Formulation of Multi-Unit Tablets Combining

Pulsatile and Sustained Effects of a Model Drug

for the partial fulfillment of master degree in pharmaceutical sciences
(Industrial Pharmacy)

A Thesis Presented by

Kirolos Raafat Habib Georgy

Under the Supervision of

Prof. Dr. Ehab Rasmy Bendas

Professor of Pharmaceutics and Industrial Pharmacy
Faculty of Pharmacy
Cairo University

Asst. Prof. Dr. Randa Latif Aziz

Associate Professor of Pharmaceutics and Industrial Pharmacy
Faculty of Pharmacy
Cairo University

Asst. Prof. Dr. Ragwa Mohamed Farid

Associate Professor of Pharmaceutics and Pharmaceutical Technology
Faculty of Pharmacy and Drug Manufacturing
Pharos University in Alexandria

Department of Pharmaceutics and Industrial Pharmacy

Faculty of Pharmacy
Cairo University
2019
 Abstract
Oral drug delivery is the most convenient route of drug administration. More
efforts were performed to optimize this route for therapeutic maximization and
side effects minimization. Controlled drug delivery was developed to enhance
drug performance and increase patient compliance. There are several factors
affecting the anticipation of developing oral modified release systems. Such
factors are either drug or polymer related.

The aim of the present work is to formulate and evaluate controlled release oral
dosage forms of etodolac through the manipulation of different formulation
parameters to achieve the optimized formulation owning pulsatile and sustained
drug delivery. Etodolac was formulated with different polymers (Eudragit® and P P

HPMC) at different ratios.

The work in this thesis was divided into three chapters:

Chapter one: Formulation and Evaluation of Etodolac Hydrophilic Matrix

Controlled Release Dosage Forms; Fast and Sustained Release Formulations

Different etodolac formulations were prepared and the resultant dosage forms
were evaluated for their physical properties and drug release profiles.
Superdisintegrants as sodium starch glycolate and croscarmellose sodium were
added in varying ratios for discovering their effect on fast release tablets. Starch
was also added as a disintegrant to quicken the tablet disintegration and hence the
drug release. Eudragit® RSPO and Eudragit® RLPO were incorporated, whether
P P P P

separately or in combination, to test the impact of methacrylic acid derivatives

polymers on sustaining etodolac release from the matrix tablet. HPMC was added
to certain formulations to yield more sustained etodolac release effect. The
optimized fast and sustained release formulations were selected for further
studies. All formulations were subjected to pre- and post-formulation tests. DSC
and FT-IR tests were performed to study whether there were any interactions
between the etodolac and the added excipients.

Results of this chapter showed that:

 All formulations, either fast or sustained release, possessed good flowability

parameters represented in small angle of repose, optimized values for Carr’s
index and Hausner’s ratio. Also, these formulations passed post-compression
tests represented in weight uniformity, thickness uniformity, diameter
uniformity, hardness and friability.
 PEG 6000 was added to etodolac (1:1), and mixing was performed by solid
dispersion technique using the solvent evaporation method to increase the
wettability of the etodolac particles which resulted in enhanced drug solubility.
 Increasing the starch amount in the tablet accelerated the tablet disintegration.
 The same concept was detected in superdisintegrants where increasing the
percentage of sodium starch glycolate in the formulations speeded the tablet
disintegration and subsequently the drug release.
 In-vitro release studies of fast release formulations showed that starch caused
lower acceleration in drug release than sodium starch glycolate and
croscarmellose sodium.
 Inclusion of croscarmellose sodium in the tablets quickened the drug release
but to a limited extent i.e. tablet disintegration was faster until reaching certain
concentration of croscarmellose sodium above which the disintegration was
not quickened.
 The incorporation of Eudragit® RSPO and Eudragit® RLPO resulted in
P P P P

extending the etodolac release time due to their ability to swell and release the
drug slowly by diffusion. Eudragit® RSPO showed better ability in sustaining
P P

the drug release than Eudragit® RLPO.

