Effect
of Different Polyoxyethylene Matrices on Extended
Release Formulation of Cephalexin Trihydrate
Sarita Garg1, Meenakshi
Bhatia1 and Pradeep Kumar2*
1Division of Pharmaceutics,
Department of Pharmaceutical Sciences,
Guru Jambheshwar University of Science and Technology,
Hisar-125001,
2Chitkara College of
Pharmacy, Chandigarh Patiala National Highway, Rajpura-140401, Patiala, Punjab,
India
ABSTRACT
The present study was undertaken to evaluate the effect of different
viscosity grades of polyoxyethylene, their content
level and the method of tablet preparation on the release profile of cephalexin trihydrate from matrix
systems. Matrix tablets were prepared using Polyox
N-10, Polyox N-80, Polyox
N-60 K, Polyox 301 and Polyox
303 as rate-retarding agents by direct compression process. The release of drug
from these hydrophillic matrices was studied over
12-hours in buffer media of pH 1.2. Statistically significant difference was
found among the drug release profile from different matrices. The release kinetics
was found to be governed by the type and content of hydrophillic
materials in the matrix. Tablets granulated by PVP K-30 solution have higher
hardness than those prepared by direct compression. However, drug release was
not influenced by the method of tablet preparation. Formulations containing Polyox N-60K, Polyox 301 and Polyox 303 released 82%, 76% and 70% of the drug
respectively, indicating that increasing viscosity can drastically reduce the
release rate. Further, a decrease in polymer
concentrations resulted a slight increase in thickness and friability, while a increase in polymer level resulted a increase in hardness
and decrease in release rate. Numerical fits indicated that the formulations
followed the Zero order release pattern which was further confirmed by the domination of
super case-II transport in polyox tablets.
KEYWORDS: Polyoxyethylene, Cephalexin
trihydrate, hydrophilic matrix, release kinetics
INTRODUCTION
The development of oral modified-release dosage forms
has attracted much attention in recent years. Many strategies are available for
design and development of modified-release drug delivery formulations.1-2 The primary purpose of these drug delivery devices is to
improve the state of disease management by modifying the pharmacokinetic
profiles of therapeutic agents normally administered as conventional tablets.
Conventional oral dosage forms often produce fluctuations of drug plasma level
that either exceed safe therapeutic level or quickly fall below the minimum
effective level; this effect is usually totally dependent on particular agent’s
biological half-life, frequency of administration, and release rate. It is
recognized that many patients can benefit from drugs intended for chronic
administration by maintaining plasma levels within a safe and effective range.3
Cephalexin is a broad spectrum bactericidal
antibiotic. It is almost completely absorbed from the gastrointestinal tract,
its plasma half-life is about 1 h, and more than 80%
of the dose is excreted unchanged in the urine during the first 6 h.4 However,
because the physical properties of the trihydrate are
superior to those of the tetra- and monohydrate, a number of attempts have been
made in recent years at the production of trihydarte. As compared with the tetrahydrate, the trihydrate has higher nascent oxygen content, and it can be
stored better at higher temperatures as a result of its higher melting point
and its low water vapor partial pressure.
