Formulation and Evaluation of Multiunit Pellet System of Venlafaxine Hydrochloride

M Srujan Kumar et al.
/ JPBMS, 2012, 18 (05)

1 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 18, Issue 18

Available online at www.jpbms.info

JPBMS

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

Formulation and Evaluation of Multiunit Pellet System of Venlafaxine Hydrochloride
*M. Srujan Kumar
1
, Binayak Das
1
, S.V.S.Rama Raju
2

1
Department of Pharmaceutics, Samskruti college of Pharmacy,Kondapur,R.R District,Hyderabad,India.
2
Department of Pharmaceutics, C.L.Baid Metha College of pharmacy, Chennai, India.
Abstract:
Compaction of multiparticulate, commonly called MUPS, is one of the more recent and challenging technologies that
combine the advantages of both tablets and pellet-filled capsules in one dosage form. Venlafaxine is an anti depressant,
having an elimination half-life of 52 hrs and its maximum daily dose is 300mg. Since the drug belongs to BCS class I, it is
necessary to retard dissolution to ensure extended release of drug. The objective of the study is to prepare venlafaxine
extended release pellets by extrusion spheronization technology, coating them with mixture of rate controlling polymers
Ethyl cellulose and different grades of (Hydroxy propyl methyl cellulose (HPMC) using Wurster process to achieve the
desired dissolution pattern and compressing the pellets into tablets. The pellets were analyzed for the parameters such as
bulk density, tapped density, compressibility index, Hausners ratio and the results were found to be within the limits.
Drug release rate was more when compared with the innovator sample. The Venlafaxine hydrochloride extended release
pellets were compressed into the tablets. The dissolution profile of the prepared Venlafaxine hydrochloride extended
release tablets were compared with that of Innovator (VENLAR). Finally conclude like extended release pellets in tablets of
formulation (F9) have more drug release rate rather than innovator (VENLAR) and it have better Bioavailability.

Keywords: Extrusion and Spheronization, HPMC, MUPS, multiparticulate, wurster process.
Introduction:
The oral route of administration of drugs is the most
important method for achieving systemic effects. In the
process of absorption of drug from oral route dissolution is
the rate limiting step. Since the drug belongs to BCS class I,
it is necessary to retard dissolution to ensure extended
release of drug. Venlafaxine is an anti depressant, having
an elimination half-life of 52 hrs and its maximum daily
dose is 300mg. Hence it is an ideal candidate for extended
release formulation. The objective of the study is to
prepare venlafaxine extended release pellets by extrusion
spheronization technology and further coating them with
mixture of rate controlling polymers Ethyl cellulose and
hydroxy propyl methyl cellulose using Wurster process to
meet the desired dissolution pattern and compressing the
pellets into tablets.
Modified release can be categorized into delayed release
and extended, or prolonged, release. The primary aims of
using delayed release are to protect the drug from an un
favorable environment in the gastrointestinal tract, to
protect the gastrointestinal tract from high, local
concentrations of an irritating drug compound, or to target
a specific region of absorption or action. Delayed release
products are typically enteric-coated or targeted to the
colon. Extended release products aim at releasing the drug
continuously at a predetermined rate to ncrease the
patient compliance
1, 2
. The method pelletization technique
developed in the early 1960s and since then researched
and discussed extensively. Interest in the technology is still
strong, as witnessed by the extent of coverage of the topic
in scientific meetings and symposium proceedings, as well
as in scientific literature. The technology is unique in that it
is not only suitable for manufacture of pellets high drug
loading but it also can be used to produce extended release
pellets in certain situations in a single step and thus can
obviate the need for subsequent film coating. Pellets are
agglomerates of fine powders or granules of bulk drugs
and excipients. They consist of small, free-flowing,
spherical or semi-spherical solid units, typically from about
0.5 mm to 1.5 mm, and are intended usually for oral
administration
1, 2.

Pellets are agglomerates of fine powders or granules of
bulk drugs and excipients. They consist of small, free-
flowing, spherical or semi-spherical solid units, typically
from about 0.5 mm to 1.5 mm, and are intended usually for
oral administration. Implants of small, sterile cylinders
formed by compression from medicated masses are also
defined as pellets in pharmacy. Pellets can be prepared by
many methods, the compaction and drug layering
techniques being the most widely used today. Regardless
of which manufacturing process used, pellets have to meet
the following requirements.
1. They should be near spherical and have a smooth
surface; both considered optimum characteristics for
subsequent film coating.
2. The particle size range should be as narrow as possible.
The optimum size of pellets for pharmaceutical use are
considered between 600 and 1000 m.
3. The pellets should contain as much as possible of the
active ingredient to keep the size of the final dosage form
within reasonable limits. In the last two decades, pellets
have established their place for many reasons.
Pellets offer a great flexibility in pharmaceutical solid
dosage form design and development. They flow freely and
ISSN NO- 2230 7885
CODEN JPBSCT

