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A REVIEW ON SOLID ORAL DOSAGE FORM OF ANTIEPILEPTIC DRUGS
BY PELLETIZATION TECHNIQUES Kundu Subrata*1, Srinivasan Ganga2
1Shri JJT University, Rajasthan 2Vivekananda College of Pharmacy, Mumbai University
ABSTRACT:
Epilepsy is one of the severe diseases and it has wide scope in research. Various Antiepileptic
drugs are available in market in the form of Tablet, Capsule, Solution, Suspension, Gel etc.
Whereas, the Multiple unit dosage form manufactured by Pelletization technique gain a lot of
popularity due to its advantages like increased surface area and dissolution, easy to fill in
capsule, higher distribution in GI track, and flow of pellets. Pelletization is the growing
technique in pharmaceutical field. Most of the drugs are now a day available in pellet forms.
The current review focuses on Pelletization technique, coating of these pellets and the release
of the drug from these coated pellets. Brief focus on different types of release patterns such as
immediate release, sustained release, extended release, controlled release are mentioned.
Need of Pelletization in formulation of antiepileptic drugs is also discussed. Coating of the
pellets can be done in the fluidized bed processor and different parameters are discussed like
Polymeric particle size, Film-forming temperature, Plasticizer, Blend polymer, Hydration of
polymer, Properties of the core surface and other parameters like spray rate, product
temperature, Atomization pressure etc. Also the theories of film formation like Wet sintering
theory, Capillary pressure theory, sintering theory are discussed. Mechanism of drug release
from the coated pellets is described.
Key words: Antiepileptic drugs, Pelletization, Multiparticulate.
INTRODUCTION:
Epilepsy, a disease that has been in
existence for ages, continues to affect
approximately 50 million individuals
worldwide. The disease is often
accompanied by neurobiological,
cognitive, psychological, and behavioral
changes that may heighten susceptibility to
seizures and affect quality of life.
Anti-epileptic drugs (AEDs) are the
primary option for the management of
epilepsy. Anti-epileptic drugs (AEDs) are
also known as the anticonvulsant drugs or
anti seizure drugs. Now a day’s new drugs
are developed to treat the epilepsy as well
as the existing drugs are designed in novel
forms like pellets filled in capsule etc.
Dosage Forms of Antiepileptic Drugs:
Various drugs are available for the
treatment of epilepsy. Specific use of a
drug in treatment of epilepsy is not
possible it depends upon the type of
Corresponding Author*
Kunda Subrata
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epilepsy, drug properties and also on the
patient compliance [1, 2]
. Various dosage
form available for different antiepileptic
drugs are summarized in table 1.
Table 1: Dosage Forms of Antiepileptic Drugs
Tablet Capsule Injectable Suspension Solution Gel
Acetazolamide Acetazolamide Acetazolamide Carbamazepine Gabapentin Diazepam
Carbamazepine Carbamazepine Diazepam Felbamate Oxcarbazepine
Clonazepam Clorazepate Lorazepam Phenytoin Valproic acid
Clorazepate Divalproex
Diazepam Ethosuximide
Divalproex Gabapentin
Ethosuximide Phenytoin
Felbamate Pregabalin
Gabapentin Topiramate
Oxcarbazepine Valproic acid
Lamotrigine Zonisamide
Phenytoin
Primidone
Tiagabine
Topiramate
Trimethadione
Pharmacokinetics:
Antiepileptic drugs are slightly soluble and
exert good absorption i.e. 80-100% of drug
reaching to the circulation. All drugs have
penetration in to CNS. So they are
administered by oral route [3]
.
