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Abstract
Purpose: The objective of this research work was to prepare and evaluate the effect of
Eudragit RS PO and Eudragit RL PO polymers on the physical property and release
characteristics of carbamazepine matrix tablets.
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Methods: Matrix tablets containing carbamazepine were prepared with Eudragit RS PO
alone as the rate-retarding polymer (coded batch series ‘A’) and also with a combination of
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Eudragit RS PO and RL PO (coded batch series ‘B’). The tablets were characterized for
hardness as well as for carbamazepine release. The release data were subjected to different
models in order to evaluate their release kinetics and mechanisms.
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Results: The hardness of batch series ‘A’ matrix tablet was >160 kg/cm while for batch
2
series ‘B’, it was >170 kg/cm . Carbamazepine tablets containing only Eudragit RS PO
showed very slow release (less than 6% in 8 h) but when Eudragit RL PO was blended with
Eudragit RS PO, the release rate improved significantly to 44% in 24 h (p < 0.05). Drug
release mechanism was a complex mixture of diffusion and erosion.
Conclusion: Carbamazepine matrix tablets of satisfactory hardness were produced.
Furthermore, by blending Eudragit RS PO with Eudragit RL PO in the matrix, tablets of
varying release characteristics can be prepared.
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Keywords: Carbamazepine, Matrix tablet, Hardness, Eudragit RS PO, Eudragit RL PO,
Release kinetics.
Acrylic polymers are widely used as tablet The carbamazepine matrix formulations were
coatings and as retardants of drug release in composed as shown in Table 1. Batch series
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sustained released formulations . The most ‘A’ consisted of tablets made with Eudragit RS
interesting acrylic polymers are high PO alone as the matrix while the matrix of
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permeable Eudragit RL and low permeable batch series ‘B’ tablets comprised of both
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Eudragit RS, both of which are neutral co- Eudragit RS PO and RL PO. The mixture (for
polymers of poly (ethylacrylate, methyl 20 tablets), in each case, was well mixed in a
methacrylate) and trimethyl aminoethyl locally fabricated laboratory drum blending
methacrylate chloride, and are insoluble in machine at 40 rpm for 10 min and then an
water and digestive juices; but they swell and equivalent amount of dry powder (808
Batch code
Ingredient (mg)
A1 A2 A3 A4 A5 B1 B2 B3 B4 B5 B6
Carbamazepine 400 400 400 400 400 400 400 400 400 400 400
Ludipress LCE 0 50 100 150 200 200 200 200 200 200 200
Eudragit RS PO 400 350 300 250 200 160 140 120 100 80 60
Eudragit RL PO 0 0 0 0 0 40 60 80 100 120 140
Talc 3 3 3 3 3 5 5 5 5 5 5
Mg-stearate 3 3 3 3 3 3 3 3 3 3 3
Aerosil 2 2 2 2 2 2 2 2 2 2 2
Total weight (mg) 808 808 808 808 808 810 810 810 810 810 810
Table 2: Mean hardness of batch series “A” and “B” matrix tablets
The dissolution data were also fitted according Drug release from matrix tablets
to the well-known exponential equation of
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Peppas et al (Eq 3) which is often used to The cumulative release data for
describe drug release behavior from polymeric carbamazepine from batch series “A” matrix
systems. tablets show that less than 10% drug was
released in 8 h (see Figure 1). However,
Mt addition of Eudragit RL PO to Eudragit RS PO
= kt n ……………………………….…(3) (i.e., batch series “B”) enhanced release rates
Mα
to as high as > 40% (Figure 2). Increase in
Eudragit RL PO content up to 50% of the total
polymer matrix produce release rates that Release kinetics and mechanism of
increased slowly and linearly (Figure 2) but carbamazepine tablets containing Eudragit
this changed to a sudden and sharp rise in RS PO
release rate when the proportion of Eudragit
RL PO exceeded 50%. The release rate An ideal matrix formulation should contain
attained a value of approximately 45% in 12 h polymers and diluents at amounts as little as
when Eudragit RL PO constituted 70% of the possible, as well as releasing its content in a
matrix. The release data obtained were fitted sustained release profile over a reasonable
into various release kinetic models and the length of time, preferably with zero-order
outcome is listed in Table 3. 19
kinetics . Carbamazepine release kinetics
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was determined by multiple coefficients (R )
Discussion for individual formulation (Table 3). From the
correlation coefficient values, it appears that
In view of the importance of carbamazepine in
carbamazepine release mechanism from
the treatment of epilepsy and trigeminal
formula ‘A’ was mainly zero-order since it had
neuralgia, the preparation of a suitable 2
a higher “R ” value for the whole release
sustained release dosage form would not only
process. The zero-order rate describes
increase the efficacy of treatment and patient
systems where drug release rate is
compliance but should also produce desirable 14
independent of drug concentration .
blood concentrations and decrease the
incidence of adverse effects.
