Dhameliya et al Journal of Drug Delivery & Therapeutics; 2014, 4(3), 132-137 132

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RESEARCH ARTICLE

PREPARATION AND EVALUATION OF SUSTAINED RELEASE TABLET OF

EPERISONE HYDROCHLORIDE BY COMPRITOL ATO 888 AS A MATRIX FORMING
AGENT
Dhameliya Pankit B*, Vyas Jigar R, Narola Mahesh, Patel Kinjal, Upadhyay Umesh
Department of pharmaceutics, Sigma Institute of Pharmacy, Vadodara, India, Pin- 390022
*Corresponding Author’s Email: [email protected]

ABSTRACT
Objective: The objective of this work was to prepare and evaluate oral sustained release matrix tablet of highly water soluble
drug and to study the effect of proportion of wax and addition of release liner on in-vitro release of drug.
Method: The matrix tablets were prepared by melt granulation method using drug:wax in 1:1, 1:2 & 1:3 proportions and
evaluated for on in-vitro drug release. Then the proportion 1:1 was selected and wax matrix tablets were prepared by three
techniques melt granulation, wet granulation and direct compression to check their in-vitro release profiles.
Results: The study revealed that Compritol ATO 888 is potent sustained release polymer and released only 72.45% in 24 h
even at 1:1 proportion. So, lactose was added as release liner in further study which helped in achieving complete release in
24h.
Conclusion: The present study has concluded that Compritol ATO 888 can be used as matrix-forming agent to control the
release of a highly water soluble drug such as Eperisone HCl. It was also observed that melt granulation technique was found
more effective. Release liner like lactose may help enhancing the release profile when it is marginally slow.
Keywords: - Eperisone Hydrochloride, Compritol ATO 888, Sustained release, Melt granulation, Release liner

INTRODUCTION
A sustained-release dosage form is defined as “any drug ATO 888 (glyceryl behenate), Precirol ATO 5 (glyceryl
or dosage form modification that prolongs the palmitostearate) can be used for the preparation of
therapeutic activity of the drug”1. Development of oral sustained release dosage forms5. The esterification of
sustained release (SR) tablets of highly water soluble glycerol by long chain fatty acid gives them a
drugs or bioactives has always been a challenge and pronounced hydrophobic character with a low HLB
therefore, opportunity for formulation scientist. Most of value of 2 6. Several techniques including melt
these drugs if not formulated properly, may be released granulation 7, melt pelletization 8, hot melt extrusion 9
at a faster rate resulting in exceeding the maximum and hot melt coating 10 have been used to obtain
therapeutic levels and hence will lead to toxic side sustained release dosage forms from glycerides-based
effects. Sustained delivery of such drugs ensures formulations.
improved drug delivery and patient compliance, greater
Melt granulation (MG) is a solvent-free process which
safety and efficacy, desired release kinetics and helps in
involves the use of a substance that melts at a relatively
maintaining the plasma drug concentration within the
low temperature. This substance can be added in the
therapeutic window for extended period of time2,3.
molten form over the substrate or in the solid form,
Lipids (such as Compritol ATO 888) are considered as which is then heated above its melting point. The
an alternative to polymer in the design of sustained drug substance acts as a liquid binding agent, and the
delivery systems due to their advantages such as the low technique does not require the use of organic solvents.
melt viscosity (thus avoiding the need of organic Moreover, in melt granulation drying is not necessary
solvents for solubilization), absence of toxic impurities and thus, the process is less consuming in terms of time
such as residual monomer catalysis and initiators, and energy compared to other methods 4. Sustained
potential biocompatibility and biodegradability4. release matrix tablets have been produced with
However, research data obtained by experiments suggest Compritol ATO 888 by various methods including MG
11
that Compritol ATO 888 may be recommended as a , wet granulation (WG) and direct compression (DC) 12.
matrix agent in the development of sustained release
formulation in spite of its traditional role as a lubricant.
*For Correspondence:
Lipids like glycerides are a family of excipients which
have generated considerable interest in the preparation of Dhameliya Pankit B.
oral dosage forms. Some glycerides such as Compritol Sigma Institute of Pharmacy, Bakrol, Vadodara, India-390022
(Mob.) 07383337899, Email ID: - [email protected]
© 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO
Dhameliya et al Journal of Drug Delivery & Therapeutics; 2014, 4(3), 132-137 133