P P
 The addition of Eudragit® RLPO to Eudragit® RSPO resulted in decreasing the
sustained effect. This was a result of increasing the hydrophilic groups (from
Eudragit® RLPO) in the tablet matrix.
P

 The addition of 10% HPMC prolonged the etodolac release period. In contact
with water, HPMC swelled forming a viscous gel layer around the tablet, which
decreased its hydration and hence the pores formation inside the gel layer.
Erosion of the tablet occurred after complete hydration of HPMC and
Eudragit® polymers. Tablets containing HPMC and Eudragit® showed better
sustained release of etodolac than those containing Eudragit® only.
P P

 The in-vitro release profile of formulations containing 10% HPMC with

Eudragit® were found to be highly retarded, so all these formulations were
escalated for further studies.
 DSC study showed the disappearance of the endothermic peak of etodolac in
solid dispersion due to its solubility in PEG 6000 at its melting point.
 FT-IR tests were performed on the drug and excipients, and the results
suggested that no significant interaction took place between etodolac and any
of the excipients.

Chapter two: Formulation and Evaluation of Etodolac Coated Bilayer

Tablet Matrix System Combining Pulsatile and Sustained Release Effects

The fast and sustained release formulations chosen from the previous chapter
were compressed together forming bilayer tablets. The sustained release
formulation was first compressed into the first layer, then the fast release
formulation was placed above the first layer and compressed again forming the
double-sided bilayer tablets. In-vitro drug release study was performed on the
bilayer tablets. Evaluation of post-compression tests were performed on the
tablets. The optimized bilayer formulation passed through three successive
coating processes, starting with 10% Opadry® II forming an isolation layer, then
8% HPMC to form swellable layer, and finally Surelease® (10% ethyl cellulose)
to form the outer rupturable layer. The coated tablets were also subjected to in-
vitro release study and post-compression tests. Surface topography was studied
using a scanning electron microscope.

Results of this chapter showed that:

 The fast release layer of the bilayer tablet was completely disintegrated within
15 minutes. This was visually detected through the individual layer coloration.
 The in-vitro release profile of the uncoated bilayer tablets showed rapid drug
release of the fast release layer containing either 15 mg of croscarmellose
sodium or 40 mg of sodium starch glycolate. The optimum fast release layer
containing 40 mg of sodium starch glycolate was chosen. The sustained release
layers were tested and the optimum formulation was found to contain 400 mg
of Eudragit® RSPO and 160 mg of HPMC.
 Successive coating processes resulted in the creation of two hours of lag time
prior to the beginning of the drug release. The Surelease® (ethyl cellulose) was
furtherly ruptured, also HPMC undergo swelling. The swelling and erosion of
the coating layers, permeation of dissolution medium to the matrix core, and
outward diffusion of drug solution consumed at least two hours represented as
lag time.
 Regarding swellable layer, the addition of small portions of higher grade
(HPMC K 4 M) was found to prolong the lag time to reach four hours. This was
R R

due to the increase in the viscosity of the formed gel layer resulting from the
added HPMC.
Chapter three: In-vivo Comparative Study of optimized Etodolac
Formulation and Conventional Tablet

Optimized tablets were tested in rats. Special 6 mm tablets were manufactured in

order to be safely administered by the rats. The rats were divided into three sets;
the first set received no treatment, the second set received conventional ETD
tablets, and the third set received optimized tablets. Induction of inflammation
was performed by injecting the rats’ right hind paws with formaldehyde.
Assessment of the anti-inflammatory activity of the tablets was performed
through the determination of the percentage maximum possible effect and
monitoring the swelling degrees.