Compared with the
monohydrate, trihydrate has advantages also; for
instance, it possess a better mechanical stability and a better ability to be
stored, the monohydrate being hygroscopic.5 The use of CR formulations offers
many potential advantages like sustained blood levels, attenuation of adverse
effects, and improved patient compliance, it is realized that in case of
antibiotics with short half-life, it is necessary to maintain the constant
blood levels as otherwise microorganisms will become resistant to the
antibiotic. Therefore, formulating cephalexin in CR
dosage forms will increase the therapeutic efficacy and patient compliance.6
Therefore, to reduce the frequency of
administration and to improve the patient compliance, an extended release
formulation of cefalexine trihydrate
is desirable. The most commonly used method of modulating the drug release is
to include it in a matrix system. Hydrophilic polymer matrix systems are widely
used in oral controlled drug delivery because of their flexibility to obtain a
desirable drug release profile, cost effectiveness, broad
regulatory acceptance and no complex production procedures such as coating and pelletization are required. Hydrogels
are being increasingly investigated for controlled-release. In addition the hydrogels have the ability to release the entrapped drug in
aqueous medium and to regulate the release by controlling the swelling. Hydrogels can be applied for the release of both
hydrophilic and hydrophobic drugs and charged solutes.7
Polyox
(Polyethylene oxide) is the most commonly and successfully used hydrophilic
retarding agent for preparation of oral controlled drug delivery systems. Polyox resins are among the fastest hydrating water-soluble
polymers in pharmaceutical systems. They very quickly form hydrogels
that initiate and regulate release of active ingredients. Systems using Polyox resins are often superior to others in approaching
zero order release models. Polyox resins are available in wide range of molecular weight.8
Maggi et al., 2002, reported that higher molecular
weight polyethylene oxide swells to greater extent and tends to form,
upon hydration, a stronger gel, which is therefore less liable to erosion, if
compared to the lower molecular weight polyethylene oxide.9
In
the present study, various matrix systems were designed and tested for extended
delivery of cefalexine trihydrate.
The objectives of the study were (I) to investigate the performance of
hydrophilic matrix system with polyethylene oxide in extending the release of
drug and (II) to find out the release kinetics and mechanism of release from
these matrices.
MATERIALS AND METHODS:
Materials:
Cephalexin trihydrate was a kind
gift sample from Ranbaxy Research Laboratories, Hoshiarpur,
PB,
Table 1: Composition with different
method of preparation in Polyox
matrix
|
|
mg/tab |
|
||||
|
Ingredients |
15 B |
20 A |
|
|||
|
Cephalexin Trihydrate |
200 |
200 |
|
|||
|
Avicel PH 101 |
111 |
- |
|
|||
|
Avicel PH 102 |
- |
115 |
|||
|
Polyox 301 |
75 |
75 |
|||
|
PVP K-30 |
10 |
- |
|||
|
Water |
q.s. |
- |
|||
|
Magnesium stearate |
4.0 |
2.0 |
|||
|
Aerosil 200 |
- |
8.0 |
|||
|
Total weight |
400 |
400 |
|
|||
Methods:
Batch 15B
was prepared by wet granulation method and other batches by direct compression
method. Polymers of different grades and levels were adopted to obtain an
optimized composition as shown in Table 1, Table 2 and Table 3.
Procedure for direct
compression:
Drug,
diluent and polymer were weighed accurately, sifted through BSS #30 sieve and
they were mixed in a polybag properly for 10 min.
Blend was lubricated for 2 min and compressed into tablets (400mg) using a
round punch (10.5 mm) (Cadmach Machinery Co. Pvt.
Ltd., India).
Procedure for wet
granulation:
All intragranular ingredients were weighed accurately and
sifted through BSS #30 sieve. The premix was
granulated with a 10%w/w Polyvinylpyrrolidone (PVP
K-30 grade in water) binder solution. The wet granules were dried in a lab
scale fluid bed drier or by using tray drier at a temperature of 600C
till a LOD of less than 2.0% (1050C, 10 min) was achieved. Dried
granules were sized, lubricated and compressed into tablets using a round punch
of size 10.5 mm for 400mg tablet and caplet punch of size 20´9 mm.
Assessment of tablets:
Tablets
were assessed for the following parameters:
Weight variation:
Total
weight and individual weight of 20 tablets were checked using electronic
weighing balance (ER 200 A,
Hardness:
Hardness
of tablets (5 units) was determined by using Schleuniger
hardness tester (VK-200,
Thickness:
Thickness
of tablets (5 units) was measured by using Digital Vernier
Caliper (500-144,
Friability:
Preweighed tablets (10 units) were placed in Roche’s Friabilator
(Serwell Instruments) and subjected to 100 rotations
in 4 minutes. The percentage difference between initial and final weight (after
dedusting) was calculated.