Research article
M Srujan Kumar et al. / JPBMS, 2012, 18 (05)
pack easily without significant difficulties, resulting in
uniform and reproducible fill weight of capsules and
tablets. Successful film coating is applied on pellets due to
their ideal spherical shape and a low surface area to
volume ratio. Pellets composed of different drugs are
blended and formulated in a single dosage form. This
approach facilitates the delivery of two or more drugs,
chemically compatible or incompatible, at the same sites or
different sites in the gastrointestinal tract even pellets with
different release rates of the same drug is supplied in a
single dosage form. The most important reason for the
wide acceptance of multiple-unit products is the rapid
increase in popularity of oral controlled-release dosage
forms. Controlled-release oral solid dosage forms are
usually intended either for delivery of the drug at a specific
site within the gastrointestinal tract or to sustain the action
of drugs over an extended period With pellets, the
abovementioned goals are obtained through the
application of coating materials (mainly different
polymers), providing the desired function or through the
formulation of matrix pellets to give the desired effect. The
advantage of multiple-unit products as a controlled-release
dosage form believed to be their behaviour in vivo because
of their advantageous dispersion pattern in the
gastrointestinal tract and their special size characteristics.
The transit time of a gastrointestinal drug delivery system
along the gastrointestinal tract is the most limiting
physiological factor in the develop of a controlled-release
gastrointestinal drug delivery system targeted to once-a-
day medication. Gastro-intestinal transit time, greatly
affects the bioavailability of a drug from an orally
administered controlled release preparation. Gastric
transit of both single and multiple-unit solid dosage forms
prolonged in a fed stomach compared to a fasting one
1, 2, 3
.

Extrusion and spheronization:
The concept of multiparticulate dosage forms introduced
in the 1950s with the increasing use of multiparticulate
controlled release (CR) oral dosage forms, in recent times
there has been a rise in interest in the methods of
preparing these dosage forme. A method that has gained
increased usage over the past few years is that of extrusion
and spheronization.it has extensively as a potential
technique and also as a future method of choice for
preparation of multiparticulate CR dosage forms.
This is a multi step process involving dry mixing, wet
granulation, extrusion, spheronization, drying and
screening. The first step is dry mixing of the drug and
excepients in a suitable mixer followed by wet
granulation, in which the powder is converted into a plastic
mass that is easily extruded. The extruded strands
transferred into a spheronizer, where they are
instantaneously broken into short spherical rods on
contact with the rotating friction plate and pushed
outward and up the stationary wall of the processing
chamber by centrifugal force. Finally, owing to gravity, the
particles fall back to friction plate, and the cycles repeated
until the desired sphericity achieved.

Extrusion-spheronization is a multistep process involving a
number of unit operations and equipment. However, the
most critical part of processing equipment dictates the
outconme of overall quality of pellets.

Figure 1: Overview of the Formulation of ER Pellets

Extrusion:
Shaping of the wet mass into long rods are called as
extrusion. A variety of extruders, which differ in design
features and working principles, are currently on market
and can be classified as screw-fed extruder, gravity-fed
extruder and ram extruder. Screw-fed extruder have
screws that rotate along the horizontal axis and hence
transport the materials horizontally, they may axial or
radial screw extruders. The product temperature
controlled during extrusion by jacketed barrels. In radial
extruders, the transport zone is short, and the material
extruded radially through screens mounted around the
horizontal axis of the screws. Gravity-fed extruders include
the rotating cylinder and rotating gear extruders, which
differ primarily in the design of two counter-rotating
cylinders. In the rotating cylinder extruder, one of the two
counter rotating cylinders is hallow and perforated, where
as the other cylinder is solid and acts as a pressure roller.
In ram extruders, piston displaces and forces the materials
through a die at the end. Ram extruders preferred during
formulation development they designed to allow for
measurement of the rheological properties of formulation.
In an extrusion-spheronization process, formulation
components such as filler, lubricants and ph modifiers play
a critical role in producing pellets with desired attributes.
The granulated mass must plastic and sufficiently cohesive
and self lubricating during extrusion. During the
spheronization step, it is essential that the extrudates
break at appropriate length and have sufficient surface
moisture to enhance the formulaion of uniform spherical
pellets. Excepients play an important role during extrusion
spheronization than during with other pelletization
process. they facilitate extrusion and determine the
spherecity of the wet pellets, imparts strength and
integrity of the pellets.
Microcrystalline cellulose (MCC) is the most commonly
used excipient in extrusion spheronization it leads to the
formation of round spheres with desirable characteristics.
During spheronization, moisture entrapped in the MCC
microfibrils adds plasticity to the extrudates into spherical
pellets.
The pellet properties can be affected by many operational
variables during the extrusion stage, the spheronization
stage, or the drying stage. Both drying technique and
drying temperature have a considerable affect on the pellet
structure and properties. The variables that affect the final
pellet qualities are screen pressure, screen hole diameter,
extruder type and speed, the type of friction plate, and
spheronization time, speed and load. There is considerable
interaction between spheronization time and
spheronization load. With small and large spheronization
loads, the yield of large pellets increases with longer
spheronization time, an effect that is exacerbated by faster
spheronization speed. Unsuitable processing parameters
lead to pellet with poor qualities.

Spheronization:
During the third phase of extrusion spheronization process
the extrudates dumped on to the spinning plate of the
spheroniser, call the friction plate, where the extrudate
broken up into smaller cylinders with a length equal to
there diameter, those plastic cylinders rounded due to
frictional forces. In the spheronization process different
stages are distinguished depending on the shape of the
particles, I.e; starting from a cylinder over a cylinder with
rounded edges, dumbbells and elliptical particles to
eventually perfect spheres. Baert and remon (1993)
suggested that another pellet forming mechanism might
exist. In this mechanism twisting of a cylinder occurs after
the formation of cylinders with rounded edges, finally
resulting in the breaking of the cylinder into two distinct
parts. Both parts have round and flat side. Due to rotational
and frictional forces involved in the spheronization process
the edges of the flat side fold together like a flower
forming the cavity observed in certain pellets. The
spheronization of a product usually takes 2-10 minutes. A
rotational speed of friction plate in the range between 200
and 400 RPM would be satisfactory to get highly spherical
pellet. This statement is in a sharp contrast with most
reports indicating the use of spheronization speeds
exceeding 400 RPM. This contradiction are explained by
the fact that not the absolute speed is important but the
speed in combination with the diameter of the friction
plate. From those two parameters the plate peripheral
velocity is calculated and this data should be compared
instead of absolute rotational speed of the friction plate.
The friction plate has a grooved surface to increase the
frictional forces. Two types of geometry of the grooves
exist, cross hatch geometry where the grooves from right
angles and radial geometry where a radial pattern used.