Results of this chapter showed that:

 In-vivo testing of the optimized coated bilayer tablet showed no activity in

decreasing the inflammation in rats’ hind paws in the first hour, this could be
due to the coating of the tablets. At the second hour there is a marked
decrease in the edema of the paw indicating the disintegration and release of
the fast release layer. Gradual inflammation diminish was detected
represented in decreased oedema with time till the end of the six hours.
 Introduction
Tablet disintegration is an essential step in achieving fast drug release from the
matrix system. Disintegration of the system ensures its availability for
dissolution. Disintegrants are materials incorporated into tablets or capsules to
facilitate their breakup into small fragments. These fragments will easily dissolve
in the surrounding aqueous medium due to the increase in their surface area.
Disintegrants promote the penetration of moisture into the tablet matrix. Tablets
prepared by granulation method have their disintegrants added in two steps;
extragranularly and intragranularly. This causes first the splitting of tablet into
granules, then the dissolution of the granules.

Recently, new excipients were developed named as “Superdisintegrants”. These

excipients showed more effectiveness in disintegration at lower concentrations
than ordinary disintegrants. Superdisintegrants exert their activity due to dual
effects; water absorption and swelling. Swelling increases the surface area of the
particles, which promotes the wettability and dispersibility of the system.
Disintegration and dissolution are enhanced by superdisintegrants.

There are different mechanisms by which superdisintegrants perform their action.

The most common mechanism is the swelling. Swelling is associated with
dimensional amplification of disintegrant particles. This results in the breakup of
tablet matrix. Several factors affect the swelling ability of disintegrants. The most
prominent among these factors are the chemical structure and the crosslinking
degree. The porosity also plays an important role in their performance, where low
porosity matrices show better disintegration than high porosity ones.

Another mechanism of disintegration is wicking. It can be defined as the entrance

of surrounding liquid through capillarity to displace the entrapped air. Water
imbibition is a pre-requisite to the wicking disintegration. Strain recovery is
considered a disintegration mechanism. During tablet manufacturing, the
constituents are subjected to high compression force. This may cause deformation
of particles and bogus hardness. Upon contacting aqueous medium, the
disintegrant particles restore their original shape causing matrix fragmentation.

Starch has a definite chemical structure. It is found mainly as a polysaccharide in

seeds, stems and roots of plants. Native starches were used as disintegrants.
However, modified starches are generally used as superdisintegrants in
immediate release formulations. Modification processes include grafting,
acetylation and phosphate ester derivitization. Gums obtained from natural plant
origins are also used as disintegrants. Natural gums possess many advantages as
being biodegradable, non-toxic and low costing in addition to being edible. Gums
absorb water and swell causing tablet disruption. They are able to swell up to 5
times their original volume, which leads to tablet breakage. The used gums
include gellan gum, leucaena seed gum, agar and guar gum.

Although swelling accelerates the drug release in some cases, it may also have an
inverse role in extending the drug release. HPMC is a semi-synthetic polymer that
is widely used in the pharmaceutical industry. It has the ability to swell in the
presence of the dissolution medium. The swelling behavior of HPMC containing
tablets was examined. When the matrix gets in contact with the dissolution fluid,
water penetrates to the inside of the matrix and swells the macromolecular chains.
The swelling is observed by the formation of distinct front that is able to separate
the swollen and non-swollen regions. During swelling, the swelling front
separates the rubbery region (where swollen HPMC have its temperature
exceeding Tg) and the glassy region (where the experimental temperature of
HPMC does not reach Tg). The erosion front is another front separating the matrix
from the solvent. A gel layer is formed on the glassy core of the swollen matrix.
This layer is the controlling factor of the drug release kinetics. The layer
undergoes several changes in the structure and composition. This can be due to
the molecular extension of the solvated polymeric chains. The swelling and
erosion fronts control the thickness of the gel layer. The diffusion front separating
the dissolved and undissolved drug particles is dependent on the drug solubility,
in addition to the loaded amount. At the end, diffusion and erosion front partitions
identify the drug’s dissolved gel layer. HPMC was widely tried to sustain the drug
release of different drugs. It has been conjugated with diclofenac sodium and
chondroitin sulfate. Chavanpatil et al., used HPMC to sustain the drug delivery
of ofloxacin. Sustained release matrix tablets of nicorandil was formulated using
celluslose polymer inculding HPMC. HPMC and MCC were used by
Basak et al., in the manufacture of sustained release tablets of ambroxol
hydrochloride.

