Pharmaceutical Characterization and Assessment of Drug Release Behaviour of Diclofenac Sodium Extended Release Matrix Devices
Pharmaceutical Characterization and Assessment of Drug Release Behaviour of Diclofenac Sodium Extended Release Matrix Devices
Pharmaceutical Characterization and Assessment of Drug Release Behaviour of Diclofenac Sodium Extended Release Matrix Devices
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Vol. 2, Issue-1, JAN-JUNE, 2009
Int J Pharm Sci Tech (© 2009)
cation, the absorption process and subsequently drug action, quantities of hydroxy propyl methyl cellulose, sodium algi-
can be controlled5. nate and sodium carboxy methylcellulose along with drug
One of the first commercially available product to provide sus- for F1 to F6 (Table 1) mixed by geometric dilution method
tained release of a drug formulation was Dexedrine spansules®, in a double cone mixer at 90 rpm for 15 min. The granu-
made by Smith Kline & French6. After this many more sus- lating agents (water for F1 to F5, and 4 % ethanolic solu-
tained release products came to the market, some successful, tion of ethyl cellulose for F6) were added slowly to this
others potentially lethal. Each delivery system was aimed at elimi- blend. After enough cohesiveness was obtained the mass
nating the cyclical changes in plasma concentration seen after was sieved through 22 mesh size and the granules so ob-
the administration of conventional delivery system7. tained were dried in an oven at 40° C and were kept in a
With most orally administered drugs, targeting is not a desiccators for 12 hr. talc and magnesium stearate were
primary concern, unless for the drugs having very specific ab- finally added as glidant and lubricant, the tablets were com-
sorption window, as it is usually intended for drugs to permeate pressed using a single punch tablet machine9.
to the general circulation and perfuse to other body tissue rather
it is desired to get a controlled absorption providing prolonged
duration of action and minimizing the side effects. For this rea-
son, most systems employed are of the sustained release vari-
ety. It is assumed that increasing concentration at the absorption
site will increase the rate of absorption and therefore increase
circulating blood level which in turn promotes greater concen-
tration of drug at site of action. If toxicity is not an issue, thera-
peutic level can thus be extended. In essence, drug delivery by
these systems usually depends on release from some type of
dosage form, permeation though the biological milieu, and ab-
sorption though epithelial membrane to the blood8.
The present study focus on the release retardant matrix tablet
dosage form for controlled release of diclofenac sodium using
polymer backbone of HPMC, sodium alginate and sodium
carboxy methylcellulose in different combinations and ratios. The
diclofenac sodium is well established anti-inflammatory drug. The
aim of study is to develop a once daily sustained release tablet
dosage form of diclofenac sodium by optimizing the release profile The prepared tablets were studied for thickness,
of drug through varying the composition of polymer backbone. diameter, diameter/height ratio (D/H ratio), hardness,
2. MATERIALS AND METHODS: weight variation, drug content, and in vitro drug release
2.1. Materials: studies; before tablet preparation, the granules were evalu-
Diclofenac sodium was kindly gifted by the Apco Pharmaceuti- ated for angle of repose, bulk density, hausner’s ratio, com-
cals Ltd. (Haridwar), Cetosteryl alcohol (CDH, New Delhi), pressibility index and particle size determination.
Magnesium stearate (SD fine chemicals New Delhi), Sodium
hydroxide (Ranbaxy fine chemicals), Spray dried lactose (Merk 2.2.2. Estimation of Drug:
India Ltd., Mumbai), Sodium hydrogen phosphate (Merk India The content of diclofenac sodium in tablets and its release
Ltd. Mumbai) and Disodium hydrogen phosphate (Merk India as a function of time was estimated spectrophotometri-
Ltd. Mumbai). The marketed brands of the Diclofenac Sodium cally using an UV spectrophotometer (U2001 Hitachi, Ja-
SR tablets taken in present study were Nac SR, Voveran SR, pan) based on the measurement of absorbance at 276 nm
Relaxyl SR, Zobid SR, Vovo SR and Divon SR. (l max) in aqueous buffer medium (pH 6.8) using standard