Figure 2: Mechanism of pellet formation

A special kind of spheronizer designed by NICA-systems
with a lip around the rim of the friction plate which claims
to reduce the milling affect of the friction plate resulting in
small amount of fines. Depending upon composition of
formulation, substance soluble in the granulation liquid
might migrate to the outside of the pellets during
spheronization, leading to an in homogeneous distribution
of the substance throughout the pellet. Snapshot of
spheronization process:

Figure 3: Snap shot of spheronization process

Courtesy :- http:/ / spheronizer.com/ html/ spheronization.html
Wurster process
The wurster process can appropriately be described as an
upward moving, highly expanded pneumatically
transported bed of pellets coupled with a downward-
moving, more condensed, fluidized bed of pellets on the
periphery of a vertical column. The two beds separated by
tubular central partition. As the pellets pass through the
atomizer they wetted by the coating fluid and then
subjected to drying conditions created by the heated
conveying air moving upwardly in the column. The
partially coated solid pellets move downwardly in a
weightless condition along the periphery of the column,
where further drying occurs. When the solid pellets reach
the lower end of the column those directed back into the
upwardly moving bed and the entire process repeated.
The air pump, heater, provides the heated support air for
the process, and the distribution plate directs the proper
volume of air to the central and peripheral regions of the
column. The proper adjustment of the air flow, the
temperature, and fluid application rate is critical to the
successful operation of the process. Obviously, the drying
kinetics is influenced by air flow rate and the temperature
of the air. This kinetics in turn dictates the fluid application
rate. Since drying is a cooling process. The temperature of
the pellet surface is lower than either the inlet or exhaust
air temperature.
This permits the coating of heat-sensitive materials, since
process conditions are adjusted so that the exhaust
temperature will not exceed the temperature in which the
product can tolerate. Thus, it is readily apparent that the
drying kinetics are enhanced by increasing either the air
flow rate or air temperature while maintaining the fluid
application rate constant
1, 2
.
From the literature survey:
Steven H. Neau et al., (2010) evaluated the potential of
coarse ethyl cellulose (CPEC) and high molecular weight
polyethylene oxide (PEO) as excipients in the production of
beads by extrusion-spheronization. CPEC was investigated
as a diluents and PEO as an extrusion aid and a binder.
Beads manufactured with caffeine as a model drug. release
studies were conducted, and the bead size, shape, yield,
and friability determined. The results confirmed that
immediate release, spherical beads with low friability and
narrow size distribution to be produced with minimum
amounts of MCC
3
.
Fridrun podczeck et al., (2009) has studied influence of
adding two concentrations (5 and 25% ) of non-ionic
surfactants, one hydrophilic and the other hydrophobic,
plus mixtures of equal parts of the two, on the rheological
properties of a mixture of equal parts of microcrystalline
cellulose and ibuprofen with water by capillary rheometry .
The mixtures are also used to form pellets by extrusion-
spheronization and their in vitro dissolution in simulated
intestinal fluid measured. The 25% level of each of the
surfactant formulations provided a rapid release of drug
(100% within 30 minutes) but the 5% level and the mixed
surfactant formulations provided lower drug release
profiles
4
.

Lieven Baert et al., (2009) produced pellet formulation
containing a high drug loaded (80%) of the poorly soluble
HIV-protease inhibitor darunavir, using wet extrusion-
spheronization with K-carrageenan or microcrystalline
cellulose (MCC) as pelletization aid. When compared with
MCC pellets the bioavailability of darunavir was
substantially improved by sixty fold in K-carrageenan
pellets, likely due to their better disintegration behavior
5
.

Podczeck F. et al., (2008) investigated the ability to
incorporate non-ionic surfactants into pellets produced
from MCC by the process of extrusion-spheronization and
the properties of the pellets. A hydrophilic surfactant,
polysorbate 60 (PS 60), and two hydrophobic surfactants,
sorbitan monostearate (S 60) and sorbitan monooleate (S
80), Were included in the water used to form pellets in the
concentration ranging from 5 to 95%. The highest
concentration of the surfactant in water that is used to
form pellets ranged from 50% for S 60, to 80% for S 80 and
95% for PS 60. The maximum amount of surfactant, which
would be incorporated into final pellet, however, was
found approximately 22.5% for both hydrophobic
surfactants and 32.5% for hydrophilic surfactant
6
.

Sriamornsak et al., (2007) has investigated the
possibility in producing alginate-based pellets by
extrusion-spheronization and also to improve the
formation of spherical alginate-based pellets by
investigating the effect of additive in granulation liquid on
characteristics and drug release from resulting pellets.
Higher amount of 3% calcium chloride as granulating
liquid, formulations showed higher mean dissolution time
resulting from cross linking properties of calcium ions to
the negative charges of alginate molecules
7
.

Ramo n Marti nez-Pacheco et al., (2005) studied the
utility including superdisintegrants (croscaramellose
sodium or sodium starch glycolate) in microcrystalline
cellulose extrusion-spheronization pellets as means of
increasing the dissolution rate of hydrochlorothiazide.
Drug dissolution rate was slightly higher in pellets
prepared with sodium starch glycolate, propably because
this disintegrants higher swelling capacity
8
.