Polyacrylates and polymethacrylates are mainly branded as Eudragit®. Numerous

grades of Eudragit® are commercially available in the form of powder, spheres,
aqueous dispersion or organic solution. The most commonly used Eudragit®
grades in modified drug release are Eudragit® L, Eudragit® RL, Eudragit® RS,
Eudragit® RLPO and Eudragit® RSPO. Eudragit® RS & Eudragit® RL are
ammonium salts of methacrylate polymers. The difference between these two
grades is the percentage of quaternary ammonium groups. Eudragit® RS contains
10% of quaternary ammonium groups, while Eudragit® RL contains 5% only.
The presence of these groups provides the polymer with the property of being
pH-independent. Eudragit® RS acquires less permeability compared to Eudragit®
RL. Recent studies showed that Eudragit® RS and Eudragit® RSPO caused slower
drug release than Eudragit® RL and Eudragit® RLPO, respectively. The drug
release from Eudragit® polymers is controlled by diffusion mechanism. Eudragit®
RSPO and Eudragit® RLPO was used in combination with other polymers and
coating materials for the manufacturing of once-daily sustained release tablets of
venlafaxine hydrochloride. The same combination was tried in formulation of
metoclopramide hydrochloride in sustained release matrix. Recently,
Ahmed and Nath observed that the inclusion of Eudragit® RSPO in a matrix
system of nicorandil increases its lipophilicity. This results in the decrease of
interfacial area between the drug particles and the dissolution medium leading to
low liquid penetration into the matrix. As a result, drug diffusion rate from the
matrix system decreases.

The work in this chapter comprises the formulation and evaluation of fast and
sustained release tablet formulation, in addition testing of evaluation of physico-
chemical characteristics of the drug and excipients. Then the production and
evaluation of bilayer tablets, followed by coating by three successive layers and
evaluation of the coated tablets.
 Aim of Work

The main objective of the present work is to provide fast and sustained drug
release for the management of night and morning symptoms of rheumatoid
arthritis, beside the protection of the stomach from the undesirable adverse effects
of the anti-inflammatory drug. This will be done through the formulation of a
bilayer tablet with fast and sustained release layers, followed by multiple coating
processes to prevent the drug release in the stomach. Solubility of etodolac is
enhanced through solid dispersion of the drug with PEG 6000. Superdisintegrants
are used in different quantities to achieve rapid release of the fast release layer.
Different polymers are mixed in different ratios to extend the drug release over
prolonged period of time. All ingredients are tested physicochemically to detect
any incompatibility.

The optimized individual layers and bilayer tablets are tested for their release,
hardness, friability and disintegration. Imaging of the optimized bilayer tablet is
done using a scanning electron microscope. In-vivo evaluation of drug action is
finally performed.

Therefore, the work in the thesis is divided into two chapters:

Chapter I: Formulation and Evaluation of Etodolac Hydrophilic Matrix
Controlled Release Dosage Forms; Fast and Sustained Release
Formulations

