Download FABRICATION AND EVALUATION OF EXTENDED RELEASE MATRIX TABLETS OF TRAMADOL HYDROCHLORIDE

Academic Sciences
International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 5, Issue 3, 2013
Research Article
FABRICATION AND EVALUATION OF EXTENDED RELEASE MATRIX TABLETS OF TRAMADOL
HYDROCHLORIDE
B.SELVARAJa, P.MALARVIZHIa AND P.SHANMUGAPANDIYANb *
aPrist
University, Thanjavur - 613403, Tamilnadu, India, b Mohamed Sathak A.J College of Pharmacy, Sholinganallur, Chennai- 600119,
Tamilnadu, India. Email: [email protected]
Received: 14 Jan 2013, Revised and Accepted: 26 Apr 2013
ABSTRACT
Objective: Tramadol Hydrochloride is an opiod analgesic which acts centrally by blocking the transmission of pain signals sent by the nerves to the
brain. It is widely used in the treatment of osteoarthritis. In this study an attempt was made to prepare extended release matrix tablets of Tramadol
Hydrochloride using Ethyl cellulose and Chitosan. Ethyl cellulose and Chitosan have been extensively studied in microencapsulation and film
forming experiments; however their candidature for matrix tablets were not studied in detail in the past.
Methods: Various formulations were tried with Ethyl cellulose and Chitosan matrix forming agents individually and in combinations. Direct
compression method was employed for preparing tablets with Dicalcium Phosphate, Magnesium Stearate, Colloidal Silicondioxide as excipients. The
precompression parameters were evaluated for flow properties, compressibility index, etc. The rate retarding effects of polymers were studied by
invitro dissolution studies.
Results and conclusion: Chitosan in higher concentrations resulted in poor tablets and lower concentration gave less hours retardation of drug
release. Higher concentration of Ethyl cellulose gave a good release profile when compared to Chitosan. Combinations of Ethyl cellulose and
Chitosan also retarded the release of drug from matrix. It is evident from this study that Ethyl cellulose is a satisfactory candidate for preparing
extended release matrix tablets of Tramadol Hydrochloride.
Keywords: Matrix, Extended Release, Ethyl Cellulose, Tramadol Hydrochloride
INTRODUCTION
Patients suffering from painful conditions are in deliberate need of
analgesics continuously. However due to various reasons like
patient compliance, half life of drug, poor bioavailability etc, patients
miss their drug requirement. To overcome these issues extended
release tablets come in handy to provide required levels of drug in
systemic circulation. Tramadol Hydrochloride is one such drug
which finds immense requirement for long periods in patients who
suffer from osteoarthritis [1]. It is an opiod analgesic used to treat
moderate to moderately severe pains. It is a centrally acting drug
which acts by blocking the transmission of pain signals sent by the
nerves to the brain [2]. Tramadol Hydrochloride is a very weak
opioid receptor agonist which induces serotonin release and inhibits
the uptake of nor-epinephrine. It is white or almost white crystalline
powder freely soluble in water [3].
Matrix tablets are one of the choices for preparing extended release
tablets which contain an intimate mixture of drug and release rate
retarding polymers along with excipients in a defined proportion. In
this present study an attempt was made to prepare and characterize
extended release matrix tablets [4] of Tramadol Hydrochloride by
using Ethyl cellulose and Chitosan [5] as rate retarding polymers.
The polymers were used in formulation as standalone rate
retardants and also in combinations at various proportions [6].
MATERIALS AND METHODS
Tramadol Hydrochloride was obtained as gift sample from M/s.
Stedman Pharmaceuticals Pvt Ltd, Chennai. Excipients like Dicalcium
phosphate, Ethyl cellulose, Magnesium stearate, Colloidal silicon
dioxide of Pharmacopoeial grades were obtained as gift samples
from M/s Safetab Life sciences, Pondicherry. Chitosan (Chitopharm
M) was obtained as gift sample from M/s Cognis. Other materials,
reagents and solvents used were of an analytical grade.