Steckel.H et al., (2003) successfully prepared chitosan
pellets replacing MCC. pellets with a maximum of 50%
(m/ m) of chitosan could be produced using demineralized
water and the mass fraction of chitosan within the pellets
could be increased to 100% by using diluted acetic acid for
the granulation step
9
.

Ingunn tho et al., (2003) studied low-soluble pectin
derivative, PA (degree of methoxylation, 10%) as an
extrusion aiding excipient in pellet preparation by
spheronisation / extrusion.

The substance has a high drug loading capacity and
produces disintegrating pellets that are well suited for fast
delivery of drugs with a low water-solubility. The pellets
are also mechanically stable, compared to MCC
10
.

Newton. J.M et al.,(2002) has experimented on five drug
models , 4-para hydroxyl benzoic acid(4HBA), methyl,
propyl and butyl benzoic acid and propyl gallate(PG) . All
of similar chemical natures were mixed in different
proportions (50-73.7%) with MCC (26.3-50%) plus
various levels of water (26.9-50%). The wet powder mass
extruded and spheronized under standard conditions. The
pellets produced, evaluated in terms of their median
diameter, their modal size range, the % within a given size
range (0.7-1.7 mm) and their shape factor. For the
majority of formulations, all drug models, except 4HBA,
produced pellets
11
.

Gayot .A et al.,(2002) successfully produced 400m
spheroids that is sprinkled on food to improve patient
compliance particularly in case of children and old people.
Gelucire 50/ 02 wetted with a sodium lauryl sulphate
solution at 0.5% was used which showed plastic flow
through the 400 m diameter orifice
12.

Materials and methods:
Table 1: List of Materials used
S.No
Active and inactive
pharmaceutical
ingredients
Suppliers
1 Venlafaxine Matrix laboratories ltd, Hyd.
2
Microcrystalline cellulose
(avicel PH 101)
FMC Biopolymer, USA
3
Hydroxypropyl
cellulose(Klucel)
Aqualon , USA
4 Opadry Clear Colorcon , Goa
5 Ethylcellulose (Ethocel) DOW , USA
6
Hydroxyl propyl methyl
cellulose
DOW , USA

Table 2: List of Equipments used:
S.No Equipments Manufacturers
1 Electronic balance Mettler Toledo, USA.
2 Rapid mixer granulator Kevin, Ahmedabad.
3 Extruder Fuji paudal co.Ltd, Japan.
4 Spheronizer/ Marumerizer
TM
Fuji paudal co.Ltd, Japan.
5 Rapid dryer Retsch, Germany.
6 Mechanical stirrer Heidolph, Germany.
7 Fluid bed coater Glatt, GmbH, Germany.
8 Mechanical sieve shaker Retsch, Germany.
9 Dissolution apparatus Electrolab, Mumbai.
10
UV-Visible
spectrophotometer
Shimadzu, Japan.
11
Tapped density apparatus
USP
Electrolab, Mumbai.
12 Tablet Punching machine Cadmach , Germany

Preparation of standard calibration graph of
Venlafaxine hydrochloride:
Preparation of standard solution of Venlafaxine
hydrochloride:
Stock solution: 100mg of venlafaxine HCl weighed
accurately and transferred into a 100 ml volumetric flask.
Then the volume made upto 100ml using water.
Standard solution: 10ml of solution was withdrawn from
the above stock solution and then made up to 100ml in

Another 100ml volumetric flask and this solution
considered as standard solution (100g/ml).
From the above standard solution 0.5, 1, 1.5, 2,
2.5ml was withdrawn and diluted to 10ml to get 5,
10, 15, 20, 25g/ml concentration.
The solutions analysed spectrophotometrically at 226nm
using UV visible spectrophotometer.

Table 3: Standard Calibration Curve
S.No Concentration g/ml UV Absorbance at 226 nm
1 0 g/ml 0.00
2 5g/ml 0.1830.02
3 10g/ml 0.3580.02
4 15g/ml 0.5360.02
5 20g/ml 0.7100.02
6 25g/ml 0.8910.02

Formulation development:
Preparation of pellets:
Granulation:
Venlafaxine HCl, microcrystalline cellulose (avicel PH 101),
hydroxy propyl cellulose (klucel) passed through 30#
mesh, and the sifted material transferred into rapid mixer
granulator (Kelvin). Then the material allowed for dry
mixing for 10 min by using impeller speed of 150 RPM and
water was added for 3 min till formation of granules.
Chopper run for 3 min at 1000 RPM to complete the
granulation process.
Preparation of pellets: The granules passed through Fuji
Paudal extruder using 0.8 mm screen at 40 RPM, the
obtained spaghetti like extrudates collected and placed on
Fuji paudal Marumerizer using 2mm plate. The
spheronizer run at 800 RPM for 30 sec, 1800 RPM for 90
sec and 1300 RPM for 60 sec to get pellets of satisfactory
sphericity. The pellets collected and dried in rapid dryer at
45
0
C for 2 hrs and then sized through 16/ 30 mesh.

Coating of pellets:
Sub coating:
Pellets loaded into fluid bed wurster and initial subcoating
made with opadry clear at 4%build up.
Polymer coating: polymer EC: HPMC coating was done in
the ratio of 65:35 by giving 20% buildup to pellets.