Mechanism of Action:
Mechanism of various antiepileptic drugs
is schematically mentioned in the
following figure- 1[4]
;
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Figure 1: Mechanism of various antiepileptic drugs
DIFFERENT RELEASE PATTERN
FOR ORAL SOLID DOSAGE FORMS:
Various antiepileptic drugs are available
with different release profile. Immediate
release dosage forms are either uncoated or
coated with immediate release film
forming polymers. Modified release
(delayed, extended, sustained and/or
extended release) dosage forms are either
matrix based and/ or coating based with
dissolution rate controlling hydrophilic or
hydrophobic polymers. Based on the
pharmacodynamic and pharmacokinetic
Properties of the Antiepileptic drugs,
dosage form design are decided.
Advantages of Extended release
products:
1. Maintain therapeutic concentrations.
2. Avoids the high blood concentration.
3. Extended release formulations have the
potential to improve the patient
compliance.
4. Drug absorption is slower so it reduces
the toxicity.
5. Protect the drug from hydrolysis or
other degradative changes in
gastrointestinal tract.
6. Minimize the local and systemic side
effects.
7. Improvement in treatment efficacy.
8. Minimize drug accumulation with
chronic dosing.
9. Improve the bioavailability of some
drugs.
Disadvantages of Extended release
products:
1. Expensive in preparation.
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2. The release rates are varied by various
factors such as food and the rate of
transit through the gut.
3. Some differences in the release rate
from one dose to another dose.
4. Extended release formulation contains a
higher drug load and thus any loss of
integrity of the release characteristics of
the dosage form.
5. Sometimes the target tissue will be
exposed to constant amount of drug
over extended period results in drug
tolerance.
WHAT IS PELLETS?
In pharmaceutical application, an
agglomeration process that results in
agglomerates of a rather wide size
distribution within the range of 0.1 – 2.0
mm, with a high intra-agglomerate
porosity (about 20 – 50 %) is named a
granulation process, and the agglomerates
are called granules.
If the final agglomerates are spherical, free
flowing, and of a narrow size distribution
in the size range of 0.5 – 2.0 mm, and a
low intra-agglomerate porosity (about 10
%), the process is often referred to as
pelletization process, the agglomerates are
called pellets.
Advantages:
Pellets can disperse freely
throughout an area of the
gastrointestinal tract after
administration and consequently
the drug absorption is maximized
as a large gastrointestinal surface
can be involved in this process.
Peak plasma level of the drug can
be reduced by the use of spherical
particles with different release
rates; potential side effects are
minimized without markedly
lowering drug bioavailability;
The wide distribution of spherical
particles in the gastrointestinal tract
limits localized build-up of the
drug, avoiding the irritation effect
of some drugs on the gastric
mucosa;
Modified-release multiparticulates
delivery systems are less
susceptible to dose dumping than
single-unit dosage forms.
Disadvantages:
Often pellets cannot be pressed into
tablets because they are too rigid.
In that case, pellets have to be
encapsulated into capsules [5]
.
The production of pellets is often
an expensive process and / or
requires highly specialized
equipment.
The control of the production
process is difficult (e.g. the amount
of water to be added is critical for
the quality of the pellets and over
wetting can occur very easily).
REASONS FOR PELLETIZATION
Pelletization is very important area of
interest in pharmaceutical industry due to
various reasons:
Prevention of segregation of co-
agglomerated components,
resulting in an improvement of the
uniformity of the content;
Prevention of dust formation,
resulting in an improvement of the
process safety, as fine powders can
cause dust explosions and the
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respiration of fines can cause
health problems;
Increasing bulk density and
decreasing bulk volume;
The defined shape and weight
improves the appearance of the
product;
Improvement of the handling
properties, due to the free-fl owing
properties;
Improvement of the hardness and
friability of pellets;
Controlled release application of
pellets due to the ideal low surface
area-to-volume ratio that provides
an ideal shape for the application of
film coatings.
All these aspects can be considered as
technological advantages of pelletization.
METHODS OF PELLETIZATION:
Pelletization involves the agglomeration of
active pharmaceutical ingredients and
excipients in spherical beads called pellets.
Variety of techniques is available for pellet
manufacturing [6]
.
