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Formulation and In-vitro Characterisation of Sustained ReleaseMetronidazole

Cocoa Butter Suppositories

Article · October 2012

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 RESEARCH ARTICLE

Formulation and In-vitro Characterisation of Sustained Release

Metronidazole Cocoa Butter Suppositories
V Ravi Sankar1*, Y Dastagiri Reddy1, G Hanumantha Reddy1, G Sudheer Kumar Reddy1
Abstracts: Suppositories are spherical shaped solid dosage form of medicament meant for insertion into body cavities other
than mouth. They are generally intended for use in the rectum, vagina, and to lesser extent, the urethra. Metronidazole is the
FDA-approved drug for clinical use for the treatment of vaginal infections either alone or in combination with other antibiotics.
Metronidazole is absorbed rapidly following oral administration producing peak plasma concentration within 1-2 hours
with100% bioavailability. Elimination half life is 6-7 hours and is usually administered in a dose of 200-500 mg in order to
maintain effective concentration throughout the day. So the present work involves use of suppositories which has no first pass
effect. This will ensure minimum fluctuations in the plasma drug concentration and reduced dosing frequency which will result
into improved patient compliance. The objective of the work is to Formulate and evaluate the Metronidazole containing cocoa
butter suppositories, to study the effect of different surfactants and different concentration of individual surfactants on the drug
release behavior. To perform stability studies as per ICH guidelines. The study has shown that different physical properties and
release rates depends up on the formulation contents Tween 80, SLS and Span 20 at various levels are used for formulation
studies. From the results it was conclude that Twee 80 has shown a considerable increase in disintegration and dissolution
behavior and Sodium lauryl sulphate 2% has shown a good sustaining property for a period of 12 hours.

INTRODUCTION Preformulation Study

Suppositories are spherical shaped solid dosage form of Drug Excipient Compatibility Study
medicament meant for insertion into body cavities other Fourier Transforms Infra-red (FTIR) Spectroscopy
than mouth. They are generally intended for use in the FTIR study was carried out to check compatibility of drug
rectum, vagina, and to lesser extent, the urethra. Rectal and with base (cocoa butter). Infrared spectrum of
urethral suppositories usually employ vehicles that melt or metranidazole was determined on Fourier transform
soften at body temperature, whereas vaginal suppositories, Infrared Spectrophotometer using KBr dispersion method.
sometimes also called pessaries, are also made as The base line correction was done using dried potassium
compressed tablets that disintegrate in the body fluids 1. bromide. Then the spectrum of dried mixture of drug and
The rectum is a convenient route for the systemic potassium bromide was run followed by drug with various
administration of drug. The abundant supply of blood polymers by using Parkin elmer-Pharmaspec-1 FTIR
vessels and rapid diffusion of drugs through the rectal spectrophotometer.
mucosa permits rapid absorption of many drugs 2-3. The
venous drainage in the rectum contains lower, middle and Formulation of Suppository
upper hemorrhoidal veins. The lower and middle Metronidazole, drug was passed through the 120 mesh and
hemorrhoidal veins drain directly into the general cocoa butter and the surfactant are mixed in required
circulation and avoid the first pass metabolism 3. proportions and mixed thoroughly in mortor and pestle
Metronidazole is a nitroimadazole derivative and it is and transfer to china dish. Heat the contents until it melts
the drug of choice for intestinal amoebiasis 4-6. Due to its by continuous stirring. The suppository mould is lubricated
activity against anaerobic bacteria, metronidazole useful in with liquid paraffin to avoid sticking of suppository and
the treatment of Periodantal disease. It is indicated for the then place it in ice. The melted mass is then transferred
treatment of trichomoniasis, vaginitis and urethritis caused into suppository mould which was placed in ice. Allow it for
by Gardnerella vaginalis 7.
solidification of the mass. After formation of the
Depending upon the indication the dosage regimen of
suppository detach it from the mould and wrap in
Metronidazole can vary from 250mg three times daily for 7
aluminium foil and store in refrigerator 11.
days to 750mg three times daily for 10 days 8. Metronidazole
is BCS Class I drug and it is rapidly absorbed with a
Evaluation of Suppositories 12
bioavailability higher than 90%. It is metabolized primarily
Suppositories are evaluated for the visual parameters
in liver by oxidation and glucoronide conjugation and
such as fissuring, pitting, blooming, exudation, migration
excreted in urine. It has the elimination half life 8hrs 9-10.
of active ingredient and physical parameters such as
MATERIALS AND METHODS length, width, weight variation, hardness (crushing/
Metronidazole procured as a gift sample from Bio plus p.v.t mechanical strength), friability, melting time,
limited hosur, India. Cocoa Butter purchased from local saponification value of prepared suppositories were
dealers, Sodium Lauryl Sulphate, Tween 80, and Span 20 determined.
were purchased from Loba Cheme pvt. Ltd., Mumbai, India.
Visual Characterization 12
The randomly selected suppositories (six from each batch)
1Department of Pharmaceutics, C E S College of Pharmacy, Kurnool-
were cut longitudinally and examined with naked eye
518218, Andhra Pradesh, India.
E-mail: ravi_srmcp@yahoo.co.in (subjective evaluation) to assess the homogeneity of
*Corresponding author surface appearance and colour of suppositories by 1)

