Formulation and Evaluation Theophylline Floating Tablets and the Effect of Citric Acid on Release.
Tom Damien, Someshwara Rao B.*, Ashok Kumar P., Amith S. Yadav and Suresh V. Kuikarni
Department of Pharmaceutics, Sree Siddaganga College of Pharmacy, Tumkur, Karanataka
*Corresponding Author E-mail: bsrao.borigey720@gmail.com
ABSTRACT:
The objective of this research work was to formulate and evaluate the floating drug delivery system containing theophylline as a model drug. Theophylline tablets were prepared by granulation method incorporating Methocel as swelling polymer, sodium bicarbonate, as gas generating agent, citric acid as release rate enhancer and excipients such as Magnesium stearate and lactose. Dissolution profiles were studied in medium 0.1N Hcl. The influence of variables like polymer type, citric acid on theophylline release profile was studied. The release mechanisms of theophylline from floating tablets were evaluated on the basis of Peppas’s model. The ‘n’ value of all the formulations ranges from lowest 0.752 to highest 0.960 which was in the range of 0.45<n<1.0 which indicate the mechanism of release of theophylline was anomalous (non-Fickian) transport. The thickness, hardness, friability, weight variation, drug content uniformity of the formulated floating tablets was evaluated. Tablets were also evaluated for swelling index, floating lag time and floating duration of all the formulations were within the range and floating duration of all the formulations were in the range of 7 to >10 hrs. Based on the evaluation results, S3 formulation was selected as the best formulation and was checked for stability at different temperatures 25ºC / 60% RH, 35ºC / 65% RH and 40ºC / 75% RH. These results indicated that the selected formulation was stable. The drug release profile of the best formulation was well controlled and uniform throughout the gastrointestinal tract. Scanning electron microscopy (SEM) study represents the formation of gel structure. Different excipients were tested for their compatibility with theophylline such as FT-IR and DSC studies, which revealed that there is no chemical interaction occurred with other excipients.
KEYWORDS: Floating drug delivery systems (FDDS), Compatibility, FT-IR, Scanning electron microscopy (SEM), Differential scanning colorimetry (DSC), Theophylline, citric acid.
INTRODUCTION:
Floating drug delivery system is an oral dosage form design to prolong the residence time of dosage form with in the GI tract, such dosage form having density less than that of the gastric fluid floats on the gastric juice for an extended period of time while slowly releasing of the drug.
On contact with gastric fluid, the intragastric floating tablet maintains a bulk density less than 1 .So it remains buoyant in the gastric fluid in stomach until the entire dose has been released. This drug delivery system not only prolongs GI residence time but does so in an area of the GI tract that could maximize drug reaching its absorption. In the present study hydrodynamic balance system approach has been selected to control the delivery for longer period in stomach from floating drug delivery system.
Theophylline, one of the popular drugs is used to treat bronchial asthma. Peak serum theophylline concentration occur 1-2 hr, after ingestion of the liquid preparation, capsules and uncoated tablets and b/w 4 and 12 h after ingestion of the sustained release preparations. Optimum serum theophylline ranges from 10-20 µg/ml. It has an average half life of 8.7 h but in smokers, it is 4.4h. Hence, it requires frequent dosing for achieving therapeutic drug concentration in the target tissue1.
MATERIALS AND METHODS:
Materials:
Theophylline was received as a gift sample from Bakul chemicals and Aromatics Pvt Ltd, Mumbai, India. Methocel K100LV (100 cps apparent viscosity as a 2% solution) and methocel K15M (15,000 cps apparent viscosity as a 2% solution) were purchased from Colorcon Asia Pvt. Ltd., Goa, India. Magnesium stearate, hydrochloric acid, sodium bicarbonate and citric acid anhydrous (hereafter referred to as citric acid) was purchased from S.D. Fine-Chem Ltd, Mumbai, India. Polyvinyl pyrrolidone K-30 (PVP K-30) was procured from Nice chemicals Laboratories. Lactose and purified talc were purchased from S.D. Fine-Chem Ltd, Mumbai. All other ingredients were of laboratory grade.