Preparation of Matrix Tablets
Preformulation studies were performed to characterize the drug and
excipients (as shown in table 1). Tramadol Hydrochloride and
excipients like Dicalcium Phosphate, Magnesium Stearate, Colloidal
Silicon dioxide including the polymers [7] (Ethyl cellulose and
Chitosan individually as well as in combinations) were admixed
thoroughly (as shown in table 2) after sieving through 30. This
blend was directly compressed using 9 mm circular standard
concave punches in a 16 station rotary tablet punching machine [8].
Direct compression was chosen to make the process very simple and
thereby to provide better product stability with conservation of
energy and resources. In the Design of Experiment, three level of
polymer concentration with two variables (polymers) [9] were
selected which resulted in a 32 factorial design.
Evaluation of Matrix Tablets
Prepared extended release matrix tablets were evaluated for weight
variation, hardness, friability, thickness, diameter, drug content,
dissolution and stability. Weight variation for the tablets were done
by weighing twenty tablets collectively and individually and then
compared with average weight of the tablet. The crushing strength
of the tablets and friability were evaluated using hardness tester and
friabilator.
Digital Vernier was engaged to determine the thickness and
diameter of tablets. Invitro dissolution studies were conducted using
USP Type I basket apparatus in 0.1N HCl at 37º C ± 0.5º C with 100
rpm. Aliquots were withdrawn for upto 8 hours and perfect sink
conditions maintained by replenishing the media samples are
subjected to UV absorbance at 270 nm to evaluate the percentage of
drug release. Marketed product was also used to compare the
dissolution profile along with the test formulations.
RP-HPLC method was employed to estimate the drug content in
tablets using Hypersil BDS C18 column. Acetonitrile/ Triflouro acetic
acid (295 ml Acetonitrile: 705 ml, 0.02% v/v Triflouro acetic acid)
was used as mobile phase with flow rate of 1.0 ml/min and UV
detector was engaged to measure the absorbance at 270 nm.
Compatibility Studies were performed by using FT-IR to compare
the spectra of pure drug, polymer [10] and tablet. Accelerated
stability studies were conducted for the test formulation F3 for 6
months at 40º C ± 2º C and 75% RH ± 5% RH and evaluated for
physico-chemical properties.
Release rate studies were performed for F3 by applying Zero order,
First order, Higuchi, Hixson-Crowell and Korsmeyar-Peppas
equations.
Shanmugapandiyan et al.
Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971
RESULTS AND DISCUSSION
containing Ethyl cellulose at 40% is a better formula for maximum
period of release [13].
Nine formulations of Tramadol Hydrochloride 100 mg sustained release
tablets were prepared using Ethyl Cellulose and Chitosan as rate
retarding polymers [11]. The polymers were used at various
concentrations (20%, 30% & 40%) individually and also in
combinations (10% + 10%, 15% + 15%, & 20% + 20%) (as shown in
table 3). Most the formulations exhibited good flow properties and
compressibility index except for Chitosan at higher concentration. The
bulk density, tapped density, angle of repose, compressibility index and
hausner’s ratio of the blend were in the range of 0.50 - 0.74, 0.58 – 0.92,
24.1 – 29.20, 11.11 – 23.59 and 1.12 – 1.30 respectively.
Release rate studies indicate that F3 followed Higuchi, Hixson
Crowell and Korsmeyer Peppas equations with a regression value of
0.9165, 0.9759, and 0.9221 respectively (as shown in table 6). First
order and Zero order plots gave regression values of 0.8401 [14].
Formulation F3 was subjected to FT-IR studies and the results
indicated that there was no incompatibility between the drug
Tramadol HCl and polymer Ethyl cellulose. The IR Spectrum of pure
drug-Tramadol HCl, polymer - Hydroxy propyl cellulose [15] and
tablet F3 were taken and investigated for any additional peaks.