Preparation of Tablets:
Granular part:
Hydroxyl propyl cellulose, microcrystalline cellulose,
aerosol, sodium stearyl fumarate blended in a roller
compactor to form hard mass, then the resulting hard mass
milled through 1.5mm screen and the obtained granules
are passed through sieve no 20# mesh at top and 60#
mesh at the bottom the particles retained on the 60# mesh
considered as the granules and the particles passed
through the sieve no 60# considered as fines, and the fines
are again subjected to milling and the same cycle is
repeated for several times to produce 60% of granule and
40% fines.

Extra granular part:
Sodium stearyl fumarate and aerosil taken for the
lubrication purpose.

Compression of tablet:
Required amount of pellets were taken and mixed with
granular part and extragranular part by mechanical
agitation and compressed into tablets in a 16 mm oval
shaped punch with a compression force of 5K.

Table 4: Formulation of venlafaxine hydrochloride pellets
Ingredient F 1 F 2 F 3 F 4 F5 F6 F7 F8 F9 F10 F11
Core spheroids
Venlafaxine HCl (Eq to
venlafaxine)
169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7
MCC (PH 101) 165.3 134.3 134.3 134.3 134.3 134.3 165.3 165.3 134.3 165.3 165.3
Lactose(Granular 200) 100 55 55 55 75 100 100 75 55 50 75
HPC(Klucel EXF) 10 6 10 6 10 10 6 1 6 6 10
Water QS
Total core spheroids 445 365 369 365 389

414 441 391 365 391 420
Sub coat
HPMC 4 cps 14 10.5 10.5 10.5 10.5 10.5 14 10.5 10.5 14.5 15.5
Talc 6 4.5 4.5 4.5 4.5 4.5 4.5 6 4.5 6 6
Total sub coated
spheroids
465 380 384 380.0 404 429 459.5 407.5 380 411.5 441.5
EC coating
Ethyl cellulose 20 cps 56 45 45 66.6 56 66.6 75 75 56.2 75 75
HPMC 4 cps 10.5 11 12 16.2 12.5 12.5 17 17 13.7 12 15
PEG 400 3.5 6 7 8.88 9.5 9 11 11.5 7.5 13 15
Total EC Coated
spheroids
535 442 448 471.8 482 516.8 562.5 511 457.5 511.5 546.5


Table 5: Preparation of MCC granules
Preparation of MCC granules %w/ w
MCC 101 93
Aerosil 2
HPC LH 11 5
Total 100

Table 6: Compression of Tablets
Compression of Tablets using EC coated spheroids

Trial 1 Trial 2
Ingredient
(CP3) eq to 75 mg
venlafaxine
(CP3) eq to 150 mg
venlafaxine
mg/ tab mg/ tab
EC coated Spheroids 228.75 457.5
MCC Granules 653.25 657.5
Aerosil 9 10
Sodium stearyl
fumarate
9 10
Total tablet weight 900 1135

Evaluation
Evaluation of Pellets [Lachmann et al., 1987]
The pellets evaluated for in process quality control test.
The following tests performed for ER pellets
1. Determination of Bulk Density and Tapped Density:
An accurately weighed quantity of the granules/ powder
(W) was carefully poured into the graduated cylinder and
volume (V0) measured. Then the graduated cylinder was
closed with lid and set into the tap density tester (USP).
The density apparatus set for 100 tabs and after that the
volume (Vf) measured and continued operation till the two
consecutive readings were equal (Lachman et al., 1987).
The bulk density and the tapped density calculated using
the following formulae.

Bulk density =W/ V0
Tapped density =W/ Vf

Where, W=Weight of the powder
V0 =Initial volume
Vf =final volume

2. Compressibility Index (Carrs Index):
Carrs index (CI) is an important measure that can be
obtained from the bulk and tapped densities. In theory, the
less compressible a material the more flowable it is
(Lachman et al., 1987).

CI =(TD-BD) x 100/ TD

Where, TD is the tapped density and BD is the bulk density.

Table 7: Carrs Index Values
S.No. Carrs Index Properties
1 5-12 Free flowing
2 13-16 Good
3 18-21 Fair
4 23-35 Poor
5 33-38 Very poor
6 >40 Extremely poor

3. Hausners Ratio:
It is the ratio of tapped density and bulk density. Hausner
found that this ratio related to interparticle friction and, as
such, could be used to predict powder flow properties.
Generally a value less than 1.25 indicates good flow
properties, which is equivalent to 20% of Carrs index.

4. Particle size distribution:
100gms of pellets shifted into a sieve shaker where a series
of sieves was placed (16#, 22#, 25# and 30#). The machine
was run for 5 minutes, all the meshes were taken out and
retained granules collected by respective mesh and the
percentage retention of pellets by that mesh calculated.
5. Friability Test:
From each batch, 6.5gms of pellets accurately weighed and
placed in the friability test apparatus (Roche friabilator).
Apparatus was operated at 25 rpm for 4 minutes and
pellets observed while rotating. The tablets were then
taken after 100 rotations, the pellets were taken out and
intact pellets again weighed collectively after removing
fines using sieve#44. % friability calculated as follows

% Friability =(W1 W2) x 100/ W1
Where W1 =Initial weight of the 20 tablets.
W2 =Final weight of the 20 tablets after testing.

Friability values below 0.8% are generally acceptable.

6. In-vitro drug release:
In vitro drug release of the samples carried out using USP-
type 1 dissolution apparatus (Basket type). The dissolution
medium, used was water 900ml (as specified by the office
of generic drugs USFDA), placed into the dissolution flask
maintaining the temperature of 370.5
o
C and 100 RPM.
Accurately weighed pellets were placed in each flask of
dissolution apparatus. The apparatus allowed to run for
24hours. Samples measuring 10ml withdrawn using
cannula attached to a syringe. The samples were filtered
through 45m filter, which was in line with syringe. The
fresh dissolution medium replaced every time with same
amount of sample. Filtered samples were suitably diluted
with water (1ml diluted to 10ml) and analyzed at 226nm.
The cumulative percentage drug release calculated.