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 RESEARCH ARTICLE

Table 1: Shows Composition of Suppository Formulation

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Metronodazole* 200 200 200 200 200 200 200 200 200 200
Cocoa Butter* 800 800 800 800 800 800 800 800 800 800
Methyl Paraben** 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01
Tween80** - 2 4 6 - - - - - -
SLS ** - - - - 0.5 1 2 - - -
Span 20** - - - - - - - 2 4 6
*All the quantities are expressed as mg per suppository. ** All the quantities are expressed as percentage (%)

Table 2: Table Shows Physicochemical Characterization of Metronidazole Suppositories

Dimension Crushing Strength Friability (%) Weight Variation Drug Content

Code
Diameter (cm)** Thickness (cm)** (kg/cm2)** *** (%)*** (%w/w)*
F1 2.4±0.1 1.2±0.12 3.2±0.12 0.41±0.05 1.0±0.12 99.81±1.4
F2 2.4±0.0 1.2±0.12 3.4±0.11 0.31±0.08 1.0±0.12 99.67±1.7
F3 2.4±0.0 1.2±0.13 3.5±0.12 0.36±0.03 0.9±0.11 98.75±0.5
F4 2.4±0.2 1.2±0.17 3.6±0.10 0.37±0.01 1.0±0.10 99.47±1.3
F5 2.4±0.6 1.2±0.14 3.8±0.22 0.36±0.08 0.9±0.99 100.07±0.5
F6 2.4±0.0 1.2±0.11 3.9±0.12 0.28±0.06 1.0±0.02 100.38±0.8
F7 2.4±0.3 1.2±0.13 3.9±0.02 0.41±0.03 0.9±0.91 100.01±1.7
F8 2.4±0.0 1.2±0.12 3.9±0.16 0.36±0.12 1.0±0.12 98.24±0.6
F9 2.4±0.0 1.2±0.16 3.6±0.12 0.34±0.10 0.9±0.51 99.39±1.5
F10 2.4±0.0 1.2±0.16 3.6±0.12 0.34±0.10 0.9±0.69 99.39±1.5

Table 3: Table Shows Dissolution Data of All Formulations in (%) (F1 – F10)

