 10 15 20 25 30 35
time(min)

Fig 4.12