Powder layering
Solution/Suspension layering
Extrusion-Spheronization
Spherical agglomeration or Balling
Spray congealing/Drying
Cryo Pelletization
Melt spheronization
Freeze Pelletization
Hot melt extrusion
THEORY – PELLET FORMATION
AND GROWTH:
It is necessary to understand the formation
and growth of pellets before selecting the
pelletization procedure. Numbers of
theories are available for the mechanism of
growth and formation of pellets. Some of
them are derived from research while
others are postulated from visual
observations [7, 8]
.
Pelletization process mainly involves 3
steps:
Nucleation
Transition
Ball growth
But based on experiments on the
pelletization technique steps proposed are
Nucleation, coalescence, layering &
abrasion transfer.
Figure 2: Pelletization process
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COATING OF
MULTIPARTICULATES:
Mainly the coating of pellets can be done
by polymeric solutions as well as
polymeric dispersion. In such type of
coating the mechanism in film formation is
the critical step.
MECHANISM OF FILM
FORMATION:
Coating is achieved mainly by spraying
and drying process of the dispersion which
is composed of three phases: gas phase,
aqueous phase, and polymeric particles.
Water is evaporated leaving the polymeric
solid. These residual solid composed of
discrete particle, become a homogenous
film.
Muroi[9]
reviewed many proposed theory
for film formation and its application in
pharmaceuticals was discussed by
Lehmann[10]
and Steuernagel [11]
. Fusion
and film formation of polymeric particles
can be explained by following theories:
Wet sintering theory[12]
Capillary pressure theory[13]
Dry sintering theory[14,15]
FORMULATION AND PROCESSING
FACTORS
[A] Polymeric particle size:
The film formation is stronger with
decreased size of polymer and difficult
film formation from large size dispersion
polymer. Latexes and pseudo latexes are
easier for film formation due to its
submicron size. Nakagami et al[16]
reported
effect of particle size on film formation of
2-methyl-5-vinyl-pyridine-methylacrylate-
methacrylic acid copolymer suspension
and observed film formation from
polymeric particles.
[B] Film-forming temperature:-
Polymers are deformable above Ts which
is necessary for film formation. The
softening of polymer films is related to
glass transition of polymer. And both
correspond to sharp increase in polymer
chain mobility[17]
. Amer et al[18]
reported
relation between Tg and bed temperature.
They concluded that when coating is done
at 10ᵒC or less above the Tg the film
formation was certain but such operation
may lead to agglomeration which is
minimized by dusting powder directly into
the coating chamber.
[C] Plasticizer:-
Plasticizer is used to decrease Ts and Tg
values. The degree of decrease in Ts
depends on the plasticizer concentration
and physiochemical properties of
plasticizer. In order to promote polymer
mobility and flexibility plasticizer must be
compatible with the polymer.
Toyoshima[19]
evaluated the capacity of
plasticizer to break the bond between
molecules by dissolving temperature of the
polymer in plasticizer and interaction force
between polymer and plasticizer molecules
by the cloud point (CP).
[D] Blend polymer:-
Blending of polymer is done to adjust the
softening temperature of the polymer. For
example: Eudragit NE30D has low Ts at
18°C and is blended with Eudragit RS30D.
Upto 40% of Eudragit NE30D, there is
slight decrease in temperature but above
40% of NE30D there is drastic change in
temperature. The blend of Eudragit RS30D
/ Eudragit NE30D are in the ratio of 2:3
with Ts of 53ᵒC. Release profile of this
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blend was very fast indicating poor film
formation.
[E] Hydration of polymer:-
For excellent film formation hydration of
polymer is important apart from polymer
particle size. For example: Eudragit L30
D55 shows excellent film forming ability
due to its small size and also it contains
hydrophilic methacrylate (MA) of 50% as
the molar fraction of monomer[20]
. The
hydrogen bond between the polymer and
pendent ester can be broken by water
molecules and hydration causes lowering
of mechanical strength of particle and
polymer particle to deform. Hydrogen
bond between water and carboxyl groups
act as driving force for film formation.