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
0.3 2.17±0.95 1.63±0.93 2.32±0.06 3.0±0.38 2.39±1.67 2.59±1.39 2.84±1.99 2.07±1.44 4.43±2.34 6.84±1.11
1 4.16±0.96 3.6±0.42 5.46±1.55 7.32±0.64 4.72±1.37 5.52±0.91 6.33±1.37 4.72±1.2 9.37±0.87 14.06±0.40
2 9.21±0.81 10.34±0.62 13.71±0.30 17.15±0.26 11.04±0.63 12.32±0.48 13.62±0.37 12.56±0.61 21.65±0.39 30.75±0.57
4 20.4±0.29 31.3±0.62 38.22±0.22 45.22±0.12 29.72±0.24 30.82±0.17 31.96±0.32 33.85±0.15 51.12±0.20 68.43±0.06
6 36.0±0.27 82.52±0.09 66.16±0.09 79.67±0.05 52.64±0.09 54.44±0.13 56.25±0.13 59.4±0.72 79.64±0.14 99.46±0.65
8 56.81±0.11 76.91±0.08 88.51±0.05 100.03±0.63 79.83±0.11 77.71±0.05 75.59±0.06 84.09±0.08 92.13±0.1 99.89±0.27
10 80.61±0.10 99.02±0.12 99.52±0.05 100.04±0.05 99.96±0.15 100.12±0.32 101.0±0.20 100.01±0.07 99.83±0.35 100.02±0.06
12 86.28±0.62 100.05±0.04 99.99±0.09 100.06±0.05 100.06±0.05 100.17±0.25 100.6±0.52 100.06±0.05 100.07±0.07 100.06±0.11

Table 4: Shows Diffusion Data of all Formulations in (%)

Time
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
(hours)
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
0.3 1.66±0.91 2.03±1.23 2.74±1.09 3.47±0.87 1.74±1.44 2.31±0.86 2.91±0.34 1.78±0.64 2.05±2.02 2.36±1.7
1 3.32±0.45 4.46±0.68 4.94±1.01 5.45±0.56 3.56±1.86 4.08±0.64 4.61±0.33 3.64±0.57 3.98±0.63 4.27±1.07
2 6.82±4.1 9.79±0.27 10.16±0.45 10.53±0.39 7.8±0.12 8.44±0.53 9.03±0.67 12.74±0.23 14.35±0.17 16.07±0.27
4 16.58±2.11 23.18±0.17 23.26±0.19 23.35±0.02 19.45±0.24 20.09±0.14 20.75±0.18 25.05±0.14 27.08±0.25 29.26±0.07
6 22.54±0.25 31.62±1.07 33.28±0.54 35.29±0.14 22.89±0.06 23.62±0.13 24.32±0.12 32.46±0.05 36.63±0.11 40.93±0.11
8 29.69±1.2 41.03±0.27 42.29±0.2 43.83±0.08 31.48±0.08 32.07±0.18 32.54±0.13 42.62±0.075 48.73±0.08 54.86±0.09
10 32.79±0.5 45.76±0.47 48.53±0.16 51.5±0.01 34.6±0.04 36.13±0.13 37.62±0.08 48.93±0.10 57.92±0.04 66.91±0.01
12 39.6±1.02 55.61±0.04 58.84±0.07 62.13±0.07 40.73±0.12 42.81±0.03 44.93±0.1 52.61±0.03 62.35±0.03 72.81±0.02

Absence of fissuring. 2) Absence of pitting. 3) Absence of fat Crushing Strength 12

blooming. 4) Absence of exudation. 5) Absence of migration The Crushing strength was determined for measuring
of the active ingredients. fragility or brittleness of suppositories. This can be
performed by taking suppositories randomly and subjected
Length and width12 for crushing using Monsanto hardness tester and the values
The width and length of the randomly selected were recorded.
suppositories (six suppositories from each batch) were
measured for their physical dimension. After that the same Weight Variation 12
number of suppositories were selected and cut Twenty suppositories were weighed and average weight
longitudinally and the surface was examined with the was calculated. Each suppository was then individually
naked eye for the homogeneity. weighed by using digital balance. Not more than 2 of the

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 RESEARCH ARTICLE

Table 5: Table Shows Different Kinetic Models for Stavudine Floating Tablets (f1 to f10)

F Zero Order First Order Higuchi Peppas n Value Best Fit Model
F1 0.976 0.957 0.749 0.975 0.660 Zero Order
F2 0.979 0.801 0.782 0.985 0.567 Peppas
F3 0.965 0.866 0.820 0.986 0.614 Peppas
F4 0.923 0.971 0.835 0.984 0.647 Peppas
F5 0.976 0.685 0.828 0.978 0.619 Peppas
F6 0.980 0.976 0.786 0.983 0.645 Peppas
F7 0.982 0.989 0.799 0.986 0.671 First Order
F8 0.974 0.985 0.802 0.9870 0.602 Peppas
F9 0.928 0.992 0.871 0.986 0.735 First Order
F10 0.804 0926 0.883 0.974 0.824 Peppas