Table 2: Composition with different level
of Polyox N -60K, Polyox
301 and Polyox 303
|
|
mg/tablet |
|||||||||
|
Ingredients |
23D |
23E |
11A |
15A |
20A |
23A |
20B |
11B |
23B |
23C |
|
Cephalexin
trihydrate |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
|
Avicel
102 |
55 |
115 |
55 |
90 |
115 |
140 |
165 |
55 |
115 |
140 |
|
Polyox
N-60 K |
135 |
75 |
- |
- |
- |
- |
- |
- |
- |
- |
|
Polyox 301 |
- |
- |
135 |
100 |
75 |
50 |
25 |
- |
- |
- |
|
Polyox
303 |
- |
- |
- |
- |
- |
- |
- |
135 |
75 |
50 |
|
Aerosil |
8.0 |
8.0 |
8.0 |
8.0 |
8.0 |
8.0 |
8.0 |
8.0 |
8.0 |
8.0 |
|
Magnesium
stearate |
2.0 |
2.0 |
2.0 |
2.0 |
2.0 |
2.0 |
2.0 |
2.0 |
2.0 |
2.0 |
|
Total
weight |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
Drug Content:
Tablets (10 units) were powdered using mortar and pestle. An amount
equivalent to 50 mg drug was extracted with 200 ml of 0.1N HCl
and sonicated for 30 minutes. The solution was
filtered through nylon filter and properly diluted with 0.1N HCl. Drug content was then calculated
spectrophotometrically with absorbance maximum set at 260 nm.
In vitro Release Study:
The level of the drug release from the tablets was measured by the
paddle method at 50 rpm. Tablets equivalent to 75 mg drug content were placed
in USP dissolution apparatus II (Distek
Dissolution System-2100C, USA) in 900
ml hydrochloric acid 0.1N (pH 1.2), 37˚C containing sinker BSS # 10 and at
different time intervals, 5 ml of the solution was withdrawn until 12 hr. An
equal volume of the medium was introduced into the container after each
withdrawal to maintain a constant volume. The amount of the drug release was
measured spectrophotometrically employing a UV-spectrophotometer (Shimadzu
UV-1601) at 260 nm. The mean values of
drug released were plotted as percentage cumulative release vs. time.
Erosion study:
For
conducting erosion studies, the dissolution jars were marked with the time
points of 4, 8 and 12 hrs. One tablet was placed in each dissolution jar
containing 900 ml of 0.1N HCl and the apparatus was
run at 50 rpm using paddle. The tablets were taken out after completion of the
respected stipulated time span as mentioned above. The wetted samples were then
dried in an oven at 60 0C up to constant weight. The dried samples
were weighed. The degree of erosion was determined using following formula:
% Erosion = (Initial weight of tablet - final weight of dried tablet) ´ 100
Initial
weight of tablet
RESULTS AND DISCUSSION:
Polyox was
used as matrix forming polymer. They very quickly form hydrogels
that initiate and regulate release of active ingredients.
Effect of method of preparation:
Formulations were developed by wet granulation (15B)
and direct compression (20A) method. Physical properties of developed tablets
such as, average weight, hardness, thickness, friability and drug content were
determined and shown in Table 4. Tablets granulated by PVP K-30 solution have
higher hardness than those prepared by direct compression. These results might
be ascribed to the better binding properties of the PVP K-30 solution in water.
In vitro release profile of drug from 15B and 20A is shown in Figure 1.
Figure 1: Percentage drug released data
depicting the effect of method of preparation (n=3).
No
significant changes were found in drug release rate from 15B and 20A indicated that
the drug release was not influenced by the method of tablet preparation (Figure
1). So further formulations were preceded by Direct
Compression method because of low equipment costs, short processing time and
limited steps. As has been found previously by Dow
Chemical Company that Polyox resins perform well as
binders in economical direct compression systems. They often provide
better flow and compaction properties than other binders.10
Effect of different viscosity grades:
Formulations
were designed with different viscosity grades of polyox.