Evaluation of tablets:
1. Thickness:
Twenty tablets from the representative sample were
randomly taken and individual tablet thickness measured
by using digital vernier caliper. Average thickness and
standard deviation values calculated.
2. Hardness:
Tablet hardness measured by using Monsanto hardness
tester. From each batch six tablets were measured for the
hardness and average of six values noted along with
standard deviations.
3. Friability Test:
From each batch, ten tablets were accurately weighed and
placed in the friability test apparatus (Roche friabilator).
Apparatus operated at 25 rpm for 4 minutes and tablets
were observed while rotating. The tablets were then taken
after 100 rotations, dedusted and reweighed. The friability
calculated as the percentage weight loss.
Note: No tablet should stick to the walls of the apparatus. If
so, brush the walls with talcum powder. There should no
capping also.
% friability was calculated as follows:

% Friability =(W1 W2) x 100/ W1
Where W1 =Initial weight of the 20 tablets.
W2 =Final weight of the 20 tablets after testing.
Friability values below 0.8% are generally acceptable.

4. Weight Variation Test:
To study weight variation individual weights (WI) of 20
tablets from eachformulations werenoted using
electronic balance. Their average weight (WA) calculated.
Percent weight variation was calculated as follows.
Average weights of the tablets along with standard
deviation values calculated.

% weight variation =(WAWI) x 100/ WA

As the total tablet weight was 120 mg, according to IP
1996, out of twenty tablets 7.5 % variation can be allowed
for not more than two tablets.
According to USP 2004, 10% weight variation can be
allowed for not more than two tablets out of twenty
tablets.

5. In -Vitro Drug Release Characteristics:
In vitro drug release: in vitro drug release of the samples
carried out using USP-type II dissolution apparatus (Paddle
type). The dissolution medium, used was water 900ml (as
specified by the office of generic drugs USFDA), placed into
the dissolution flask maintaining the temperature of
370.5
o
C and 100 RPM. Tablets placed in each flask of
dissolution apparatus. The apparatus was allowed to run
for 24hours. Samples measuring 10ml were withdrawn
using cannula attached to a syringe. The samples filtered
through 45m filter, which was in line with syringe. The
fresh dissolution medium was replaced every time with
same amount of sample. Filtered samples were suitably
diluted with water (1ml diluted to 10ml) and analyzed at
226nm. The cumulative percentage drug release calculated
and compared with the innovator product (Effexor).

Results and discussion:
Pre-Formulation studies:
Table 8: Preformulation Studies of API (Venlafaxine Hydrochloride)

Table 9: Calibration Graph
S.No Concentration
g/ml
UV Absorbance 226 nm
1 0 0.00
2 5 0.1830.02
3 10 0.3580.02
4 15 0.5360.02
5 20 0.7100.02
6 25 0.8910.02

Figure 4: Standard Calibration Curve of Venlafaxine hydrochloride

Pre-Formulation studies
Table 10 : Bulk Density, Tap Density, Carrs Index, Hausners Ratio Of
Venlafaxine Hydrochloride Pellets
Formul
ation
code
Bulk density
(g/ cc)
Tap density
(g/ cc)
Carrs
Index
(%)
Hausners
ratio
F1 0.234 0.220 3.54 0.56
F2 0.324 0.320 3.24 0.43
F3 0.236 0.356 2.93 0.45
F4 0.421 0.254 3.87 0.36
F5 0.286 0.296 4.12 0.78
F6 0.412 0.342 4.23 0.99
F7 0.221 0.456 3.56 0.56
F8 0.332 0.451 4.56 0.68
F9
*
0.61 0.592 5.71 1.06
F10 0.286 0.523 3.67 0.83
F11 0.312 0.561 3.12 0.41
*The pellets were analyzed for the parameters such as bulk density,
tapped density, compressibility index, Hausners ratio and the
results were found to be within the limits.
Bulk density and tapped density values range between 0.446 0.480
gm/ cc and 0.539 0.637g/ cc tabulated and the values were found to
be within limits

Compressibility index has proposed as an indirect measure
of bulk density, size, shape, surface area and cohesiveness
of materials. Compressibility index values ranges between
5-12% for F1 to F11 formulations and the values tabulated.
Hausners ratio it is the ratio of tapped density and bulk
density. Hausner found that this ratio related to
interparticle friction and, as such, could be used to predict
powder flow properties. Generally a value less than 1.25
indicates good flow properties, which is equivalent to 20%
of Carrs index.

Table 11: Particle Size Distribution of Venlafaxine hydrochloride
Sieve number % Cumulative retains
#16 0
#18 2.9
#20 31.0
#25 95.0
#30 100

Formulation development
Based on the literature search and reference product
review, prototype development initiated with preparation
of core spheroids by extrusion spheronization technique
and coating the spheroids with an extended release rate
controlling polymer by wurster process. The composition
is given in table 5.