Eperisone Hydrochloride, an established Muscle relaxant Wet granulation method: Drug & excipients (except
acts by relaxing both skeletal muscles and vascular magnesium stearate) were blended geometrically in a
smooth muscles and demonstrates reduction of myotonia, mortar and pestle for 15 minutes then wet granulation
improvement of circulation, and suppression of pain was performed by addition of IPA in sufficient quantity.
reflex in case of Spastic paralysis, Neck-shoulder-arm dough mass was passed through 16# sieve (ASTM) and
syndrome, scapulohumeral periarthritis and low back dried at 35-40°C for 15 min. dried granules were passed
pain. The melting point of Compritol ATO 888 and from 40# sieve and compressed into tablets using multi-
Eperisone hydrochloride is 65-77 and 167°C, station rotary tablet compression machine.
respectively. Therefore, it is a thermally stable drug and
Direct Compression method: All the ingredients were
MG technique should not affect the thermal stability of
passed from 60# sieve (ASTM) and directly compressed
the drug. It has a plasma elimination half-life of 1.6-1.87
into tablet using multi-station rotary tablet compression
h with a usual dosage regimen of 50 mg trice daily.
machine.
Therefore, to reduce frequency of administration and
improve patient compliance, a sustained release dosage Evaluation of drug - Excipient interaction: The pure
formulation of Eperisone Hydrochloride is desirable. The drug, wax and the matrix tablet formulation were
drug is associated with certain side effects such as Shock subjected to IR spectroscopy using FT-IR
and anaphylactoid reactions like redness, itching, spectrophotometer (Shimadzu – 8400, Japan). Their
urticaria and Toxic epidermal necrolysis. Therefore, a spectra were obtained over the wave number range of
properly designed sustained release dosage form of the 4000 – 400 cm-1.
drug should also minimize fluctuation in blood
concentration, reduced risk of side effects and show In-vitro drug release: In vitro release studies were
conducted using USP type II paddle apparatus (VDA-6D
uniform pharmacological response 13-15.
USP Std -VEEGO) run at 50 rpm. The buffer was kept at
Sustained release matrix tablets of Eperisone thermostatically controlled temperature of 37±0.5°C. The
Hydrochloride have previously been produced using test was carried out in 900 ml of 0.1 M HCl for 2 h and
hydrophilic polymers like HPMC, HPC 16 The objective then replaced with phosphate buffer (pH 6.8) as the
of the present study was to prepare oral sustained release dissolution medium for another 22 h. The pH change of
matrix tablet of a highly water soluble drug by MG using medium was effected by adding 4.32 g of sodium
Compritol ATO 888, and to evaluate the effect of the hydroxide and 6.08 g of potassium dihydrogen phosphate
concentration of the lipid and presence of release liner on dissolved in 5 ml water to the previous acidic medium
the release of the drug. Such a sustained release (0.1 M HCl) 17. Five milliliters samples were withdrawn
formulation, if achieved, would be substantially more at the time intervals of 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20
affordable than those previously developed. and 24 h and replaced with equal volume of fresh
dissolution medium. The samples were filtered through
METHODS
0.45 µm filter and analyzed for drug content at 260 nm
Materials by UV spectrophotometer.
Eperisone Hydrochloride was a gift from Sharon Bio- The release profile of prepared tablets was matched with
Medicine, Mumbai, India while Compritol ATO 888 was the set values of drug release at different time points,
obtained free of charge from Gattefosse SAS India. Di- mentioned below
Calcium phosphate, magnesium stearate, lactose, Aerosil
Initial 2 h 20-30%
200, isopropyl alcohol, concentrated hydrochloric acid,
At 8th h 50-60%
sodium hydroxide and potassium dihydrogen phosphate
At 14th h 70-80%
were purchased from SD Fine chemicals, Mumbai, India.
At 20th h NLT 85%
Double distilled water (D.W.) was prepared freshly
whenever required. Other chemicals and reagents used Drug release kinetics: To determine the mechanism of
were of analytical grade. drug release from the formulations, the data were
subjected to zero-order (Eq 1), first order (Eq 2) and
Methods
Highuchi (Eq 3) release kinetics 18, 19
Preparation of Eperisone hydrochloride matrix tablets
Mt = M0 + k0t ………………………. (1)
Preparation of wax matrix tablets was done by three In Mt = In M0 + k1t ………………… (2)
methods: MG, WG and DC as follows. Mt = M0 + kHt1/2 ……………...……... (3)
Melt granulation method: The wax(Compritol 888 ATO) where Mt is the cumulative amount of drug released at
was melted in a porcelain dish over a water bath any time, t, and M0 is the dose of the drug incorporated
maintained at 75-80°C for 3 min and Eperisone in the delivery system. k0, k1 and kH are rate constants for
Hydrochloride was gradually added with continuous zero-order, first order and Higuchi models, respectively.
stirring until uniformly mixed. The molten mixture was The dissolution data were also fitted according to the
allowed to cool and solidify at room temperature crushed well-known exponential equation of Peppas 20, as in Eq
in a mortar and passed through a 40# sieve. The granules 4, which is often used to describe drug release behavior
were compressed into flat–faced tablet using multi- from polymeric systems.
station rotary tablet compression machine (Karnavati
Mt/M∞ = ktn…………………….... (4)
engineering Pvt. Ltd. India) at a constant compression
force.