[F] Properties of the core surface:-
Core used must be porous granules.
Protiman and Brown et al[21]
reported that
application of an aqueous dispersion of
Copolymer of ethyl acrylate-methyl
methacrylate (EA-MMA) to porous
surface resulted in higher minimum flim
forming temperature (MFT) values which
indicates lesser period for capillary
pressure to act due to water penetration
resulted in incomplete film formation.
Since most drugs are surface active they
migrate from core to film layer which
decreases the capillary pressure (driving
force for film formation). Yang and
Ghebre-Sellassie reported this problem [22]
resulted in poor film former. Migration of
drug can be avoided by slow coating at
initial stage or seal coating of cores.
[G] Additives:-
Solid additives that are insoluble in water
are used as pigments (TiO2, food dyes) in
coloring the coating, membrane diluents to
thicken the membrane, example: talc or
magnesim stearate [23]
and also act as
antiadherent, anticoagulant used to
separate interactive polymeric particle and
avoid coagulation. The fumed silica in
surelease formulation and oily acetylated
monoglyceride in aquateric formulation act
as antiadherent and anticoagulant
respectively. Small amount of additives
suppress membrane permeability but
excessive additives result in discontinuous
film structure [24, 25]
.
[H] Coating of fine powders:-
Preparation of multiparticulate dosage
form by spray coating process, resulting of
agglomeration problem especially with
fine powder. In fine powder case the
interparticulate bridge of membrane
material is formed leading agglomeration
[26]. This interparticulate bridge need to be
separated in order to avoid agglomeration
but conventional top sprayed fluidized bed
usually cannot generate that much strength
to separate this bridge, so Wurster process
which is best suited for fine powder
coating is used where particles smaller
than 100µm may be coated discretely, and
smallest size particle that can be coated by
Wurster process depends on the binding
strength of membrane material. The
condition that is maintained in Wurster
process for fine powder is: the mass
median diameter is kept at 12µm at spray
pressure of 2.3 atm and a spray rate of
4ml/min. This is the spray condition with a
pneumatic nozzle can normally be used. In
aqueous produces intense separation of
particles due to the collision of particles
against the partition. Brittle crystals are
easily fractured and even lactose crystal
becomes roundish [27]
.
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APPROACHES TO FORMULATING
COATING SOLUTION
Advantage of film coating is to modifying
the release characteristic of drug from a
dosage form. Approaches to formulate
modified release coating are:
Film – forming material dissolved
in organic solvent.
Aqueous polymer dispersion.
Hot melts.
Table 2: List of Process variables in film coating
Variables Has influence on :
Coating equipment
Coating dispersion solids content
Spray rate
Atomizing air pressure / volume
Quantity of coating applied
Drying conditions (air volume, temperature,
and humidity)
With organic solvent-based solutions
With aqueous polymeric dispersions.
Quality and functionality of coating
Economics
Membrane structure
Uniformity of distribution of coating
Processing costs
Membrane structure
Uniformity of distribution of coating
Processing costs
Membrane structure
Uniformity of distribution of coating
Drug release rate
Uniformity of distribution of coating
Processing costs
Membrane structure
Drug release rate
Coalescence of film
Drug leaching
Tackiness of the coating
Drug release rate
MECHANISM OF DRUG RELEASE
FROM COATED PELLETS:
Pellets are coated with the various
polymers which are insoluble in GI track
as well as soluble in GI track. Here we will
focus on mechanism of release to predict
the in vivo behaviour of the pellet dosage
form. The major mechanism by which
drug is release in pellets dosage form
depends on the type of coating material
and method of coating. Kinetics of release
depends on the solubility behaviour of
coating material in GI condition and core
formation. Behaviour is classified
according to three general types:
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(1) Coating is insoluble in all
physiologically relevant conditions.