Pre Formulation Studies
S.No Characteristics Results
1 Nature White
2 Solubility water
3 Bulk Density (gm/ ml)
0.61

4 Tapped Density(gm/ ml) 0.592
5 Carrs Index (%) 5.71
6 Hausners Ratio 1.06
Table 12: Optimization of Microcrystalline Cellulose
Batch details
Trial with45% w/ w MCC in
core spheroids
core spheroids
core spheroids
core spheroids
Observation
Fines generation during
spheronization
Satisfactory spheroids Satisfactory spheroids. Tablet over weight

*From the table 13 it is observed that the spheroids with MCC concentration of 50% and 55% were found satisfactory hence 55% has been finalized.
Table 13: Optimization of Hydroxy Propyl Cellulose
Batch details Trial without HPC
Trial with0.5% w/ w HPC
in core spheroids
Trial with1% w/ w HPC in
core spheroids
Trial with1.5% w/ w HPC in
core spheroids
Observation
More Fines generation during
spheronization
Satisfactory spheroids,
acceptable fines generation
Satisfactory spheroids. Dumble shaped spheroids

Table 14: Selection of Extruder Screen
Batch Details 0.6mm screen 0.8mm screen 1mm screen
Observation
Spheroids found smaller with lesser
yield of #16/ 30 mesh fraction
Spheroids found with optimum
Spheroids found bigger with lesser

Table15: Optimization of Binder Concentration
Medium: Water (900ml)
Apparatus: Basket (100 RPM)
Time
(Hours)
% cumulative drug
Release
Innovator F5(0.5% HPMC) F9(1%HPMC) F4(0.7%HPMC)
2 19 21 21 21
4 38 42 41 41
8 67 67 63 63
12 87 88 86 86
20 103 107 102 102

*No much significant change is observed with change in binder concentration 0.5% is considered as optimum concentration.
Table 16: Optimization of extruder speed
Batch
Details
30 RPM 40 RPM 50 RPM
Observation Satisfactory Spheroids Satisfactory Spheroids Satisfactory Spheroids

Table 17: Selection of Spheronization Plate
Batch Details 2 mm chequered plate 3 mm chequered plate
Observation
Satisfactory spheroids 85% yield of #
16/ 30 mesh fraction
Satisfactory spheroids 85% yield of #
16/ 30 mesh fraction

Table 18 :Optimization of Spheronization Speed and Time
Batch details
Spheronization
Speed(2mm plate)
Time process Physical observation
Extrudates of 0.8mm screen
at 40 RPM
800RPM 30 to 60 sec
Cutting into small pieces
and uniform distribution
of extrudates
Satisfactory spheroids 1700-1800RPM 2 to 3 minutes spheronization
1300RPM 30 sec
Smoothening of
spheroid surface
Table 19: Optimization of spheronization speed and time
Batch details Time
Spheronization
Speed(2mm plate)
Physical observation
Extrudates of 0.8mm
screen at 40 RPM
30 sec
800 RPM
Beadlets
1minutes Beadlets
2minutes Beadlets
3minutes Beadlets
4minutes Dumble shape
Extrudates of 0.8mm
screen at 40 RPM
1minutes
1300 RPM
beadlets
2minutes Beadlets
3 minutes Dumble shape
Extrudates of 0.8mm
screen at 40 RPM
1minutes
1600 RPM
beadlets
4 minutes Spheroids with irregular shape
Extrudates Of 0.8mm
screen at 40 RPM
1minutes
1700 RPM
Beadlets
4 minutes Spheroids (fines generated)
Extrudates Of 0.8mm
screen at 40 RPM
1minutes
1800 RPM
Dumble shape
3 minutes Spheroids but still irregular shape
4 minutes Spheroids (fines generated)

Optimization of sub coating
Medium: Water
Volume: 900ml (Venlafaxine hydrochloride 75mg), Apparatus: Basket (100 RPM)
Table 20:Optimization of sub coating
Time (Hours)
% Drug Release
Innovator
F8
(Without
subcoating)
F7 (3% sub coated) F9 (5% sub coated) F3 (7% sub coated)
2 19 34 31 21 15
4 38 57 55 41 32
8 67 80 78 68 55
12 87 91 90 88 76
20 103 111 110 105 96

Figure 5 : Dissolution Profile of Optimization of subcoating

*From the table 20 and fig.9 it was observed that formulations (F7, F9,
and F3) were sub coated with different concentrations of HPMC and the
dissolution profiles were compared with the Innovator (VENLAR),
formulation F9 showed the similar release profile to that of Innovator
(VENLAR), so formulation F9 was selected as the desired formulation
with subcoating concentration of 5%.

Optimization of Controlled Release Coating Build Up
Medium: Water (900 ml)

Table 21: Optimization of Controlled Release Coating Build Up
Time
(Hours)
% Drug Release

Innovator
F2
16% build up of
EC/ HPMC
F9
16% build up
of EC/ HPMC

F1
24% build up
of EC/ HPMC

2 19 24 21 10
4 38 46 41 32
8 67 69 68 55
12 87 90 88 77
20 103 107 105 94

Figure 6: Dissolution Profile of Optimization of controlled release coating

and F1) were optimized for controlled release coating build up with
different concentrations of 16% build up of EC/ HPMC, and 24% build up
of EC/ HPMC the dissolution profiles were compared with the Innovator
(VENLAR), formulation F9 showed the similar release profile to that of
Innovator (VENLAR), so formulation F9 was selected as the desired
formulation with controlled release coating of 16% build up of EC/ HPMC.

Optimization of Coating and Channeling Agent
Ratio:
Medium: Water (900ml)
Table 22: Optimization of Coating and Channeling Agent Ratio
Time
(Hours)
% Drug Release
Innovator
F10
EC:HPMC
=60:40
F9
EC:HPMC
=60:40
F11
EC:HPMC
=60:40
2 19 25 21 11
4 38 48 41 33
8 67 71 68 60
12 87 93 88 81
20 103 110 105 99

Figure 7: Dissolution Profile of Optimization 0f coating & chanelling
agent ratio

and F11) were optimized for coating and channeling agent ratio with
different ratios of EC: HPMC (60:40), the dissolution profiles were
compared with the Innovator (VENLAR), formulation F9 showed the
similar release profile to that of Innovator (r), so formulation F9 was
selected as the desired formulation with coating and channeling agent
ratio of EC/ HPMC (60:40).

