Effect
of Swelling and Drug Release Relationship of Sustained Release Matrices containing
different Grades of Hydroxypropyl Methylcellulose
Masheer Ahmed Khan
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshshila Campus, Khandwa Road, Indore, 452001, India.
ABSTRACT:
Sustained release diclofenac
sodium matrices are used to achieve a prolonged therapeutic effect by
continuously releasing medication over an extended period
of time after administration of a single dose for analgesic, antipyretic and
anti- inflammatory activities. The current study examines the relationship
between swelling and drug release from the hydrophilic matrices of diclofenac sodium matrices prepared using combination of
different grades of hydroxypropyl methylcellulose
(HPMC), viz, HPMCK4M, HPMCK15M and HPMCK100M. The
Degree of Swelling and Percent water uptake were determined for the matrices
containing different concentrations and combinations. The results indicate that
swelling and release profiles were affected by concentration and viscosity grade
of the polymer. When the amount of HPMC in the matrix is high, wetting improves
and water uptake into matrices is enhanced. The higher amount of HPMC causes a
greater degree of swelling this in turn reduces the drug release, as the diffusional path length of drug is now longer. Conversely,
reduction in the amount of HPMC reduces the degree of swelling and the
thickness of gel layer, this enables faster drug release. Higher viscosity
grades swells to greater extent and has greater intrinsic water uptake property
than that of the lower viscosity grades. Swelling studies reveals an inverse
relationship between swelling and drug release in the sustained release diclofenac sodium matrices.
KEYWORDS: HPMC,
matrices, swelling
INTRODUCTION:
The Molecular formula of Diclofenac sodium is C14H10O2Cl2N.Na
and chemical name, 2-[(2, 6-dichlorophenyl)-amino] phenyl acetate. It is freely
soluble in methanol, soluble in ethanol (95%), sparingly soluble in water and
glacial acetic acid, practically insoluble in ether, chloroform and toluene.
Diclofenac has analgesic, antipyretic and anti- inflammatory activities. It is
a potent relatively non-selective cyclooxygenase
inhibitor and its potency is greater than that of indomethacin,
naproxen, or several other agents. In addition, diclofenac
appears to reduce intracellular concentration of free arachidonate
in leucocytes, perhaps by altering the release or uptake of the fatty acid.
Diclofenac is rapidly and completely absorbed after oral administration; peak
Concentrations in plasma are reached within 2-3 hours. It is given in the
dosage 75-150mg daily in divided doses 1
Sustained
release drug delivery system is designed to achieve a prolonged therapeutic
effect by continuously releasing medication over an extended period of time
after administration of a single dose. Hydrophilic matrices devices are one of
the least complicated approaches in the formulation of sustained release dosage
forms and are finding increasing application in the pharmaceutical field. The
aim of the present study was to investigate relationship between swelling and
drug release from the sustained release hydrophilic matrices of diclofenac sodium prepared using combination of different
grades of hydroxypropyl methylcellulose (HPMC), viz, HPMCK4M, HPMCK15M and HPMCK100M 2-6. Drug
release data from HPMC matrices follows the classical Higuchi dissolution
equation, relating drug release with square root of time. Swellable
systems consisting of hydrophilic polymers, in the presence of water, absorb a
significant amount of water to form a gel. As the dissolution medium penetrates
the matrix, polymer material swelling starts and drug molecules begin to move
out of the system by diffusion. The degree of swelling and percent water uptake
is determined to find the relationship between the drug release and swelling.
The release mechanism is obtained from the dissolution data and the value of
release rate exponent is determined. The value of release rate exponent (n) is
a function of geometric shape of the drug delivery device. The results indicate
that the mechanism of release is influenced greatly by the polymer
concentration of the formulations as can be seen from values of n and generally
in accordance with these indications. The release is mainly determined by the Fickian diffusion which is also confirmed from the n values7-9.
Diclofenac sodium was obtained as a gift sample from Pure Pharma. Ltd, Indore,
(M.P.), Methocel
(K4M, K15M, K100M) were provided by Colorcon India Ltd., Goa, dicalcium
phosphate, microcrystalline cellulose, talc , magnesium stearate
and all other reagent used were of analytical grade.
Nine formulations employed for investigations containing different
ratios of HPMC of different grades were prepared by direct compression and
coded C1, C2, C3, D1, D2, D3, E1, E2 and E3. The ratios of different grades of
HPMC employed are shown in Table 1. The amount of drug, magnesium stearate, MCC and talc were kept constant while dicalcium phosphate was taken in sufficient quantity to
maintain a constant tablet weight of 120 mg. All the products and process
variables (other than the concentrations of two polymers) like mixing time,
compaction force, etc, were kept constant. Ten tablets from each batch were weighed
individually and subjected to physical evaluation.