Table 6: Shows Stability Studies of Optimized Formulation (F5)

Characteristic Initials 1 Month 2 Month 3 Month

Hardness (kg/cm2)* 3.6±0.3 3.69±0.36 3.79±0.06 3.88±0.23
Drug content (mg/tablet)* 100.07±0.5 100.04±1.5 99.39±1.5 99.47±1.32
Saponification Values 195.3±0.15 193.3±0.15 196.3±0.15 198.3±0.15
In vitro drug release at 12 hour* 100.06±0.5 100.06±0.5 100.06±0.5 100.06±0.5

individual masses deviate from the average mass by more b = blank titration value in ml, a = actual titration value
than 5% and non deviate by more than twice that % (U.S.P., in ml, w = weight of sample
1990.).
Disintegration Test 15
Content Uniformity 12-13 The disintegration time is a critical factor in the
Content uniformity test was determined by determination of the release rate of the active ingredient(s)
spectrophotometric method. The suppository was from the suppository. During this test, the time taken for the
individually melted, dissolved in 100 ml of separate volume suppository to melt or disperse is measured when immersed
flask containing pH 7.4 Phosphate buffer and the solution in a water bath maintained at constant temperature (37°C ±
was filtered using 0.45m membrane and then the 1°C). The time required for the suppository to melt or
absorbance was measured using thermospectronic UV-1 at disperse in the surrounding water was noted.
a wave length of 275 nm.
In-vitro Dissolution 16
Friability 12 The release rate of Metronidazole from suppositories was
Twenty suppositories were weighed and placed in the determined using Dissolution Testing Apparatus type - I.
plastic chamber of Roches Fribilator. The chamber was The dissolution test was performed using 500 ml of 7.4
then rotated for 4 minutes at 25 rpm (a total of 100 phosphate buffer at 37 ± 0.5°C and 50 rpm. A sample (5 ml)
revolutions). After 100 revolutions suppositories were of the solution was withdrawn from the dissolution
removed and weighed again. A loss of less than 1 % in apparatus every half an hour and the samples were
weight is generally considered acceptable. Percent friability replaced with fresh dissolution medium. The samples were
(% F) was calculated as follows: filtered through a 0.45μ membrane filter and the
absorbance of these solutions was measured at 275nm
‹–‹ƒŽ™‡‹‰Š– െ ‹ƒŽ™‡‹‰Š– using a Elico Company SL 164 double beam UV-Visible
Ψ ൌ  ൈ ͳͲͲ
‹–‹ƒŽ™‡‹‰Š– spectrophotometer For each formulation, the experiments
were carried out in triplicate and represented in table 3.
Saponificatin Value 14
Introduce about 2gm of substance being examined into In-vitro Diffusion 17-18
200ml flask or borosilicate glass fitted with reflux Diffusion study was performed by taking 500ml of
condenser. Add 25ml of 0.5M ethanolic KOH and little phosphate buffer 7.4 in a 1000ml beaker and placed on the
pumice powder, and then boil under reflux on a water magnetic stirrer. The suppository was placed in High Media
bath for 30 minutes. Condenser was removed and to this Dialysis Membrane (HIMEDIA) and suspended in to the
1ml of phenolphthalein was added and the content was solution. A Magnetic bead was placed in the solution. The
cooled and add excess of KOH was titrated immediately diffusion study was carried out at temperature 37 ± 0.5°C
with 0.5N HCl. Repeat the operation omitting the substance and 50 rpm. A sample (5 ml) of the solution was withdrawn
being examined (i.e.) Blank titration was done excluding from the diffusion apparatus every half an hour and the
sample. The saponification value was calculated as: samples were replaced with fresh dissolution medium. The
samples were filtered through a 0.45μ membrane filter and
ʹͺǤͲͷሺ„ െ ƒሻ the absorbance of these solutions was measured at 275nm
ƒ’‘‹ϐ‹…ƒ–‹‘˜ƒŽ—‡ ൌ
™ using an Elico Company SL 164 double beam UV-Visible