Evaluation tests for the Prepared Venlafaxine
hydrochloride Tablets
Required amount of pellets were taken and mixed with
granular part and extra granular part by mechanical
agitation and compressed into tablets in a 16 mm oval
shaped punch with a compression force of 5KN, the
composition for the tablets was given in table 7.

The compressed tablets were evaluated for various post
compression parameters like weight variation, hardness,
friability etc. The results are shown in table 24.

Table 23: Evaluation tests for the Prepared Venlafaxine hydrochloride
Tablets
Formulations
Weight
variation
(mg)
Friability
(%)
Hardness
(kg/ cm
2
)
Thickness
F1* Passes 0.97 9 6.38
F2 Passes 0.98 8 6.45

*Visually examined tablets from each formulation batch showed (oval)
shaped compressed tablets.

Hardness, friability, thickness, weight variation of each
formulation was analyzed for formulations F1 to F2 and all
formulations were found to have good hardness, friability,
thickness, weight variation, so they were taken for further
studies.

In - Vitro Dissolution Study of Venlafaxine
hydrochloride pellets.
Dissolution Profile:
The dissolution test were carried out in water were taken
at predetermined time intervals and after suitable
dilutions absorbance was measured with the help of UV
spectrophotometer at 226 nm and the percentage drug
released at various time intervals calculated.
Table 24: Dissolution Profile

Time
(hours)
% Drug release
Innovator F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11
2 19 10 24 15 21 21 30 31 34 21 25 11
4 38 32 46 32 41 42 53 55 57 41 48 33
8 67 55 69 55 63 67 74 78 80 68 71 60
12 87 77 90 76 86 88 86 90 91 88 93 81
20 103 94 107 96 102 107 105 110 111 105 110 99
Figure 8: Dissolution Profile comparison of all the formulations of pellets


*Dissolution profile for the formulations (F1, F3 and F11) had poor dissolution profile, formulation (F9) showed good drug result when
compared to that of Innovator (VENLAR 75mg), and so it had been selected as desired formulation for compressing into the tablet
In - Vitro Dissolution Study of Venlafaxine
hydrochloride Tablets.
Table 25 : Dissolution Profile:

Time
(hours)
% Drug release
Innovator F1 F2
2 19 21 19
4 38 41 47
8 67 68 65
12 87 88 86
20 103 105 101

Figure 9: Dissolution Profile comparison of all the formulations of
tablets

*Pellets of formulation (F9) have been selected for compressing into the
tablets, MCC granules are added in equal quantities to the 75mg and
150mg tablets of formulation (F9). The tablet having 75mg (F1) showed
good drug result with the Innovator (VENLAR), when compared with the
formulation (F2).

Summary and conclusion:
Based on the literature search and reference product
review, prototype development initiated with preparation
of core spheroids by extrusion spheronization technique
and coating the spheroids with an extended release rate
controlling polymer by wurster process.
Spheroids with MCC concentration of 50% and 55% found
satisfactory hence 55% has finalized.
Spheroids with HPC concentration of 1% in core spheroids
found satisfactory, hence it has finalized.
Optimization of binder concentration done with HPMC
concentration of 0.5%, 1%, 0.7%. No much significant
change is observed with change in binder concentration
0.5% is considered as optimum concentration.
Optimization of binder concentration done with
concentration of 3%, 5%, 7%.the formulation with 5%
found satisfactory, hence it has finalized.
Optimization of controlled release coating builds up16%
build up of EC/ HPMC of formulation (F9). The result found
similar to that of Innovator (VENLAR 75mg).
The pellets were analyzed for the parameters such as bulk
density, tapped density, compressibility index, Hausners
ratio and the results were found within the limits.
Extended release pellets have minimum volume in size,
greater surface area and more surface activity. The area
of the drug loaded pellets release rate was also more. And
also there was no need of disintegration time for pellets in
capsules. Small volumes of pellets enter into the systemic
circulation very fast. Moreover there was no accumulation
of drug in the body. Drug release rate was more when
compared with the innovator sample.
The Venlafaxine hydrochloride extended release pellets
compressed into the tablets. It showed good results in
formulation of stable dosage. The dissolution profile of the
prepared Venlafaxine hydrochloride extended release
tablets compared with that of Venlafaxine hydrochloride
extended release capsules (Venlar) of the product. The
release found more in the case of pellets loaded in tablets.
The desired formulation was found to be formulation (F9),
due to its release profile was more when compared to the
Innovator (VENLAR) and dissolution profile of Venlafaxine
hydrochloride extended release tablets was compared with
that of innovator (VENLAR). The release was found similar
to that of innovator. So the prepared product said to be
equivalent with innovator.
Finally conclude like extended release pellets in tablets of
formulation (F9) have more drug release rate rather than
innovator (VENLAR) and it have better Bioavailability.
Nowadays Venlafaxine hydrochloride marketed
formulations (VENLAR.VENLEF) loaded in pellets. The
present formulation was compressed into a tablet; it is
more advantageous when compared to the pellets that
loaded in pellets by low cost, less chance of degradation.

References:
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Source of funding: - None
Conflict of Interest: - Not declared.

Corresponding Author:-
M.Srujan Kumar.(Asst.Professor)
Samskruti college of Pharmacy
Kondapur,R.R District,Hyderabad,India-501301.

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