© 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO
Dhameliya et al Journal of Drug Delivery & Therapeutics; 2014, 4(3), 132-137 134

Where, Mt/M∞ is the fraction of drug released at time t, k with elimination rate constant K, one can show that AUC
is the kinetic constant, and n is the diffusional exponent is proportional to the total amount of drug absorbed by
for drug release. The diffusion exponent, n, is dependent the body (i.e. the total amount of drug that reaches the
on the geometry of the device as well as the physical blood circulation). The proportionality constant is 1/K.
mechanism of release. Zero order release describes a
In present study, AUC is calculated for in vitro drug
release rate independent of drug concentration while the
release by plotting graph of %CDR versus time using Eq.
Higuchi square root kinetic model describes a time
(6)
dependent release process. The value of n indicates the
drug release mechanism; if 0.1 < n < 0.5, Fickian t C +C
(AUC)t0 = 0 n n +1 X (t n − t n−1 )
diffusion is indicated while 0.5 < n < 1 indicates non- 2

Fickian diffusion. …………………. (6)

Mean dissolution time: MDT is the mean time for the Where,
drug to dissolve under in vitro dissolution conditions. C = % cumulative drug release,
n
i=1 tmid ΔM t = time point,
MDTin-vitro = n ……………. (5)
i=1 ΔM
AUC was used for the optimization purpose here. %
Where, difference in AUC values can give idea about
i = the sample number, n is the number of dissolution comparative drug release amount in 24h. It was applied
samples, when other statistical parameters were giving similar
results. Here, profiles showing 10% difference in AUC
tmid = the time at the midpoint between i and i – 1, were considered as dissimilar.
M = the additional amount of drug dissolved between i RESULTS AND DISCUSSION
and i-1
Interaction between drug and wax was checked by FT-IR
MDT value is used to characterize the drug release rate Spectroscopy. As shown in Figure 1, the major IR peaks
from the dosage form and the retarding effect of the observed in the spectra for tablet formulation were, the
polymer. As it is readily apparent, the higher the polymer sharp absorption band of the conjugation carbonyl group
level, the higher the value of MDT and the greater the around 1674 (C=O) and 1604 cm−1 (C=C), -N-H stretch
retarding effect of the polymer (21). at 1566cm-1, C-H bend at 1465cm-1, which are
Area under cure: AUC is the area under the characteristic of Eperisone Hydrochloride. When this is
curve (mathematically known as integral) in a plot of compared to the spectra of the formulations, it would
concentration of drug in blood plasma against time. The appear that there was no obvious interaction between
AUC (from zero to infinity) represents the total drug drug and the Compritol ATO 888.
exposure over time. Assuming linear pharmacodynamics

Figure 1: FTIR spectra of Eperisone hydrochloride (A), Compritol ATO 888 (B) and tablet formulation containing all
the Ingredient (C).

Wax matrix tablet of Eperisone Hydrochloride was prepared by MG in three different proportion (1:1, 1:2, & 1:3) and
effect of proportion of wax matrix on in-vitro release profile of drug was studied.