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 RESEARCH ARTICLE

Figure 1: Showing the FTIR of metranidazole

Figure 2: Showing the FTIR of metranidazole and cocoa butter

spectrophotometer. For each formulation, the experiments First Order 19

were carried out in triplicate and represented in Table 4. Ž‘‰  ൌ Ž‘‰ ଴ െ  ୲ ȀʹǤ͵Ͳ͵
Where, C0 - is the initial concentration of drug, K - is the
Surface area of suppository = 11.304 sqcm. first order constant, t - is the time in hrs.
Assay Higuchi 20-21
The suppository containing 200 mg of metronidazole was
– ൌ – ଵΤଶ
dissolved in anhydrous glacial acetic acid and Titrate with
0.1M perchloric acid using crystal violet as indicator. Carry Where, Qt - is the amount of the release drug in time t, K-
out the blank titration is the kinetic constant and t- is time in hrs

‹–”ƒ–˜ƒŽ—‡ ൈ “—‹˜ƒŽ‡–ˆƒ…–‘” ൈ Korsmeyer Peppas 20-21

…–—ƒŽ‘”ƒŽ‹–› –Ȁλ ൌ –
Ψ—”‹–› ൌ ൈ ͳͲͲ
‡‹‰Š–‘ˆƒ’Ž‡ ൈ
‹˜‡‘”ƒŽ‹–› Where Mt-represents amount of the released drug at
time t, M∞-is the overall amount of the drug (whole dose)
Kinetics of In-vitro Drug Release released after 12 hrs, K-is the diffusional characteristic of
To study the release kinetics of In-vitro drug release, data drug/ polymer system constant, n-is a diffusional exponent
was applied to kinetic models such as zero order, first that characterizes the mechanism of release of drug.
order, Higuchi and Korsmeyer-Peppas.
Stability Study
Zero Order 19 Stability studies were carried out for the optimized
C=K0t formulation F5 as per ICH specifications for a period of up
Where, K0 - is the zero-order rate constant expressed in to 3 months at accelerated condition (40°C ± 2°C at 75%
units of concentration/time, t -is the time in hrs. RH ± 5%RH) to find out the effect of aging on hardness,

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 RESEARCH ARTICLE

Percentage release Vs. TIme Percentage diffusing Vs. Time

120 80

70
100

Percentage diffusing (%)

Percentagerelease(%)

F1 60
80 F2 F1
F3 50 F2
F4 F3
60 40 F4
F5
F5
F6 30
40 F6
F7 F7
F8 20 F8
20 F9 F9
F10 10 F10
0 0
0 5 10 15 0 5 10 15
Time(Hours) Time (Hours)

Figure 3: Cumulative drug release vs. time Figure 4: Cumulative percentage diffusing vs. time

Percentage Release Vs. Time

120

100
Percentagerelease (%)

80

60
Initial
40 1 month
2 months
20 3 months

0
0 5 10 15
Time(Hours)
Figure 5: Shows comparisons for drug release profile of before and after stability studies for optimized formulation F5