(2) Solubility changes at some point in GI
tract.
(3) Coating slowly erodible under GI
condition.
1. Coating is insoluble in all
physiologically relevant conditions:
[A] Solution / diffusion through the
continuous plasticized polymer phase:-
The mechanism assumes that polymers
forms continuous phase with the
plasticizer and additives are homogenously
dispersed. Diffusion of solute within
amorphous polymer phase involves co-
operative movement of drug and polymer
chain segment around it [28]
. Thermal
fluctuation between adjacent chains
permits the passage of a drug. Another
mechanism of release is configurational
diffusion. Frequency of diffusion of drug
depends on (i) size and shape of drug, (ii)
force of attraction between adjacent
polymer chain, and (iii) stiffness of
polymer chains. In general if the film is
continuous i.e. lacks pores and flexible and
drug has high affinity for polymer relative
to water, promote the diffusion mechanism
of release.
[B] Solution / Diffusion through
plasticizer channels:-
When plasticizer is uniformly distributed
and is in high concentration then it forms a
continuous phase in the form of patches
channels. Diffusitivity in plasticizer is
lower than in water as it is more viscous
than water. Ozturk et al[29]
estimated K
value from solubility ratio to the
distribution coefficient for
phenylpropanolamine HCl between water
and four plasticizer and K value ranges
from 1.694 / 40 for triacetin to 3.954 / 40
for Myvacet, which suggested that this
mechanism is too slow to explain the
release rate observed.
[C] Diffusion through aqueous pores:
This coating is not homogenous and
continuous but is provided with pores.
These pores are filled with solution when
it comes in contact with aqueous medium,
thus facilitating diffusion of drug. This
mechanism is seen in coating done with
aqueous dispersion as pseudo-latexes than
organic solvent as pseudo-latexes particles
do not fuse completely, thus creating pores
in the coating.
[D] Osmotically driven release:
When the coating is porous, release of
drug may be due to osmotic difference
between the core materials and release
environment source of osmotic pressure in
core formulation include low molecular
weight excipients (example: the sugar
constituting Nu – Pareil seeds) and the
drug. Drug released through osmotic
pressure must be highly water soluble and
must be of low molecular weight.
Osmotically driven release act when
pellets come in contact with water it
imbibes water to the core drug and
excipients get dissolved in water
generating interior osmotic pressure. The
osmotic pressure difference between the
core and external medium provides force
to efflux through pores in the coating.
2. Solubility changes at some point in
GI tract.
Coating which are pH sensitive have
increased solubility at some point in the GI
tract which is used to prevent release in the
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stomach but complete release in the
intestine. The pH difference is about 5 pH
units[30]
between stomach and small
intestine at fasted state but it is reduced
when food is ingested as gastric fluid
become buffered with food. Thus narrow
range is provided over which the coating
solubility must change. Achieving release
in colon is difficult as compared to small
intestine, as the pH difference between
ileum and proximal colon is much less
than between stomach and small intestine.
3. Bioerodible coating:-
To achieve prolong release using enteric-
coating one can employ heterogenous
coating such as shellac [31]
. Acidic nature
of hydrolysate explains enteric properties
of shellac coatings, while the heterogeneity
of composition explains prolong release of
drug. Triglycerides and ether wax / fat is
also utilized as coating to provide prolong
drug release and their digestion and
dissolution is facilitated by lipase released
in pancreatic juice and by bile salts. To
predict invivo release from invitro
experiments, incorporate physiological
amount of pancreatin and bile salts in
release media. High degree of colonization
of colon by bacteria favours designing of
site-specific release to colon [32]
. This is
used for treating inflammatory bowel
disease as high concentration of the drug is
achieved in local tissue. The
Azoreductases is used in colon- specific
delivery and studies are going on use of
glycosidic linkage. In bioerodible coating,
the polymer includes catalyst like
polyorthoesters to speeden the release as
bioerodible polymer alone erode too
slowly in GI tract. By adding phthalic
anhydride in the polyorthoester matrix,
surface erosion mechanism is achieved
resulting in zero- order release because
rate of water penetration into the polymer
becomes the rate limiting step of its
erosion. The advantage of this type of
design is three folds:
1. Release relatively independent of
GI condition.
