ISSN: 2319-5894

Pharma Utility Volume 6, Issue 3, 2012

Original Research Article

Development and evaluation of sustained release wax matrix tablet of
Cyclobenzaprine Hydrochloride
Authors: Paresh R. Mahaparale* and Bhanudas S. Kuchekar1
*Padm. Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune, MS, India, Pin- 411 044
1
MAEER’S Maharashtra Institute of Pharmacy, Pune, MS, India, Pin- 411 038

ABSTRACT
Cyclobenzaprine hydrochloride is a centrally acting skeletal muscle relaxant. Drug is highly
water soluble and comes under BCS class I. Sustained release wax matrix system of drug was
developed using Compritol and Hydrogenated vegetable oil by melt granulation method. From
study it was observed that sustained release matrix tablet prepared using hydrogenated vegetable
oil retarded more release of drug, may be due to more hydrophobicity of hydrogenated vegetable
oil.
It was observed that when wax was used in lesser concentration can not retard release of drug
and when it was used in higher concentration, the initial release of drug not occur properly and
even and complete release of drug not occurs. Hence lactose was used as release liner in wax
matrix system. It was found that lactose acts as good release liner and showed desired release
profile of drug. This may be due to solubility of lactose and formation of aqueous channel in wax
matrix system which causes uniform release of drug.
Effect of sintering temperature and time was studied. It was observed that temperature of 800c
for an hour is sufficient to sustain the release of drug. This may be due to melting of wax at
800c.There was no significant effect of sintering time at 800c.

Keywords: Compritol, Hydrogenated Vegetable Oil (HVO),

Cyclobenzaprine hydrochloride, Melt granulation.

*Address for Correspondence

Prof. Paresh R. Mahaparale,
Padm. Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune, MS, India, Pin- 411 044
Mobile +919822623781
Email id- [email protected]

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Pharma Utility Volume 6, Issue 3, 2012

INTRODUCTION
Cyclobenzaprine hydrochloride is a centrally acting skeletal muscle relaxant. It is freely soluble
in water and drug comes under BCS I system. Estimates of mean oral bioavailability of
Cyclobenzaprine ranges from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics
over the dose range 2.5 mg to 10 mg. It is prescribed three times a day. Thus it is necessary to
develop a sustained dosage form with reduced risk of drug administration, side effects and
patient compliance [1-3].
Hydrophobic materials have major application in sustained release system, especially for highly
water soluble drugs. Such hydrophobic material provide several advantages like fewer
processing steps, less time required, solvent or water is not required ranging from good stability
at varying pH value and moisture levels to well established safe application in human. Matrix
delivery system using hydrophobic materials usually employ a core of drug embedded in the
hydrophobic material which is in the molten form. Melt granulation is the method in which drug
is dispersed in molten wax matrix system. The various meltable substances used for the sustained
drug delivery systems are Bees wax, Carnauba wax, Glyceryl Behenate (Compritol 888 ATO),
Glyceryl Palmitostearate (Precirol ATO 5) and Hydrogenated Vegetable Oil. Due to
hydrophobicity of wax substances, it can retard release of BCS class I drug for more time[4,9]
In present work an attempt has been made to develop extended release (modified release) tablets
of Cyclobenzaprine hydrochloride by melt granulation technique using different hydrophobic
matrix substances. Hydrophobic substances namely Compritol 888 ATO and Hydrogenated
Vegetable oil (HVO) were used for the formulations.

MATERIALS AND METHODS

Materials
Cyclobenzaprine HCl and Hydrogenated vegetable oil was obtained as a gift sample from Lupin
Research Park (Pune) . Compritol 888 ATO was obtained from Gattefosse Corporation, Frnace
through Colorcon Asia Pvt Ltd (Goa). Other excipients like lactose, DCP, Avicel PH 101 was
obtained from Signet chemical corporation Ltd. (Mumbai.).

Drug excipient compatibility study (FTIR Spectroscopy)

Drug excipient compatibility study was carried out using FTIR Spectroscopy (Shimadzu).

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Preparation of Sustained Release Matrices by Melt Granulation Technique

The waxy substances like Compritol 888 ATO and HVO were respectively melted in porcelain
dish on a water bath maintained at constant temperature as per their melting points.
Cyclobenzaprine HCl was gradually added to the molten wax with continuous stirring. The
molten mixture was allowed to cool and solidified at room temperature. The solidified mass was
pulverized in mortar and passed through sieve no. 22. The obtained mass was compressed to
prepare tablet. In order to study the effect of different wax substance, different ratio of drug :wax
(1:3, 1:4) were prepared (Table 1)[8,10].. Formulations were also prepared using different
excipients. Also one formulation was prepared using direct compression to study effect sintering
temperature and sintering time[5,13].