Prominent sharp peaks at 1606, 1578 of pure drug-Tramadol HCl
and sharp peaks at 1604, 1579 of Tablet F3 were visible in the
spectrum. This clearly proves that there is no incompatibility (as
represented in figure 2 a,b,c). It is evident that only slight shift in
some of the functional groups of the drug-Tramadol HCl took place
with overlapping and broadening. No prominent new peaks were
detected in the FT-IR spectra of tablet F3 indicating no interaction
between the drug-Tramadol HCl and polymer Ethyl cellulose. The
stability studies performed on F3 for a period of 3 months at
accelerated conditions gave satisfactory results on physico chemical
properties [16]. These results indicated that the F3 is a stable
composition.
The weight variation of the tablets was within acceptable limits and
ranged within ± 5%. The tablets possessed satisfactory friability and
were <2% except for Chitosan at higher concentration formulation with
a hardness ranging from 1 kg/cm3 to 8.5 kg/cm3. The thickness and
diameter of the tablets was within 3.50 mm to 4.27 mm and 9.00 to 9.06
mm. Drug content was found to be in the range of 97.98% to 99.28%
indicating a very good blend of the tablet.(as shown in table 4)
Formulation F6 with stand alone Chitosan at higher level
concentration (i.e, 40%) rendered poor tablets which resulted
crumbling during evaluation and hence friability & hardness data
could not be generated.
The results of dissolution studies indicated that all the formulations
retarded the release at various degrees. All the formulations
retarded the release of drug from matrix tablets for extended
periods. Formulation F3 containing Ethyl cellulose at 40%
concentration gave a release for upto 8 hours when compared to F2
at 30% concentration and F1 at 20% concentration which gave upto
6 hours & 4 hours respectively (as shown in table 5).
CONCLUSION
The overall evaluation of formulations F1 to F9 indicate that F 3
containing Ethyl cellulose at 40 % is a suitable composition for
producing sustained release matrix tablets of Tramadol Hcl (100
mg) where an action of upto 8 hours is desired. This is comparable
with the Marketed Product which also gave a release for upto 8
hours. The Hixson Crowell and Higuchi equation best defines the
release pattern indicating both dissolution and diffusion. Korsmeyer
Peppas equation indicated the fickian diffusion with an ‘n’ value of
0.40. Formulations of Chitosan F4, F5, and F6 are not comparable
with Ethyl cellulose in retarding the release rate of drug for an
extended period. However combinations of polymers gave a
satisfactory retardation of release. The present study indicates that
proportion of polymers is also directly influential in retarding the
release of drug. Higher concentration of polymers yield much more
extended period of release.
Compositions containing Chitosan were not comparable to Ethyl
Cellulose containing formulations. However the period of release for
Chitosan formulations were upto 4 hours for F6, F5 and 2 hours for
F4 formulations. Combinations of Ethyl Cellulose & Chitosan
formulations also delivered delayed release in which F7, F8 & F9
gave a release for upto 2 hours, 4 hours and 6 hours respectively (as
represented in figure 1 a,b).