Formulations prepared with 70% Polyox N-10 (44A) and
with 70% Polyox N-80 (44B). Other formulations were
composed of 18.75% Polyox N-60K (23E), 18.75% Polyox 301 (20A) and 18.75% Polyox
303 (23B).
Physical
properties are presented in Table 4. In
vitro release profile of drug from 44A, 44B is shown in Figure 2 and from
23E, 20A, 23B is shown in Figure 3.
Figure 2: Percentage drug released from
matrices with 70% polymer content, (n=3).
Figure 3: Percentage drug released from
formulations with different grades of Polyox.
Formulation
44A and 44B released 94% and 84%of the drug respectively, over 6 hrs (Fig. 2).
Release was very fast even using high concentration of polymer that means the
grades are not successful in controlling the drug release. To avoid the higher
concentration (70%) of these polymer grades, we prepared other formulations
with higher viscosity grades in low concentration.
Formulations containing Polyox
N-60K, Polyox 301 and Polyox
303 released 82%, 76% and 70% of the drug respectively, over 12 hrs (Fig. 3).
As we moved towards higher viscosity grades, there was decrease in release
rate. Increasing viscosity can drastically reduce the release rate as observed
in 44A and 23B due to large difference in molecular weight. These results might
be attributed to the higher molecular weight polyox
swells to greater extent and tends to form a stronger gel upon hydration, which
is therefore less liable to erosion, if compared to the lower molecular weight polyox. These results are in confirmation with those
obtained by Maggi L., 2004.9
|
Ingredients |
23 E |
20 A |
23 B |
44 A |
44 B |
|
Cephalexin trihydrate |
200 |
200 |
200 |
200 |
200 |
|
Avicel 102 |
115 |
115 |
115 |
- |
- |
|
Lactose |
- |
- |
- |
90 |
90 |
|
Polyox N-10 |
- |
- |
- |
700 |
- |
|
Polyox N-80 |
- |
- |
- |
- |
700 |
|
Polyox N-60 K |
75 |
- |
- |
- |
- |
|
Polyox 301 |
- |
75 |
- |
- |
- |
|
Polyox 303 |
- |
- |
75 |
- |
- |
|
Aerosil 200 |
8.0 |
8.0 |
8.0 |
- |
- |
|
Magnesium stearate |
2.0 |
2.0 |
2.0 |
10 |
10 |
|
Total
weight |
400 |
400 |
400 |
1000 |
1000 |
Effect of polymer level:
Formulations
were designed with Polyox N-60K, Poyox
301, and Polyox303 in different concentrations. Polyox
N-60K formulations were prepared with 33.75% (23D) and 18.75% (23E) of polymer.
Polyox 301 formulations were prepared with 33.75%
(11A), 25% (15A), 18.75% (20A), 12.50% (23A) and 6.25%
(20B) of polymer. Formulations composed of Polyox 303
were prepared with 33.75% (11B), 18.75% (23B) and 12.50% (23C) of polymer.
Physical
properties data is presented in Table 4. In vitro release profile of
drug from Polyox N-60K formulations, Polyox 301 formulations and Polyox
303 formulations is shown in Figure 4, Figure 5 and Figure 6 respectively.
Figure 4: Percentage drug released from
different level of Polyox N-60K, (n=3).
Figure 5: Percentage drug released from different level
of Polyox 301, (n=3).
Figure 6: Percentage drug released from
different level of Polyox 303, (n=3).