Table 1: Formulation of Theophylline floating tablets.
Sr. no |
Ingredients ( mg) |
S1 |
S2 |
S2 |
S4 |
S5 |
S6 |
S7 |
S8 |
S9 |
S10 |
1 |
Theophylline |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
2 |
Methocel K100 |
150 |
150 |
150 |
138 |
122 |
_ |
_ |
_ |
_ |
_ |
3 |
Methocel K15M |
_ |
_ |
_ |
_ |
_ |
150 |
150 |
150 |
138 |
122 |
4 |
Sodiumbicarbonate |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
50 |
5 |
Citric acid |
8 |
6 |
4 |
4 |
4 |
8 |
6 |
4 |
4 |
4 |
6 |
PVP K-30 |
40 |
40 |
40 |
40 |
40 |
40 |
40 |
40 |
40 |
40 |
7 |
Lactose |
97 |
99 |
101 |
113 |
129 |
97 |
99 |
101 |
113 |
129 |
*0.5%w/v talc and Magnesium stearate total wt of tablets is 450mg
TABLE 2: Precompession parameters of granules S1 to S5
Formulations |
S1 |
S2 |
S2 |
S4 |
S5 |
Angle of repose (θ |
28.39+1.52 |
27.22+1.59 |
26.42±0.144 |
26.71 +0.43 |
27.76 +0.311 |
Bulk density (g/cc) |
0.236+0.007 |
0.218+0.009 |
0.210+0.007 |
0.217+0.001 |
0.211+0.002 |
tappeddensity(g/cc) |
0.267+0.012 |
0.259±0.014 |
0.253+0.017 |
0.245+0.016 |
0.246 +0.014 |
Carr index |
11.20 + 1.23 |
15.83 ± 1.56 |
16.83 + 0.64 |
11.99 + 1.55 |
14.29 + 1.24 |
The values represent mean + S.D; n=6.
TABLE 3: Precompession parameters of granules S6 to S10
Formulations |
S6 |
S7 |
S8 |
S9 |
S10 |
Angle of repose (θ |
28.56+0.49 |
27.14+1.35 |
28.07+1.41 |
28.39 + 1.52 |
29.39 + 1.18 |
Bulk density (g/cc) |
0.215+0.005 |
0.3655+0.01 |
0.3241+0.02 |
0.236+0.007 |
0.3863+0.04 |
tappeddensity(g/cc |
0.2484+0.018 |
0.4396+0.004 |
0.3859+0.002 |
0.267+0.012 |
0.4796+0.003 |
Carr index |
13.46 + 0.45 |
16.85 + 0.44 |
16.00 + 0.23 |
11.20 + 1.23 |
10.82 + 0.48 |
The values represent mean + S.D; n=6.
Method of manufacturing tablets:
The composition of different formulations of theophylline floating tablets is shown in Table 1. The ingredients were weighed accurately and mixed thoroughly. Granulation was done with a solution of PVP K-30 in sufficient isopropyl alcohol. The granules (40 mesh) were dried in conventional hot air oven at 45°C. Drying of the granules was stopped when the sample taken from the oven reached a loss on drying (LOD) value of 1 to 3%, as measured by a moisture balance at 105°C. The dried granules were sized through 40/60 mesh, lubricated with magnesium stearate (0.5%w/w) and purified talc (0.5%w/w) and then compressed on a ten punch tablet machine (Shakti Pharmatech Pvt. Ltd, Ahmedabad, India). The tablets were round and flat with an average diameter of 12.0 ± 0.1 mm and a thickness of 3.2 ± 0.2 mm.