2. Manipulating release rate by
modifying the level of catalyst
used. And
3. Complete release is possible if
polymer degrade completely
within GI transit time.
Example: Cyclobenzaprine HCl
formulation, produce release over a period
of 10 to 15 hours. This design for short –
term release formulation has been
discussed by Heller et al [33]
.
Marketed Examples of sustained release
antiepileptic drugs:
1. Formulation of Topiramate pellets
(Patent No. – US 8,298,580,B2 ):
Sugar spheres are used in the
formulation of Topiramate pellets. It
is one of the extended release type
dosage form. In this the spheres were
firstly seal coated then the drug
layering is done by using fluidized
bed processor. Then pellets were
subjected for rate controlling layer
coating using polymers like ethyl
cellulose, methylcellulose at level of
2-4% coating. This formulation
reduces the adverse effects related to
the CNS which are shown by
immediate release dosage form of
Topiramate [34]
.
2. Formulation of Carbamazepine
Pellets: (US 2007/0071819 A1)
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Extended release formulation
containing carbamazepine is
formulated by blending
carbamazepine with rate controlling
polymer and pharmaceutically
acceptable excipients by granulation
followed by sieving, extrusion and
marumerization or spheronization,
pelletization, micropelletization etc.
Then these pellets coated with
enteric polymer using fluid bed
processor. The rate controlling
polymers include cellulose
derivatives, starch, PVP, alginates,
acrylic acids. Suitable enteric
polymer such as cellulose acetate
phthalate, cellulose acetate
trimellitate, HPMC phthalate acetate,
HPMC acetate succinate,
Methacrylic acid copolymer such as
Eudragit L100-55, D-55 etc. These
pellets were filled in capsule. The
resultant capsule show its release in
intestine it will not show its release
in stomach[35]
.
3. Formulation of Acetazolamide
Pellets: (EP 0540 813 B1)
In this patent the Acetazolamide
Pellets were prepared by the
Extrusion Spheronization method.
Acetazolamide itself act as a binder
so binder free pellets were prepared
and then these pellets were coated
with rate controlling membrane.
Rate controlling membrane consists
of polymers like ethyl cellulose,
waxes etc. and MCC as a moisture
controlling agent. Acetazolamide
containing pellets can be filled into
soft or hard gelatin capsules
otherwise presented in a unit dosage
form [36]
.
Table 3: Composition of Pellet Core
Ingedient % Composition, dry basis
Acetazolamide 80.0
MCC 19.94
SLS 0.06
Table 4: Composition of Coated Pellets
Ingredients % Composition, Dry basis
Acetazolamide Pellets 94.52
Ethylcellulose(100 cps) 0.72
HPC (6 cps) 2.86
Mineral oil 0.41
Colorant 1.46
CONCLUSION:
This short review on drug delivery of
antiepileptic drugs by pelletization
concludes that drug delivery using
multiple units like pellets in a single
dosage form is one of the novel concepts.
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Major advantage of such system is that
drugs which degrade in gastric fluid can be
protected because pellets cannot be
stopped in stomach so it will not show
release in stomach. Such type of pellets
can be filled in capsule as well as
compressed in tablets. Extended release
dosage form show reduced side effects and
maintenance of drug in body for longer
time so the dosing frequency is also
reduced. Patient compliance and flexibility
is also there. Pelletization technique is now
a day very fast growing technique. Various
newer drugs administered by this
technique.
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Kraus DM. The pediatric Dosage
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1/
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