Table 1: Formulations of Cyclobenzaprine Hydrochloride by melt granulation method

Formulation ingredients C1 C2 C3 C4 C5 C6 C7 C8 C9 C10

Cyclobenzaprine HCl 30 30 30 30 30 30 30 30 30 30

Compritol 888 ATO 90 120 120 120 120 120

Hydrogenated Vegetable Oil (HVO) 90 120 120 120

Avicel PH 101 100

Dicalcium phosphate 100

Lactose 50 100 50 100

In vitro Dissolution Studies

In vitro drug release study for the prepared matrix tablets was conducted for period of 16 hours
using a six-station USP XXIII type II (paddle) apparatus at 37°C ± 0.50C at 50 rpm. The
dissolution studies were carried out in 900 ml of 0.1N HCl, under sink condition. At
predetermined time intervals, 10 ml aliquot samples were withdrawn from the dissolution
medium and immediately replaced by the same volume of fresh medium.
The volume were filtered through 0.45µm membrane filter (Milipore) and measured
spectrophotometrically at 290 nm for the content of Cyclobenzaprine HCl using UV
Spectrophotometer (Shimadzu model 1700)[3].

Stability Study
In the present work, stability study was carried out on formulation C4 at 40°C ± 2°C, RH 75% ±
5% conditions for 90 days[15].

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RESULTS AND DISCUSSION

Drug excipient compatibility study (IR Spectroscopy)
From FTIR study, it was observed that there was no interaction between drug and wax substance
(Fig. 1). Characteristic peaks of drug were observed in melt granulated mass also.

Fig. 1: Drug excipient compatibility study (FTIR)

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Dissolution Study:
Table 2: Dissolution data of formulations

Time (Hrs) C1 C2 C3 C4 C5 C6 C7 C8 C9 C10

1 24.735 14.906 25.964 28.994 19.985 22.606 18.52 12.531 15.432 24.981

2 30.989 15.891 31.248 39.8 25.121 29.573 23.65 13.04 21.97 30.173

4 45.505 19.7 42.82 54.561 40.317 46.834 35.65 14.964 32.077 42.194

8 63.549 27.566 63.138 70.78 53.766 61.11 53.12 20.545 50.65 60.84

12 76.12 35.23 75.23 86.23 65.12 76.12 65.22 27.85 64.85 77.62

16 88.56 43.45 84.56 97.93 75.85 87.35 78.62 35.23 75.56 88.23

t 50 4.9 -- 4.2 3.7 7.2 5.8 7.4 -- 8 5.9

t70 10.1 -- 8.9 8 14.7 11.3 13.8 -- 14.7 10.4
t90 -- -- -- 14.7 -- -- -- -- -- --
Best Fit model Matrix Matrix Matrix Matrix Matrix Matrix Peppas Matrix Matrix Matrix

Table 3: Effect of sintering temperature and sintering time on optimized formulation

Effect of sintering temperature (C4) Effect of sintering time at temp 80°C (C4)
Time (Hrs)
60°C 70°C 80° C 1 Hours 2 Hours 3 Hours

1 56.32 33.28 29.16 29.16 28.57 26.92

2 80.41 43.46 41.06 41.06 41.83 41.49

4 98.74 57.92 53.09 53.09 52.97 51.67

8 -- 81.79 72.92 72.92 71.48 70.29

12 --- 97.92 89.93 89.93 87.92 85.17

16 --- --- 98.97 98.97 97.73 97.02

t 50 0.89 3.4 3.7 3.7 3.8 3.9

t70 1.3 5.9 7.7 7.7 7.8 8
t90 3.7 10.2 12 12 12.6 13.1
Best Fit Model First order Matrix Matrix Matrix Matrix Matrix

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Effect of different wax on release profile of drug:

The tablet prepared using hydrogenated vegetable oil was found to retard more release of drug as
compared to Compritol. It may be attributed to slower penetration of dissolution medium in
matrices due to more waxy nature (hydrophobicity) of HVO[7,12] (Fig. 2).