Chapter II: Formulation and Evaluation of Etodolac Bilayer Tablet Matrix

System Followed by Coating Processes

Chapter III: In-vivo Comparative Study of optimized Etodolac Formulation

and Conventional Tablet
 Review
From the obtained results in the current study, it could be concluded that:
 Solubility of etodolac in water was enhanced by 18 folds through the solid
dispersion by solvent evaporation method using PEG 6000 in ratio 1:1.
 DSC and FTIR confirmed no incompatibility.
 The incorporation of superdisintegrants as SSG or CCNa resulted in rapid
disintegration of tablets with the release of drug in 0.1 N HCl within
15 minutes, while starch was not able to show the same disintegration effects.
 Increasing the concentration of SSG led to faster dissolution and the same for
CCNa but to limited extent. Faster drug dissolution could be achieved by
increasing the CCNa concentration until reaching a certain concentration above
which the dissolution rate was not affected.
 Incorporation of either Eudragit® RSPO or Eudragit® RLPO in tablet
formulation caused sustained ETD release due to their ability to swell. Upon
hydration, pores were formed in the tablet surface and the drug was released
by diffusion.
 Eudragit® RSPO showed better sustaining activity than Eudragit® RLPO as a
result of having less quaternary ammonium groups, and subsequently less pore
formation.
 Addition of Eudragit® RLPO to Eudragit® RSPO resulted in lower sustaining
activity than Eudragit® RSPO alone due to the hydrophilic nature of Eudragit®
RLPO that resulted in hydration and hence higher water absorption capacity.
 The addition of HPMC as a hydrophilic polymer succeeded in sustaining ETD
release with Eudragit® RSPO and Eudragit® RLPO due its high swelling
ability. Swelling of HPMC led to the formation of firm gel layer of around the
tablet. This viscous layer sustained the hydration of Eudragit® and hence the
pore formation and ETD release. Erosion of the tablet occurred after complete
hydration of HPMC and Eudragit® polymers. Tablets containing HPMC and
 Eudragit® showed better sustained release of ETD (>20 h) than those
containing Eudragit® only.
 The FR layer was disintegrated completely in 15 minutes leaving the SR layer
unaffected. The FR layer was intentionally colored for visual monitoring after
placement in the dissolution medium.
 The incorporation of 15 mg of CCNa or 40 mg of SSG caused complete FR
layer disintegration in 15 minutes. The release behavior varied according to the
composition of the SR layer.
 The bilayer tablet containing 40 mg of SSG in its FR layer, while its SR layer
carrying 400 mg of Eudragit® RSPO and 160 mg of HPMC was chosen as the
optimum bilayer tablet formulation.
 Triple coating processes was performed to apply three sequential layers. The
innermost layer is an isolation layer (Opadry® II), followed by the swellable
layer (HPMC E 5 and K 4 M), and finally rupturable layer (Surelease®) in the
R R R R

outer surface.
 The coating layers resulted in the foundation of two hours of lag time before
the beginning of ETD release.
 The incorporation of HPMC K 4 M in the swellable layer prolong the lag time
R R

from 2 hours to 4 hours.

 The selected formulation C2 showed remarkable anti-inflammatory activity in
rats. It revealed sharp decrease in the swelling degree after an hour which is the
lag time because of the FR layer, followed by more decrease in the swelling
degree due to the SR layer. The swelling of the rats’ right hind paws decreases
over a period of 6 hours.
 Summary
Formulation of Multi-Unit Tablets Combining Pulsatile and Sustained
Effects of a Model Drug

The main goal of this work is to formulate bilayer tablets combining pulsatile and
sustained effects of Etodolac (ETD) through the application of superdisintegrants
and polymers of different types, grades and amounts in order to control the drug
release at specific time points. ETD belongs to NSAIDs and perform its effect
through the inhibition of cyclooxygenase-2 pathway, ETD has low solubility due
to poor wettability. The work in this thesis comprised the preparation and
evaluation of coated bilayer tablets for the management of the symptoms
associated with rheumatoid arthritis beside avoiding the adverse effects of ETD
on the stomach. Mixing of ETD with PEG 6000 using a solid dispersion technique
by a solvent evaporation method was performed to increase the wettability of
ETD particles and hence enhance its solubility. The pre-compression, post-
compression and in-vitro evaluation for the optimized formulations were
performed. In-vivo assessment of the optimized formulation was performed on
rats.

Keywords: Multi-Unit tablets, etodolac, pulsatile, sustained, oral.

 Conclusion
The optimized tablet achieved three major goals. It ensures stomach protection
by avoiding the drug release for at least 4 hours. After this period of time, it
releases its FR layer quickly to avoid any sleep disturbance that may affect the
patient. Finally, it keeps releasing the SR over the morning to avoid joint stiffness
in the morning. The optimized tablet offers quiet continuous sleep, in addition to
pain-free morning.