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Dhameliya et al Journal of Drug Delivery & Therapeutics; 2014, 4(3), 132-137 135

Table 1: Composition of Eperisone Hydrochloride matrix tablets

Ingredients F1a F2 a F3 a F4 a F5 b F6 c
Eperisone Hydrochloride 150 150 150 150 150 150
Compritol 888 ATO 150 300 450 150 150 150
Lactose 30 30 30
Polyvinyl pyrrolidone K30 15 15 15
Di-Calcium Phosphate 12 12 12
Magnesium Stearate 3 3 3
Total 300 450 600 360 360 360
* All amount in mg/tablet
To keep the formulation uniform, ingredients required to be added in WG & DC have also been added in MG in F4.
a -Tablets prepared using melt granulation.
b -Tablets prepared using wet granulation.
c -Tablets prepared using direct compression

In-vitro release study revealed that the drug was indicate that sustaining effect from the tablets prepared
72.45±2.9, 56.43±2.3, and 41.66±2.0% cumulative drug by Wet granulation (F5, 99.12% in 20h) and direct
release at the end of 24 h for formulations F1, F2, and compression (F6, 99.25% in 16h) were significantly
F3, respectively. Thus, indicating that drug release fell as higher (p <0.05) than from the equivalent formulation
the wax content of the tablets increased. The difference made by melt granulation (F4, 98.62% in 24h)
in release rate between the batches was statistically
significant (Similarity factor f2 values were 46.86 and 100
32.55 respectively for F2 and F3 with that of F1).
90
% Cumulative Drug Releasse

100 80
90 F1 F2 F3 70
% Cumulative Drug Release

80 60
70 50
60 40
50 30
40
20
30 F4 F5 F6
10
20
0
10
0 2 4 6 8 10 12 14 16 18 20 22 24
0 Time (h)
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h) Figure 3: Comparative in-vitro Release profiles of
sustained release matrix tablet made by MG (F4), WG
Figure 2: Effect of different concentration of Compritol (F5) and DC (F6), in the ratio of 1:1.
ATO 888 on in-vitro release of formulation of eperisone
hydrochloride matrix tablets.
Drug release kinetics: Table 2 shows that the best-fit
release kinetic data with the highest values of regression
As the study aimed to develop 24 h release profile, none coefficient (r2) were shown by Higuchi models and zero
of the above fits completely. But, with change in order. The values of n were in the range of 0.502 to
composition or change in the method, the goal may be 0.693 (i.e., between 0.50 – 0.89) exhibits non-fickian
achieved in 1:1 composition. Further batches were (anomalous) transport in which the drug was delivered
prepared by different techniques like WG, & DC. by combined effect of diffusion and polymer relaxation
Addition of lactose was done as release liner along with (21). Data of r2 indicate that Peppas models also suitably
other ingredient, keeping drug:wax proportion constant described the release of Eperisone hydrochloride from
at 1:1. the matrix tablets. None of the formulation exhibited first
order kinetics.
Optimized proportion was further compared with other
methods like Wet granulation and direct compression
along with addition of lactose as release liner.
Comparison of the three methods of formulation used
© 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO
Dhameliya et al Journal of Drug Delivery & Therapeutics; 2014, 4(3), 132-137 136

Table 2: In vitro release kinetics of Eperisone hydrochloride matrix tablets

Formulation Code F1 F2 F3 F4 F5 F6
Zero order 0.876 0.898 0.932 0.925 0.865 0.856
Fist order 0.719 0.737 0.684 0.722 0.621 0.655
Higuchi 0.991 0.996 0.994 0.997 0.983 0.980
Peppas Model r2 0.99 0.994 0.979 0.991 0.945 0.956
N 0.502 0.521 0.693 0.611 0.624 0.593
K 16.26 11.46 5.28 15.35 18.37 22.80
AUC 1237.31 935.24 654.27 1347.47 1602.97 1559.65
MDT 15.11 22.34 35.9 8.19 5.83 4.42