100
90
Cumulative %drug release

80
70
60
50 C1(Compritol)
40 C7(HVO)
30
20
10
0
0 2 4 6 8 10 12 14 16 18
Time in hours

Fig. 2: Effect of type of wax on release profile of drug

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Effect of drug: wax ratio on release profile of drug:

The sustained release wax matrix tablet was prepared using ratio of 1:3, 1:4 for each wax. The
drug retardation effect increases with increase in drug: wax ratio for all waxes. At lower ratio of
wax, release cannot get retarded may be due to very high solubility of drug[7,8] (Fig. 3).

100
90
Cumulative % drug release

80
70
60 C1(compritol 1:3)
50 C2(compritol 1:4)
40 C7(HVO 1:3)
30
C8(HVO 1:4)
20
10
0
0 2 4 6 8 10 12 14 16 18
Time in hours

Fig 3: Effect of drug: wax ratio on release profile of drug

To study the effect of excipients on release profile of drug:

Excipients like Microcrystalline cellulose, Dicalcium phosphate, Lactose were used as diluents
for wax matrix tablet. Sustained release wax matrix tablets prepared with lactose showed faster
release, this may be due to formation of pores or channels due to dissolution of lactose. Along
with dissolution of lactose tablet also gets eroded and hence release was found to be faster. Wax
matrix tablets containing MCC as an excipient showed somewhat faster release as compared to
DCP as an excipient. This may be due to swelling property of MCC which causes crack and
channel formation and dissolution of drug. DCP can retard release of drug due to its insoluble
tendency (Fig. 4). The release of wax matrix tablet showed more sustained release than wax
matrix tablet containing excipient. In wax matrix system, drug is uniformly and molecularly
dispersed in wax system. When the granules are compressed drug remains in contact with wax.
Presence of excipients in wax matrix system disturbs the integrity of tablet. In both wax matrix
system of Compritol and HVO, it was observed that as concentration of lactose in wax matrix
system increases, it increases release of drug[6,11,13] (Fig. 4).

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120

100
Cumulative % drug release

80
C2(Comp alone)
60 C4(Comp+Lactose)
C5(Comp+DCP)
40
C6(Comp+MCC)

20

0
0 2 4 6 8 10 12 14 16 18
Time in hours

Fig 4: Effect of excipients on release profile of drug and Compritol

Effect of sintering temperature and time on release profile of drug

The method consisted of compression of mixture of drug, Compritol and Dicalcium phosphate
followed by direct compression. The compressed matrices were kept in hot air oven at 60°, 70°,
and 80°C for an hour. After dissolution study it was found that sintered tablet kept at 80°C
showed more retardant effect (Fig. 5). The 60°C temperature is not sufficient to melt the wax to
form wax matrix system. But at 80°C the wax gets sufficiently melted and compact mass is
formed. The drug gets entrapped in molten wax system. Hence retardation of drug release was
observed by keeping tablet at 80°C. It indicates that sintering temperature markedly affect the
drug release properties through wax matrix system. The further study trials were performed at
80°C for an hour, 2 hour and 3 hours. After dissolution study, it was observed that there was no
significant change observed on retardation of drug at 800C though the time changes from an hour
to 3 hours. As melting point of Compritol is 72°C, an hour may be sufficient to melt the wax[5,14].

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120

100
Cumulative % drug release

80

C11(60°c)
60
C12(70°c)

40 C13(80°c)

20

0
0 2 4 6 8 10 12 14 16 18
Time in hours
Fig. 5: Effect of sintering temperature on release profile of drug

120
Cumulative % drug release

100

80

C13(1 hour)
60
C14(2 hour)

40 C15(3 hour)

20

0
0 2 4 6 8 10 12 14 16 18
Time in hours
Fig. 6: Effect of sintering time on release profile of drug

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Dissolution Kinetics
Most of the formulations showed Higuchi matrix as best fit model which indicates release of
drug is by matrix diffusion mechanism.

Stability study:
From stability study, it was found that there was no significant change in hardness, friability,
assay and in vitro dissolution of drug (Table 4). As wax is hydrophobic and is having melting
point of 72° C, the stability condition not causes any change in formulation and hence not affects
any parameters.
Table 4: Stability study of optimized formulation
After 90
Conditions Parameters Initial
days
Hardness (Kg/cm2) 5.2 5.0
Friability (%) 0.27 0.32
40°C±2°C, RH 75% ± 5%
Assay (%) 98.18 97.53
In vitro dissolution (t90) 14.7 14.5

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Pharma Utility Volume 6, Issue 3, 2012

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