Table 4:
Physical properties of tablets of Polyox
formulations
|
Parameters |
15B |
20A |
44A |
44B |
23E |
20A |
23B |
11A |
15A |
20A |
23A |
20B |
23D |
23E |
11B |
23B |
23C |
|
Average wt. (mg) |
404 |
398 |
1001 |
999 |
402 |
398 |
405 |
401 |
397 |
398 |
398 |
402 |
399 |
402 |
403 |
399 |
401 |
|
Hardness (Kp) |
10 ±0.5 |
8.1 ±1.0 |
15 ±2 |
15 ±2 |
8 ± 1.0 |
8.1 ±1.0 |
8.6 ± 0.6 |
9.5 ± 0.5 |
9 ± 0.5 |
8.1 ± 1.0 |
8.0 ± 1.0 |
7.5 ± 1.2 |
8.5 ± 1.5 |
8 ±1.0 |
9 ± 0.7 |
8.6 ± 0.6 |
8.2 ± 0.5 |
|
Thickness (mm) |
4.21 ±0.04 |
4.6 ±0.3 |
6.8 ±0.02 |
6.8 ±0.05 |
4.80 ±0.06 |
4.6 ±0.3 |
4.50 ±0.04 |
4.40 ±0.03 |
4.45 ±0.02 |
4.6 ±0.03 |
4.72 ±0.06 |
4.80 ±0.04 |
4.50 ±0.03 |
4.80 ±0.06 |
4.4 ±0.03 |
4.5 ±0.04 |
4.90 ±0.07 |
|
Friability (%) |
0.08 |
0.10 |
0.20 |
0.18 |
0.14 |
0.10 |
0.08 |
0.03 |
0.08 |
0.10 |
0.12 |
0.13 |
0.06 |
0.14 |
0.06 |
0.08 |
0.10 |
|
Drug Content (%) |
95.5 |
97.0 |
96 |
95 |
97.5 |
95.4 |
98 |
96 |
97.2 |
95.4 |
98.5 |
96.7 |
96 |
97.5 |
96.2 |
98 |
97.5 |
It
was observed that decrease in polymer concentrations resulted in slight
increase in thickness of tablet formulations (Table 4). These results might
indicate that the polymers have high binding properties. The
friability of prepared tablets increased by decreasing the polymer level.
Decreased polymer concentration resulted in decrease in the hardness of the
tablets. These results were in good agreement with those of thickness and
friability.
Formulation
23D and 23E released 73% and 82% of the drug respectively, over 12 hrs (fig.
4). Drug release was slow by using 33.75% of Polyox
N-60K as observed in 23D. Release profile matched with an ideal target in 23E,
which was composed with 18.75% of Polyox N-60K.11
Formulations
11A, 15A, 20A, 23A and 20B released 67%, 69%, 76%, 84% and 90% of the drug
respectively, over 12 hrs (fig. 5). Release profile was slow in 11A, 15A and
20A that were composed of 33.75%, 25% and 18.75% of Polyox
301, respectively. Release profile matched with target in 23A, which is having
12.5% of polymer. In formulation 20B release of drug was very fast from
starting points, so 6.25% of Polyox 301 is not
suitable for controlling the drug release.
Formulation
11B, 23B and 23C released 39%, 70% and 79% of the drug respectively, over 12
hrs (fig. 6). Drug release was very slow by using 33.75% of polymer in 11B. The
drug release was slow also in 23B that was composed of 18.75% of Polyox 303. Formulation 23C which was composed with 12.5%
polymer appeared to achieve our designed objective in terms of drug release.
It
was observed that increasing the polymer level resulted in decrease in release
rate. These results might be ascribed to the increase in polymer concentration
increases the gel viscosity on the surface of tablets, which retards the
diffusion of drug from the gel layer. These results are in accordance with the
findings of Dow Chemical Company in Polyox brochure
and Efentakis et al., 2000, also reported that an
increase in content of polymer polyox results in a
decrease in the release rate of drug.10, 12
Erosion
study:
Since
the rate of erosion may affect the mechanism and kinetics of drug release, the
penetration of dissolution medium and the erosion of hydrated tablets; was
determined. The percentage erosion of tablet at various time intervals is shown
in Table 5 and figure 7. Figure 7 shows that 81%, 80% and 78% of tablet eroded
in formulation 23E, 23A and 23C respectively, over 12 hrs after contact with
aqueous medium.