Influence of proportion of Wax on in-vitro drug 100

Release. 90

% Cumulative Drug Release

As shown in figure 2 as ratio of polymers increased from 80
1:1 to 1:3, it resulted into greater retardation of drug
release. This might be due to an increased polymer 70
concentration resulting in a decrease in the total porosity 60
of the matrices (initial porosity plus porosity due to 50
dissolution of the drug), decreasing the penetration of the
dissolution medium into the matrix system and thus 40
reducing drug dissolution. In addition, increasing the 30
polymer content led to an increase in the drug diffusion 20
path length, which in turn retarded drug diffusion from F1 F4
the matrix 21. As stated earlier, based on kinetic analysis 10
of release data, Eperisone hydrochloride release occurred 0
by a non-Fickian diffusion mechanism. The initial drug 0 2 4 6 8 10 12 14 16 18 20 22 24
release (i.e., in the 2 hour) of 23.80, 33.74, and 40.62% Time (h)
for F4, F5 and F6, respectively, may be attributed to
„burst‟ release of the drug on the tablet surface Figure 4: Comparative in-vitro release profile of F1 and
irrespective to method of formulation. F4 to study influence of Lactose on release

Influence of method of formulation on Release Influence of release liner on in-vitro drug Release.
Influence of method of formulation on Release was also As shown in figure 4 addition of 10% lactose as release
studied. Results obtained from DC and WG method liner can give significant (26.17%) rise in release. F4
indicated negligible role of binding agent in release gives high initial release as well as higher release of drug
retardation, thus suggesting use of MG as the most over the time range of experiment. However, release of
effective method in sustaining Eperisone hydrochloride both batches matches to zero order and higuchi kinetic
release. Figure 3 shows release profile of Compritol data. Still MDT decreases from 15.11h to 8.19h at the
ATO 888 in 1:1 ratios prepared by MG (F4), WG (F5) same wax concentration as lactose was added.
and DC (F6). These results are in accordance with Thus, the effect of additives like lactose, MCC, DCP on
previously published results. 12, 21 In case of MG, lesser release of drug from matrices has been well established
drug release is occurring because of complete and proper and it is also known to control and differ the initial
coating of melted wax on drug particles which forms release & release over time period. In present research
uniform hydrophobic wax matrix through the tablet. So, and Studies done before shows that by including water
here penetration of dissolution medium to the matrix will soluble diluents such as lactose, near zero order release
be low hence dissolution occurs at slower rate. However, also can be achieved from matrix system 12, 21. The
in case of matrices prepared by DC or WG, it seems that overall mechanism of release of the drug from glyceryl
the dissolution of drug particle at surface of matrices behenate matrices appeared to be a diffusion-controlled
allowed the establishment of channels through which mechanism. The data of drug release were fitted to the
drug was released. Higuchi's square root of time model. The mechanism of
Relative retardation can be ranked depending upon this evidence indicated that the prepared tablets behaved
method of formulation as – as inert matrices. Visual observation of the tablets during
the dissolution studies revealed that the tablets remained
Melt granulation> Wet granulation> Direct compression intact without any significant change in their shape.
These observations support our conclusion that the
release of the drug is mainly due to diffusion through the
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Dhameliya et al Journal of Drug Delivery & Therapeutics; 2014, 4(3), 132-137 137

channels formed in the matrix. These channels are (non-fickian) and achieves almost near to zero order in
formed due to rapid dissolution of the drug particles on all the formulations.
the surface of the matrix and the presence of the water-
MG technique fits completely into the predetermined
soluble release enhancers like lactose. Then, the
parameter and criteria whereas, other two techniques
dissolution medium would penetrate these channels
lack behind. Extended release profiles can be achieved
allowing for more dissolution of the drug present in the
by any of three methods using Compritol ATO 888 at
deeper sites of the matrix.
higher proportion but MG technique achieved 24 h
It was observed that the values of AUC were higher release profile with lesser amount of was as compare to
when lactose was added in formulation F4 to F6. WG other methods.
method was showing highest value of 1602.97 but, it
ACKNOWLEDGEMENTS
could not retard the release upto 24 h. However, MG
process was found to be best fitting to all other criteria The authors are grateful to Sharon bio-Medicine,
with satisfactory AUC value of 1347.47 which was Mumbai, India for providing, gift sample of Eperisone
found best among all other formulations. hydrochloride, and Gattefosse SAS, India for the gift
sample of Compritol ATO 888.
CONCLUSION
CONFLICT OF INTEEREST
The study showed that Compritol ATO 888 is an
appropriate waxy matrix former for sustained release of The authors confirm that this article content has no
highly water-soluble drug such as eperisone conflict of interest.
hydrochloride. Drug release was diffusion-controlled

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