Flow Properties of Granules:
The flow properties of granules (before compression) were characterized in terms of angle of repose and Carr index [4]. For determination of angle of repose (θ), the granules were poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2.0cm above hard surface. The granules were poured till the time when upper tip of the pile surface touched the lower tip of the funnel. The tan-1 of the (height of the pile / radius of its base) gave the angle of repose2. Granules were poured gently through a glass funnel into a graduated cylinder cut exactly to 10 ml mark. Excess granules were removed using a spatula and the weight of the cylinder with pellets required for filling the cylinder volume was calculated. The cylinder was then tapped from a height of 2.0cm until the time when there was no more decrease in the volume. Bulk density (ρb) and tapped density (ρt) were calculated3. Carr index (IC) were calculated according to the two equations given below: values are on Table 2 and 3.
IC = (ρt– ρb)/ρt
Evaluation of Theophylline floating tablets:
1. Thickness and diameter Control of physical dimensions of the tablet such as thickness and diameter is essential for consumer acceptance and tablet uniformity. The thickness and diameter of the tablet was measured using Vernier Calipers. It is measured in mm. Values on Table 4 and 5.
2. Hardness4 Pfizer hardness tester was used for the determination of hardness of tablets. Values on Table 4 and 5.
3. Friability (F) Tablet strength was tested by Roche friabilator. Pre weighed tablets were allowed for 100 revolutions in 4 min and were deducted. The percentage weight loss was calculated by reweighing the tablets. Values on Table 4 and 5.
The % friability was then calculated by: -
(Winitial) - (Wfinal)
F= x100
(Winitial)
5. Swelling Index
The studies were carried out in petridishes using simulated gastric fluid (1.2); the prepared tablets were introduced in swelling media along with preweighed OHP sheet placing tablet on the OHP sheet. At predetermined time intervals the tablets were removed from medium, the excess water was blotted with tissue paper and immediately weighed. This procedure was repeated until the tablet reaches constant weight. The swelling index was calculated using following formula. See the figure (1)
% Swelling Index = WO -Wi-Wb / Wi x 100
WO = Weight of swollen tablet, Wi = Weight of initial tablet Wb =Weight of OHP paper.
TABLE 4: Post compression parameters of granules S1 to S5
Formulations |
S1 |
S2 |
S2 |
S4 |
S5 |
Friability (%) |
0.176 |
0.166 |
0.17 |
0.347 |
0.401 |
Thickness (mm) |
3.35±0.16 |
3.32±0.23 |
3.31±0.22 |
3.31±0.13 |
3.32±0.17 |
Hardness(kg/cm2) |
5.8±0.52 |
5.9±0.43 |
5.2±0.47 |
6.2±0.17 |
6.2±0.24 |
Diameter (mm) |
5.8±0.52 |
5.9±0.43 |
5.2±0.47 |
6.2±0.17 |
6.2±0.24 |
Buoyancy studies ( FLT(sec),FD(hr) |
1.20, >10 |
1.55,>10 |
1.70,>10 |
4.10,>8 |
5.10,>7 |
Drug content |
97.82 |
97.71 |
97.73 |
97.75 |
97.77 |
% Of Drug release |
85.58 |
92.18 |
98.19 |
91 |
90.12 |
TABLE 5: Post compression parameters of granules S6 to S10
Formulations |
S6 |
S7 |
S8 |
S9 |
S10 |
Friability (%) |
0.176 |
0.166 |
0.17 |
0.347 |
0.401 |
Thickness (mm) |
3.32±0.13 |
3.33±0.15 |
3.30±0.16 |
3.32±0.18 |
3.32±0.17 |
Hardness(kg/cm2) |
6.2±0.26 |
6.6±0.11 |
6.2±0.31 |
6.1±0.27 |
6.2±0.32 |
Diameter (mm) |
12.05±0.02 |
12.08±0.01 |
12.02±0.05 |
12.02±0.04 |
12.07±0.02 |
Buoyancy studies ( FLT(sec),FD(hr) |
2.35,>10 |
2.65,>10 |
2.50,>10 |
2.75,>10 |
3.50,>9 |
Drug content |
97.79 |
97.72 |
97.86 |
97.83 |
97.89 |
% Of Drug release |
83.43 |
84.3 |
86.46 |
89.73 |
85.9 |
Fig 1: Graph for comparison of swelling index of all the formulations at 10 hour
6. Buoyancy studies:
The in vitro floating behavior of the tablets was studied by placing them in 900ml glass beaker filled with 900 ml of 0.1 N HCl (pH 1.2). The floating lag time (time period between placing the tablet in the medium and tablet floating) and floating duration of the tablets were determined by visual observation. (Table 4 and 5).