Figure 7: Percentage erosion of tablet in
selected formulations, (n=2).
Table
5: Erosion study for selected formulations
|
0.1N HCl/ 900ml/ USPII/ 50rpm/
#10 sinker |
|||
|
Time (hrs) |
23E |
23A |
23C |
|
0 |
0 |
0 |
0 |
|
4 |
28 |
33 |
26 |
|
8 |
60 |
61 |
58 |
|
12 |
81 |
80 |
78 |
Release
kinetics and mechanism of release:
Drug
release rate was predicted by fitting drug release data into different mathematical
models to selected formulations (23E, 23A and 23C) based on release profile
according to reference (Table 6).11 To know the mechanism of drug
release from these formulations, the data were treated according to Zero order
(cumulative % drug released vs time), First order
(log of cumulative % drug remaining vs time),
Higuchi’s (cumulative % drug released vs square root
of time), Korsmeyer equation (log cumulative % drug
released vs log time) pattern.13 When the data were plotted according to zero order
equation, the formulations showed a fair linearity with regression values
between 0.9945 and 0.9977, clearly
indicating that the formulations followed the Zero order release pattern. The R2
value in case of first order equation was found between 0.5412 and 0.555
indicating that formulations did not follow first order release pattern.
Similarly, the R2 value was found between 0.8205 and 0.8385 in case
of Higuchi model indicating that formulations did not follow Higuchi’s release
pattern.
Table 6: Drug release parameters from
various mathematical models
|
Form. Code |
Zero
order |
First
order |
Higuchi |
Peppas |
Release
Mechanism |
|||||
|
k |
r2 |
k |
r2 |
k |
r2 |
n |
k |
r2 |
||
|
23E |
21.54 |
0.9945 |
0.0325 |
0.5412 |
74.873 |
0.8205 |
1.0764 |
1.2318 |
0.9948 |
Super
Case-II |
|
23A |
23.20 |
0.9977 |
0.0325 |
0.5412 |
81.079 |
0.8385 |
1..0530 |
1.2988 |
0.9976 |
Super
Case-II |
|
23C |
21.72 |
0.9960 |
0.0337 |
0.5551 |
75.669 |
0.8281 |
1.0646 |
1.2529 |
0.9968 |
Super
Case-II |
To confirm the Zero order release pattern, the data were further fitted
into Peppas’s equation as the Peppas
equation offers a clear illustration of drug release mechanism. The
formulations showed good linearity (R2: 0.9948 to 0.9968), with
slope (n) values ranging from 1.0530 to 1.0764 in polyox
matrix tablets indicating that domination of super case-II transport in polyox tablets (Table 6). The n value nearer to 1 in all formulations, indicated the tendency towards drug release
kinetics nearer to zero order.
CONCLUSION:
The present study was to carried out to make a comparative evaluation among the
various grades of polyoxyethylene those can be
potential candidates as release retarding agents. The study implies that, the
kinetics and mechanism of release exclusively depends on the type and loading
of these materials. A critical polymer-filler ratio is necessary to get an acceptable
release profile and counter the complexities of sustained release effect. The
wide range of matrix-formers available in this group endows the formulator with
higher degree of flexibility, greater scope of optimization and wider approach
to comply with compendial specifications. The study
also reveals that, it is possible to formulate matrix tablet by appropriate
combination of these hydrophillic matrices with rate
controlling agents to get an acceptable pharmacokinetic profile in the
fluctuating in vivo environment.
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Received on 22.10.2009
Accepted on 20.11.2009
© A&V Publication all right reserved
Research Journal of Pharmaceutical
Dosage Forms and Technology.
1(3): Nov. – Dec. 2009, 269-274