floating characteristic, drug content and In-vitro drug variation and drug content were determined and results of
release 22-23. the formulations (F1 to F10) found to be within the limits
specified in official books.
RESULTS AND DISCUSSION The saponification value is indicative of rancidity of the
Major functional groups present in Metronidazole show formulation the values are in the range of 189.5 to 194.3
same characteristic peaks in IR spectrum. When it is which are in the limits. The disintegration test was
checked for compatibility with cocoa butter in similar performed using Rolex company (IP/BP/USP standard)
proportions (20:80) peaks observed at different wave and was found to be 8.20 to 8.80 minutes.
numbers. O-H stretching (3422.42cm -1), N-H stretching Dissolution study results indicates when cumulative %
(3124.97 cm-1), C-N stretching (aromatic amine) drug release plotted versus time (Figure), it was observed
(1261.00 cm-1), N-H bending (677.86 cm -1), C=N that, for three of the surfactants used, an increase in
stretching (1718.36 cm -1 ), C-H stretching (2982.14 cm- surfactants concentration from 2% to 6%, (in case of tween80
1), C-H bending (555.95 cm -1), C=C stretching (1598.25 and span 20) and 0.5% to 2% (incase of SLS. The highest
cm-1) The major peaks are identical to functional group percentage to be taken as per limits is 2% so it was prepared
of Metronidazole. Hence, the cocoa butter confirmed to in 0.5% to 2%) there is an increase in the release rate.
be compatible. The physical and release properties of Metronidazole
The suppositories were observed visually and did not suppositories are influenced considerably by the bases
show any defects such as blooming, pitting, fissuring, and adjuvants employed. Tween80 and Span20 can
exudation etc. The physical characteristic of Metronidazole probably be used to formulate only immediate release
suppositories (F1 to F10) such as thickness (1.2±0.11 to suppositories while SLS can be useful for sustained
3.31±0.17), diameter (2.4±0.0 cm), hardness (3.2±0.12 to release suppositories. This can be inferred by observing
3.9±0.16), friability (0.28±0.06 to 0.41±0.05 %), weight %CRD values of the formulations mentioned in the Table

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 RESEARCH ARTICLE

3 and the Figure 3 indicates the cumulative percentage 5. Greenstein G: The role of metronidazole in the treatment of
release vs. Time. periodontal disease, J. Periodontal., 1:1. 1993.
In-vitro Diffusion studies the amount of drug that 6. Rams T E., Feik D. and Slots J: Ciprofloxacin/metronidazole
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319, 1992.
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7. Brazilian Health Surveillance Agency (ANVISA). 2009. Flagyl
tween 80 is having good diffusion capacity when compared label. Accessed December 15. at: http:// www4.anvisa.gov.br/
with sodium lauryl sulphate Table 4 and Figure 4 showing base/visadoc/BM/BM[26406--1-0].PDF, 2009.
the diffusion capacity of different formulation through the 8. Food and Drug Administration (FDA). 2004. Flagyl label.
diffusion membrane (High media) from the suppositories. Accessed December 15, 2009, at: http://www.accessdata. fda.
The kinetics of In-vitro drug release was determined by gov/ drugsatfda docs/label/2004/12623slr059 flagyl lbl.pdf
applying the drug release data to various kinetic models 9. Sweetman S C. 2009. Martindale: The complete drug
such as zero order, first order, Higuchi and Korsmeyer- reference. 36th ed. London: Pharmaceutical Press, pp 837–
Peppas. The result obtained was shown in Table 5. 841.
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11. Reiko Yahagi, Hiraku Onishi, Yoshiharu Machida. Preparation
anomalous type of diffusion from the dosage forms i.e there
and evaluation of double-phased mucoadhesive suppositories
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parameters; results are shown in Table 6. Toippet S, Kinget R. Pharm. Res., 14:1730–1737. 1997.
No major difference was found between evaluated 13. Official methods of Analysis of AOAC (1998) 16th ed, AOAC
parameters before and after stability studies and all are in International, Maryland.
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Industrial Pharmacy. CBS Publications, New Delhi. Special
CONCLUSION Indian edition: 569p. 2009.
15. British Pharmacopoeia. London: The Stationary Office; 2001:
In the present work nine formulations were prepared with
p. 2015, A235R.
different concentration of surfactants and compared with 16. Brondsted H, Andersen C, Hovgaard L J. Control. Release,
the none surfactant one from the results we can conclude 53:7–13. 1998.
that All the formulations were found to have homogeneous 17. Gjellan K, Graffner C. Comparative dissolution studies of rectal
drug distribution with content uniformity, (98.24±0.6 to formulations using the basket, the paddle and the flow-
100.38±0.8), diameter, (2.4±0.1 to 2.4±0.0), Thickness through methods. I. Paracetamol in suppositories and soft
(1.2±0.12 to 1.2±0.17), Crushing strength (3.2±0.12 to gelatin capsules of both hydrophilic and lipophilic types. Acta
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