7. Drug content5:
10 tablets were weighed and powdered. Powder equivalent to100mg of Theophylline was weighed and dissolved 0.1N HCl. Different concentrations of drug were prepared and analyzed spectrophotometrically (UV‐ Labindia 3000, Mumbai, India). (Table 4 and 5).
8.Dissolution studies6:
The in vitro dissolution study was carried out in the USP XXII dissolution apparatus type II (Electrolab, Mumbai, India) 900 ml of the dissolution medium (0.1 N HCl) was taken in covered vessel and the temperature was maintained at 37+or‐0.5 degrees c. The speed of paddle was set at 50 rpm. Sampling was done at regular intervals. For each sample 10 ml of the dissolution medium was withdrawn and same amount was replaced. The sample was filtered and diluted with 0.1N HCl and then analyzed in UV spectrophotometer (UV‐ Labindia 3000, Mumbai, India).The absorbance was measured at 270 nm and% drug release was calculated. (Table 4 and 5).
Release kinetics7:
To study the mechanism of drug release from the matrix tablets, the release data
were fitted to the following equations:
Zero‐order equation: Q = Q0‐k0t………………………... (1)
where Q is the amount of drug released at time t, and k0 is the release rate;
First‐order equation: ln Q = ln Q0 ‐ k1t…………………… (2)
where k1 is the release rate constant;
Higuchi´s equation: Q = k2t1/2…………………………….. (3)
where Q is the amount of drug released at time t, and k2 is the diffusion rate constant.
Peppa’s Model: In order to understand the mode of release of drug from swellable matrices. The data were fitted to the following peppa’s law equation.
Mt/M∞ =Ktn……………………………………………(4)
Where, Mt/M∞ = the fraction of drug released at time‘t’
K= Constant incorporating the structural and geometrical characteristics of the drug /polymer system
N= Diffusion exponent related to the mechanism of the release.
Above equation can be simplified by applying log on both sides, we get:
Log Mt/M∞ = log K +n log t
When the data is plotted as log of drug released verus log time, yields a straight line with a slope equal to ‘n’ and the ‘K’ can be obtained from Y- intercept.
For Fickian release n=0.45 while for anomalous (non-Fickian) transport, n ranges between 0.45 and 0.89 and for Zero order release, n=0.89. (Table 6).
DSC (Differential Scanning Calorimetry):
Compatibility studies were employed as a tool to investigate the physicochemical compatibility between drug and number of commonly used excipients that can affect the stability of the drug by chemical and physical interaction thus posing a threat to the drug stability or bioavalibility. One of the methods to study the compatibility of drug with the different excipients is DSC. Figure- 3
TABLE 6: Release kinetics of all formulation
Formulations |
Zero order kinetics |
First order Kinetics |
Higuchi Plot |
Peppa’s model |
||
|
Regression (r2) |
n |
K |
|||
S1 |
0.995 |
0.955 |
0.974 |
0.974 |
0.878 |
-0.928 |
S2 |
0.996 |
0.905 |
0.978 |
0.990 |
0.960 |
-0.970 |
S3 |
0.983 |
0.938 |
0.993 |
0.973 |
0.821 |
-0.846 |
S4 |
0.957 |
0.943 |
0.934 |
0.940 |
0.834 |
-0.781 |
S5 |
0.99 |
0.961 |
0.986 |
0.988 |
0.752 |
-0.677 |
S6 |
0.989 |
0.980 |
0.990 |
0.990 |
0.886 |
-0.901 |
S7 |
0.990 |
0.903 |
0.944 |
0.973 |
0.921 |
-0.936 |
S8 |
0.995 |
0.944 |
0.971 |
0.987 |
0.831 |
-0.846 |
S9 |
0.996 |
0.936 |
0.985 |
0.993 |
0.915 |
-0.929 |
S10 |
0.994 |
0.926 |
0.963 |
0.974 |
0.796 |
-0.831 |
Fig 3: DSC of pure drug theophylline and formulation S3
SEM (Scanning Electron Microscopy):