2.2. Methods: plot10, 11.
2.2.1. Preparation of Matrix Tablets:
The matrix tablets were prepared by mixing the corresponding 2.2.3. Evaluation of Granules:
2.2.3.1. Angle of repose: The angle of repose of gran-
ules was determined by the funnel method. Weighed quantity sure the absorbance of resulting solution at the maximum
of granules were taken in and poured from funnel and height of max
284.5 nm. Calculated the content of
the funnel was adjusted in such a way that the tip of the funnel C14H10Cl2NNaO2 from the absorbance obtained by re-
just touched the apex of the heap of the granules. The diameter peating the procedure using diclofenac sodium. Declared
of the powder cone was measured and angle of repose was the content of C14H10Cl2NNaO2 in diclofenac sodium9
calculated12 using formula tan è = h/r. 2.2.4.5. In-vitro drug release study: The release of
2.2.3.2. Bulk density: Both loose bulk density (LBD) and diclofenac sodium from the tablets was studied in buff-
tapped bulk density (TBD) were determined. A quantity of 20 ered aqueous medium as per USP guidelines using USP
gm of powder from each formula, previously lightly shaken to XXVI Dissolution test apparatus basket type (Campbell
break any agglomerates formed, was introduced into a 50 ml Electronics, Mumbai) at 37± 0.2 0 C with a rotating speed
measuring cylinder. After the initial volume was observed, the of 75 rpm18, 19. At preset time intervals 5ml aliquots were
cylinder allowed falling under its own weight onto a hard sur- withdrawn and replaced by an equal volume of fresh dis-
face from the height of 0.5-1.5 cm at 5 sec intervals. The tap- solution medium. The samples were withdrawn through a
ping has continued until no further change in volume was noted. membrane filter (0.45 mm) and were analyzed for drug
LBD and TBD were calculating using these formulas13. content spectrophotometrically. The in vitro dissolution
LBD = weight of the powder/ volume of packing profile studies for characterization of release kinetics were
2.2.3.3. Compressibility: The compressibility and flow prop- carried as per the SUPAC guidelines for the modified re-
erty of the granules was determined by Carr’s compressibility lease dosage forms20.
index and Hauser’s ratio calculated as below14: The concentration of diclofenac sodium was corrected
Carr’s compressibility index (%) = for sampling effects according to the following equation:
[(TBD-LBD) ×100/TBD] ------ (1)
Hausner’s ratio = [TBD/LBD × 100] ---- (2) ---- (3)
2.2.3.4. Particle size determination: A sieve stack with six
sieves in aperture progression was loaded with powder on to Where, Cn is the corrected concentration of the
the coarsest sieve of the assembled stack and nest is subjected nth sample, Mn is the measured concentration of the nth
to mechanical vibration. After 10 min, the particles are consid- sample, VT is the volume of the dissolution medium, VS
ered to be retained on the sieve mesh; then weighed the pow- is the volume of the sample withdrawn, Cn-1 is the
der retained in the sieves and the respective parameters were corrected concentration of the (n-1)th sample, and
calculated15 Mn-1 is the measured concentration of the (n-1)th
2.2.4. Evaluation of Tablets: sample,
2.2.4.1. Dimensional Analysis: The thickness and diameter 2.2.5. Statistical Analysis:
of tablets was determined using vernier caliper. Twenty tablets Data presented in the drug release figures are
from each batch were used and average values were calcu- “mean” of the triplicate study except when otherwise
lated. stated. Statistical comparisons were made using Student’s
2.2.4.2. Hardness: For each formulation, the hardness of six t-test (P< 0.05). The 95 % confidence interval was cal-
tablets was determined using the Monsanto hardness tester and culated for the slope of the line when the fraction re-
average value were calculated9, 16. leased was plotted as a function of time in different ki-
2.2.4.3. Weight variation test: Twenty tablets were selected netic models. Results are given as means ± standard er-
at random from each of the batch. Average weight and maxi- rors of the mean (S.E.M.).