Marketed product gave a release for upto 8 hours under similar
conditions [12]. Dissolution studies indicated formulation F3
Table 1: Evaluation of blend
S. No.
1
2
3
4
5
Parameters
Angle of Repose
Bulk Density
Tapped Density
Compressibility Index
Hausner’s Ratio
F1
24.6
0.56
0.63
11.11
1.12
F2
24.1
0.54
0.61
11.47
1.13
F3
25.2
0.50
0.58
13.79
1.16
F4
28.2
0.74
0.92
19.56
1.24
F5
28.5
0.70
0.90
22.22
1.28
F6
29.2
0.68
0.87
23.59
1.30
F7
27.8
0.70
0.79
11.39
1.13
F8
28.1
0.66
0.76
13.15
1.15
F9
27.9
0.62
0.74
16.21
1.19
Table 2: Formulations
S. No.
1
2
3
4
5
6
Total (mg)
Ingredients (mg)
Tramadol HCl
Dicalcium Phosphate
Ethyl Cellulose
Chitosan
Colloidal Silicondioxide
Magnesium Stearate
F1
100
134
60
3
3
300
F2
100
104
90
3
3
300
F3
100
74
120
3
3
300
F4
100
134
60
3
3
300
F5
100
104
90
3
3
300
F6
100
74
120
3
3
300
F7
100
134
30
30
3
3
300
F8
100
104
45
45
3
3
300
F9
100
74
60
60
3
3
300
Table 3: Design of Experiment
Polymer
P 1 – 20 %
P 2 – 30 %
P 3 – 40 %
Ratio
1:0
Ethyl Cellulose
F1
F2
F3
1:0
Chitosan
F4
F5
F6
1:1
Ethyl Cellulose : Chitosan
F7
F8
F9
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Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971
Table 4: Evaluation of Tablets
S. No.
1
2
Parameters
Weight Variation %
Thickness in mm
F1
±2.2
4.21 ±0.05
F2
±3.6
4.20 ±0.06
F3
±2.6
4.27 ±0.02
3
Diameter in mm
9.03 ±0.02
9.02 ±0.01
9.01 ±0.01
4
Friability %
0.76 ±0.15
0.88 ±0.10
0.87 ±0.10
4
Hardness in kg/cm3
8.20 ±0.5
8.50 ±0.4
5
Assay (Drug Content)
7.80
± 0.6
99.28 ±0.54
98.70 ±0.68
98.85 ±0.14
F4
±4.5
3.50
±0.04
9.00
±0.01
1.52
±0.14
1.50
±0.2
98.43
±0.11
F5
±5.2
3.52
±0.02
9.02
±0.03
1.78
±0.16
1.00 ±
0.4
98.10
±0.20
F6
±5.4
3.54
±0.06
9.05
±0.03
97.98
±0.60
F7
±3.8
3.82
±0.02
9.06
±0.01
1.21
±0.18
4.20
±0.2
98.52
±0.42
F8
±4.2
3.87
±0.04
9.02
±0.02
1.07
±0.12
4.66
±0.3
99.02
±0.33
F9
±3.9
3.80
±0.02
9.03
±0.02
0.90
±0.06
4.80
±0.2
99.14
±0.17
Table 5: Dissolution Profile
Sampling Time in hours
1
2
4
6
8
Percentage Drug Released
F1
F2
F3
F4
F5
F6
F7
F8
F9
51.96
76.43
96.75
-
76.08
96.87
-
68.24
89.12
98.17
-
69.14
89.80
98.68
-
60.38
96.97
-
54.19
80.07
96.48
-
48.43
72.18
89.37
97.27
-
45.78
70.01
87.15
96.28
-
40.12
68.75
82.46
91.22
97.94
Market
Product
30.54
45.68
70.51
83.92
96.14
Table 6: Stability Studies of F 3
No. of
Months
Initial
1
3
6
Temperature in º C ±
2ºC
40
40
40
40
Relative Humidity in
%±5%
75
75
75
75
Hardness in
kg/cm3
8.50
8.60
8.60
8.50
Thickness
mm
4.20
4.22
4.24
4.21
Diameter
mm
9.01
9.03
9.01
9.02
Friability
%
0.74
0.81
0.82
0.88
Assay in
%
98.85
99.26
99.10
98.66
Fig. 1: a) Dissolution Profile
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Shanmugapandiyan et al.
Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971
Fig. 1: b) Dissolution Profile
a: Pure Drug – Tramadol Hydrochloride
969
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Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971
b: Polymer – Ethyl Cellulose
c: Tablet F 3
Fig. 2: FT-IR Spectrum
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Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
Aiman A Obaidat, Rana M Obaidat: Control Release of Tramadol
hydrochloride from matrices prepared using glyceryl behenate.
European Journal of Pharmaceutics & Biopharmaceutics 2001;
52: 231- 235.
Stefan Grond, Lukas Radbruch, MD, Thomas Meuser, MD,
George Loick, MD, Rainer Sabatowski, MD, and Klaus A.
Lehmann, MD: High – Dose Tramadol in comparison to lowdose Morphine for cancer pain relief. Journal of pain and
symptom management 1999; 18(3): 174 - 179.
Julide Akbuga: The effect of the physicochemical properties of a
drug on its release from chitosonium malate matrix tablets.