Tablet powder was sputtered coated using pelco gold palladium coaters. The surface morphology of the layered powder was examined using SEM. The samples were placed in an evacuated chamber and scanned in a controlled pattern by an electron beam. Interaction of the electron beam with the specimen produces a variety of physical phenomenon’s that were detected used to form images and provide information about the specimens. Figure 4
Fig 4: Surface characteristics of formulation S3 at ×500 magnification
RESULTS AND DISCUSSION:
Flow Properties of Granules:
Flow properties play an important role in pharmaceuticals especially in tablet formulation. The bulk density of the powder was in the range of 0.210 + 0.007 to 0.3863 + 0.04 gm/cc; the tapped density was in the range of 0.245 + 0.016 to 0.4796 + 0.003 gm/cc, which indicate powder was not bulky. The angle of repose of the drug powder was in the range of 26.42 + 0.144° to 29.39 + 1.18°, which indicates good flow of the granules, the Carr’s index was found to be in the range of 11.20 + 1.23 to 16.83 + 0.64, which indicate good flow properties to granules.
Evaluation of Floating Tablets
In the current study floating tablets of theophylline were prepared using Methocel K100LV and K15 M as matrix polymers, Sodium bicarbonate as gas generating agent, Citric acid as release rate enhancer, PVP K-30 in isopropyl alcohol as a binder and lactose as diluents.
All the tablets were prepared by effervescent approach. Sodium bicarbonate was added as a gas-generating agent. Sodium bicarbonate induced carbon dioxide generation in presence of dissolution medium (0.1 N hydrochloric acid). The combination of sodium bicarbonate and citric acid provided desired floating ability and therefore this combination was selected for the formulation of the floating tablets. It was observed that the gas generated is trapped and protected within the gel, formed by hydration of polymer (methocel), thus decreasing the density of the tablet below 1 and tablet becomes buoyant. The tablet swelled radially and axially during in vitro buoyancy studies. All the batches of tablets were found to exhibit short floating lag times due to presence of sodium bicarbonate and citric acid. Decrease in the citric acid level increased the floating lag time and tablets were found to float for longer duration. The tablets with low-viscosity grade methocel K100LV exhibited short floating lag time and floated for longer duration as compared with formulations containing high viscosity grade methocel K15M. This indicated that the molecular weight distribution or viscosity of the gel-forming polymer methocel influenced the in vitro buoyancy. Reduction in methocel level in the formulations S4, S5, S9 and S10 prolonged the floating lag time and shortened the total floating time. Thus a combination of sodium bicarbonate (50mg) and citric acid (4mg) with methocel (150mg) was found to achieve optimum in vitro buoyancy and floatability.
The pH of the stomach is elevated under fed condition (~3.5) therefore citric acid was incorporated in the formulation to provide an acidic medium for sodium bicarbonate. The effect of two different grades of methocel in the tablet with varying proportion of citric acid and sodium bicarbonate was studied on the release characteristics.
In post compression parameters, the thickness of the tablet indicate that, die fill was uniform. The thickness depends on the size of the punch (12.00mm) and the weight of one tablet (450mg). The thickness of the trial formula from S1 to S10 was found to be 3.30±0.16 to 3.35±0.16 and hardness was found to be 5.2±0.47 to 6.6±0.11 kg/cm2, which indicates good mechanical strength of tablets.
In the evaluation parameters all the formulations were evaluated for swelling index, Floating Lag time, Floating duration, drug content, in vitro drug release and model fitting.