mum percent deviation (positive and negative) were determined9, For comparison of multiple dissolution profiles ob-
17
. tained, similarity testing was also performed using pair
2.2.4.4. Content uniformity: Twenty tablets were weighed wise dissolution data obtained in each individual medium
and powdered accurately, a quantity of powder equivalent to by calculating the similarity factor (F ) as per the SUPAC
50 mg of diclofenac sodium, shaken with 60 ml of methanol in guidelines for modified-release dosage forms. This fac-
a 200 ml volumetric flask and dilute to volume with methanol. tor is a logarithmic reciprocal of square root transforma-
Dilute 5 ml of this solution with 100 ml of methanol and mea- tion of one plus the average mean squared (average sum
of squares) differences of drug percent dissolved between
the two dissolution profiles over all time points.
----- (6)
3. RESULTS:
The different formulations of matrix granules were for-
mulated, and were evaluated for the particle size and allied
properties. Particle size of the prepared granules was found
in range of 82.97 ± 0.48 to 197.98 ± 0.54 mm and bulk
density measurements range from 0.256 ± 0.06 to 0.689
4. DISCUSSION:
The UV-spectrophotometric scan has reported max of
diclofenac sodium in phosphate buffer pH 6.8, to be 276 nm
and in methanol 284 nm, which was in agreement to the
reported max of diclofenac sodium in respective solvents (USP
2004) and is used in estimation of drug during the study. The
Tabel
particle size, flow properties, compressibility and Hausner’s
ratio of all the granulation was satisfactory for tableting. The
compressed tablets with differently formulated granules have
been found to be varying although the tablet hardness is not an
absolute indicator of strength. The formulation F6 showed a
comparatively high hardness value of 7.5 ± 0.02 kg/cm2. This
could be due to presence of ethyl cellulose, which is generally
Table 5: Comparison between the best marketed brand responsible for more hardness of the tablet. The low hardness
(B2) and most optimum tablet formulation (F6) value was observed with formulation F1 may be due to pres-
ence of sodium CMC, which generally have disintegrating
property. So hardness of F6 formulation was decreased. The
hardness of the tablets of all formulations ranged from 3.00 ±
0.06 to 7.50 ± 0.02 kg/cm2. In weight variation test, the phar-
macopoeial limit for the percentage deviation for the tablets of
more than 250 mg is ± 5%. The average percentage deviation
of all tablet formulations was found to be within the above
limit and hence all formulations were passed the test for uni-
formity of weight as per official requirement. The content uni-
formity in the prepared tablets reflects that the method adopted
for preparation is acceptably good.
Among the formulations, the release rate increased lin-
early with increasing viscosity grades. These polymers have
been well known to retard the drug release by swelling in aque-
ous media. SodiumCMC released the drug at faster rate than
did HPMC at the same drug and polymer ratio. A polymer’s 20th , Lippincott Williams and Willkins, Philadelphia,
ability to retard the drug release rate was dependent on its pp:903-929
viscosity grade (Raymond et al 2006). The faster dissolution 4. Theeuwes and W. Bayne (1981). Controlled release
rate observed in sodiumCMC could be due to disintegration dosage form design. In J. Urguhart (eds.), Controlled
property of sodiumCMC along with swellability. The HPMC, release Pharmaceuticals, American Pharmaceutical
which is mixed alkyl hydoxyalkyl cellulose ether containing Association, Academy of Pharmaceutical Sciences,
methoxy and hydroxypropyl groups, can potentially retard Washington, D. C., pp: 61 - 93.
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to the decreased penetration of the solvent molecules in the Acentaury of dissolution research: From Noyes and
presence of hydrophobic polymer and leading to decreased Whiteny to Biopharmaceutical classification System.
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5. CONCLUSION: 9. Tiwari S.B., Murthy T.K., Pai M.R., Mehta P.R. and
Matrix tablets could be prepared by compressing the Chowdary P.B. (2003) Controlled release formulation
granules formulated and these have shown acceptable phar- of tramadol HCl using hydrophilic hydrophobic matrix
maceutical characteristics and better release profile when com- system. AAPS Pharm. Sci. Tech., Vol. 4, No. 3, pp.
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Acknowledgement: compaction. In Carter S.J., Eds. Tutorial Pharmacy,
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