International Journal of Pharmaceutics 1993; 100: 257-261.
Chris Vervaet, Thomas Quinten, Yves Gonnissen, Els Adriaens,
Thomas De Beer, Veerle Cnudde, Bert Masschaele, Luc Van
Hoorebeke, Juergen Siepmann, Jean Paul Remon: Development of
injection moulded matrix tablets based on mixtures of ethyl
cellulose and low – substituted Hydroxy propyl cellulose.
European Journal of Pharmaceutical Sciences 2009; 37: 207-216.
Thomas Quinten, Thomas De Beer, Chris Vervaet, Jean Paul
Remon: Evaluation of injection moulding as a pharmaceutical
technology to produce matrix tablets. European Journal of
Pharmaceutics & Biopharmaceutics 2009; 71: 145- 154.
Sandra Furlanetto, Marzia Cirri, Francesca Maestrelli, Giovanna
Corti, Paola Mura: Study of Formulation variables influencing
the drug release rate from matrix tablets by experimental
design.
European
Journal
of
Pharmaceutics
&
Biopharmaceutics 2006; 62: 77-84.
Basani Gavaskar, Subash Vijaya Kumar, Dilip Dodda: Effect of
tablet formulation variables on Tramadol Hcl elementary
osmotic pump tablet. International Journal Drug Development
& Research 2010; 2(4): 730-735.
Tetsuo Hayashi, Hideyoshi kanbe, Minoru Okada, Ichiro
kawase, Yasuo Ikeda, Yoichi Onuki, Tetsuo Kaneko, Takashi
Sonobe: Invitro and Invivo sustained release characteristics of
9.
10.
11.
12.
13.
14.
15.
16.
theophylline matrix tablets and novel cluster tablets.
International Journal of Pharmaceutics 2007; 341: 105-113
Kashyap N, Modi S, Prakash J, Bala I, Hariharan S, Bharadwaj R,
Singh D, Mahajan R, Kumar N and RaviKumar M.N.V: Polymers
for Advanced Drug Delivery. Review Article CRIPS 2004; 5(3):
7.
Raghavendra Rao N.G, Gandhi Sagar, Patel Tarun: Formulation
and Evaluation of sustained release matrix tablets of Tramadol
Hydrochloride. International journal of Pharmacy and
Pharmaceutical Sciences 2009; 1(1): 60-70.
Jose M Lanao, Cristina Maderuelo, Aranzazu Zarzuelo: Critical
factors in the release of Drugs from sustained release
Hydrophilic Matrices. Journal of Controlled Release 2011; 154:
2-19.
Beom-Jim Lee, Seung Goo Ryu, Jing-Huo Cui: Controlled release
of dual loaded Hydroxy propyl methylcellulose matrix tablet
using Drug Containing polymeric coatings. International
Journal of Pharmaceutics 1999; 188: 71- 80.
LeoPoldo Villafuerte, Norma Traconis, Raul Rodriguez, Maria
elena Campos: Influence of admixed polymers on the
Metronidazole release from Hydroxy propyl methylcellulose
matrix tablets. Phannaceutica Acta Helvetiae 1997; 72: 131138.
Gul Mjid Khan, Jia-Bi Zhu: Studies on drug release kinetics from
Ibuprofen – Carbomer Hydrophilic matrix tablets: Influence of
Co-excipients on release rate of the drug. Journal of Controlled
Release 1999; 57: 197-203.
Dahl T.C, Calderwood T, Bormeth A, Trimble K: Influence of
physicochemical properties of HydroxyPropyl Methylcellulose
on Naproxen release from sustained release matrix tablets.
Journal of Controlled Release 1990; 14: 1-10.
Anjali devi N, Mohd abdul hadi, Ranjitha P, Sharma JVC and
Srinivasa rao A: Formulation and evaluation of floating
controlled release tablets of imatinib mesylate using
hydrophilic matrix system. International journal of Pharmacy
and Pharmaceutical Sciences 2013; 5(1): 271-277.
971