Drug release studies:
In vitro dissolution studies were performed for all the formulations using USP XXII dissolution apparatus type II (Electrolab tablet dissolution apparatus) at 50 rpm using 900 ml of 0.1N HCl as dissolution medium. The samples withdrawn were analyzed by using UV spectrophotometer. Formulation S3 shown good drug release when it compared to other formulations. It is evident from the in vitro dissolution data that increase in citric acid concentration increased the release rate but reduced the floating time, probably due to of excess carbon dioxide, disturbing the monolithic tablet. The citric acid level in the formulations greatly influenced the drug release, irrespective of methocel grade. The drug release from floating tablets was found to be 85.58% to 98.19% for S1 to S5 with methocel K100 LV. The drug release from formulations containing high-viscosity grade methocel K15M (S6 to S8) varied between 83.43 to 89.73%. The prepared formulations sustained the drug release for a period of 7-10 hours. Comparing the two different grades of methocel (K100 LV and K15M), it was found that low-viscosity grade methocel K100 LV provided better-sustained release characteristics with excellent in vitro buoyancy. Formulations containing sodium bicarbonate and citric acid in ratio of 5:0.4 with varying amount of methocel were studied for their effect on release profile of theophylline. It was observed that the release of theophylline from such formulations increased on decreasing the proportion of methocel in the formulation but duration of floating decreased. Figure-2.
Formulations S1 to S3 and S6 to S9 shown good water uptake up to 10 hrs with slow and uniform swelling ,whereas formulations S4, S5, S10 shown faster swelling in about 5h with complete swelling in 7h followed by erosion process attributing gradual decrease in percent swelling after 7h. With respect to Floating lag time(FLT) and Floating duration (FD) of formulations S1 to S3 had shown FLT within the range 1.20-1.70 min and FD more than 10 hrs. S4, S5, S10 had shown FLT in the range 3.50-5.10 min and disintegrated after 7 hr, 8hr, 9hr with FD less than 10 hr. S6-S9 had shown FLT in the range 2.36-2.75 min with FD more than 10 hrs.
The kinetics of theophylline was determined by finding the best fit of the dissolution data to distinct models- Zero order, First order, Higuchi plot and Peppas model. The release mechanisms of theophylline from floating tablet were evaluated on the basis of Peppas model. The n value of all the formulations ranges from lowest 0.752 to highest 0.960 which was in the range 0.45<n<1.0 which indicate the mechanism of release of theophylline is anomalous (non-Fickian) transport.
Fig 2: In vitro drug release patterns from formulations S1 to S5 (a) and S6 to S10 (b).
Based upon the evaluation parameters best formulations had been selected and subjected for stability studies as per ICH guidelines. Formulations subjected for stability studies have been checked for drug content, FLT, FD, hardness, friability and physical appearance etc. at 15 days interval up to 90 days. The formulations were found to be stable because there was no significant change has been observed in the various evaluated parameters of the formulations.
The selected formulations S3 showed n values 0.821 which was in the range of 0.45-.89 indicating anomalous transport and met the conditions of Ritger and peppas model values for the matrix tablet where cylindrical geometry is considered. Also for formulations S3 the regression values of first order, zero order and Higuchi plot model fitting was found to be 0.983, 0.938 and 0.993 respectively. As the regression value for zero order model fitting was found to be more comparing to first order model fitting in both the formulations, indicates that formulations S3 follows zero order drug release. Comparison of optimized batch (S3) with the USP tolerance limit on Table 7.
TABLE 7: Comparison of optimized batch (S3) with the USP tolerance limit
Time (hr) |
Release profile of theophylline for extended release(USP tolerance limit) % |
Optimized S3formulation % of release |
1 |
5-15 |
9.44 |
2 |
15-30 |
21.00 |
4 |
25-50 |
50.45 |
5 |
30-60 |
54.70 |
9 |
73-90 |
89.95 |
ACKNOWLEDGEMENT:
The authors are thankful to the Management, Sree Siddaganga College of pharmacy, for providing necessary facilities to carry out this work.
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Received on 18.03.2010 Modified on 29.03.2010
Accepted on 07.04.2010 © RJPT All right reserved
Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1066-1071