The diffusional exponent (see Table 3) of
It is well established that the hardness of the batches A1 and A2 imply that the release of
tablet can markedly affect the release rate of carbamazepine was case II or zero-order
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drug . Since Eudragit polymers have plastic transport. For systems exhibiting case II
deformation properties and a tendency to coat transport, the dominant mechanism for drug
drug particles, high compression forces result transport is due to polymer matrix relaxation.
in hard tablets with low porosities. But at high The diffusional exponent of batches A3, A4
compression forces, a continuous matrix is and A5 indicates non-Fickian type of release
formed and the change in tablet hardness mechanism, meaning that drug release
causes relatively small changes in porosity couples Fickian diffusion with polymer matrix
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and, therefore, release rate . A similar result relaxation - so-called anomalous diffusion -
was obtained with Eudragit matrix tablet by and may indicate that drug release is
19
other researchers . controlled by more than one process.
Table 3: Drug release parameters for batch series “A” and “B” matrix tablets
Zero-order Higuchi
Batch Diffusional
code R
2
k0 (min )
-1
r
2
kH (min
-1/2
) exponent (n)
6
6
5
5
Y
X 4
% R e le a se
4
% R e le a se
3
3
2
2
1
1
0
0 0 5 10 15 20 25
0 100 200 300 400 500 600 1/2
t
t (min)
Figure 1: Comparative release profile of carbamazepine from batches A1 (……), A2 (……), A3
(……), A4 (……), A5 (……). X = Zero-order plot; Y = Higuchi plot. Ratio of Ludipress LCE : Eudragit
RS PO was: A1 (0:1), A2 (1:7), A3 (1:3), A4 (3:5), A5 (1:1).
50
50
40
40 X Y
% Release
30
% R elease
30
20
20
10
10
0
0
0 5 10 15 20 25 30
0 100 200 300 400 500 600 700 800
1/2
t (min) t
From the correlation coefficient values (shown mechanism i.e., drug release is by coupling of
in Table 3), it appears that the Higuchi model Fickian diffusion and polymer matrix relaxation
seems the best-fitting model, which indicates - so-called anomalous diffusion - and may
a diffusion-controlled release. The erosion of indicate that drug release is controlled by
the matrix tablet might have occurred due to more than one process. The diffusional
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the lower water solubility of the drug , thus exponent of batch B6 (0.9196) indicates super
gradually reducing the diffusion path length, case II transport. In super case II transport,
which in turn attenuates the decrease of the the release curve is linear for an exponential
release rate in the Higuchi model, making the function of the release versus time. The higher
pattern to resemble zero-order model. drug release rate of Eudragit RS PO and
Eudragit RL PO combination matrix tablets
Burst release of carbamazepine occurred in (batch series ‘B’), compared to drug release
B6 formula. This can be attributed to the from Eudragit RS PO matrix tablets (batch
hydrophilic nature of Eudragit RL PO. When series ‘A’), may be attributed to the higher
exposed to the dissolution medium, the hydrophilic groups in Eudragit RL PO
solvent penetrates into the free spaces molecules, creating pores and channels and
between macromolecular chains of Eudragit thus facilitating solvent penetration and
RL PO. After solvation of the polymer chains, elevation of drug release.
the dimensions of the polymer molecule
increase due to polymer relaxation by the The carbamazepine matrix tablets did not
stress of the penetrated solvent. fulfill the USP requirement for carbamazepine
SR (sustained release) tablets, as it requires
The diffusional exponent (see Table 3) of between 65% and 90% of the drug to be
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batches B1 and B5 imply that release of dissolved within 12 hours . Pharmaceutical
carbamazepine was case II or zero-order excipients can be used to improve drug
transport. For systems exhibiting case II solubility through various mechanisms,
transport, the dominant mechanism for drug ranging from changing the pH in the
transport is due to polymer matrix relaxation. microscopic environment surrounding drug
The diffusional exponent of batches B2, B3 particles, through affecting the physical state
and B4 indicates non-Fickian type of release of drug molecules packed with each other,