Table 1.
Different ratios employed in formulations containing HPMC of different grades.
|
Formulation
Code |
HPMCK4M |
HPMCK100M |
DICLOFENAC
SODIUM |
|
C1 |
1 |
1 |
1 |
|
C2 |
2 |
2 |
1 |
|
C3 |
3 |
3 |
1 |
|
Formulation Code |
HPMCK4M |
HPMCK 15M |
DICLOFENAC SODIUM |
|
D1 |
1 |
1 |
1 |
|
D2 |
2 |
2 |
1 |
|
D3 |
3 |
3 |
1 |
|
Formulation Code |
HPMCK15M |
HPMCK 100M |
DICLOFENAC SODIUM |
|
E1 |
1 |
1 |
1 |
|
E2 |
2 |
2 |
1 |
|
E3 |
3 |
3 |
1 |
Swelling was evaluated by weight. The matrices were placed in 900
ml dissolution medium pH 6.3, at 370C. At different time intervals,
the previously weighed tablets were removed, gently wiped with a tissue to
remove surface water, and reweighed. The percent water uptake i.e., degree of
swelling due to absorbed test liquid, can be estimated at regular time
intervals using the following equation –
Dissolution studies were carried out for all the nine formulations
in triplicate, employing dissolution apparatus, using distilled water pH 6.3 as
the dissolution medium at 50 rpm and 37 ± 0.50C. An aliquot of sample was
periodically withdrawn at suitable time intervals and volume replaced with
equivalent amounts of plain dissolution medium. The samples were analyzed at
276 nm.
Physical Characteristics:
The tablet weights of all the batches vary between 120-126 mg, and
tablet hardness between 5.5-5.9 kg. The tablet friability ranged between 0.5-0.8%. The physical parameters of the manually compressed
tablets were found within control.
The weight of the polymer in the matrix (Wp) and final dry weight of the matrix (Wd) are shown
in Table 2. The percent water uptake and degree of swelling as a function of
time is reported in Table 3and Table 4 respectively. The results of swelling
studies are shown graphically for different formulations. Fig1a shows the plot
for water uptake as a function of time for formulation codes C1, C2, C3
containing HPMC K4M and K100M combinations with different ratios and Fig1b
shows plot for degree of swelling as a function of time for formulation codes
C1, C2, C3. Similar plots are shown in Fig 2a and Fig 2b for formulation codes
D1, D2, D3, containing HPMC K4M and K15M combinations with different ratios and
Fig 3a and Fig 3b for formulation codes E1, E2, E3, containing HPMC K15M and
K100M combinations with different ratios. The dissolution parameters of varied
formulation with different ratios of polymer combinations obtained during
studies are shown in Table 5.
Formulation C1 has n= 0.512, C2 has n=0.461 and C3 has n=0.452
indicating that the release mechanism is very close to Fickian
transport i.e. belong to the Higuchi model. Similar results are observed with
formulations D1, D2, D3 as well as with formulations E1, E2 and E3. In this
investigation it has been clearly demonstrated that an inverse relationship
exists between the drug release rate and matrix-swelling rate. When the amount
of HPMC in the matrix is high, wetting improves and water uptake into
matrices is enhanced. The higher amount of HPMC
irrespective of different grades causes a greater degree of swelling. This in
turn reduces the drug release, as the diffusional
path length of drug is now longer. Conversely, reduction in the amount of HPMC
reduces the degree of swelling and the thickness of gel layer and thus enables
faster drug release. It is also demonstrated that HPMC of higher viscosity
grades swells to greater extent and has greater intrinsic water uptake property
than that of the lower viscosity grades.
Table
2. Final dry weight and weight of polymer in
matrix tablets of different Formulations
|
Formulation |
Final Dry
weight (Wd) (mg) |
Weight of
polymer in matrix (Wp) (mg) |
|
C1 |
120 |
24 |
|
C2 |
127 |
48 |
|
C3 |
126 |
72 |
|
D1 |
124 |
24 |
|
D2 |
120 |
48 |
|
D3 |
125 |
72 |
|
E1 |
122 |
24 |
|
E2 |
125 |
48 |
|
E3 |
120 |
72 |
TABLE 3.
PERCENT WATER UPTAKE OF FORMULATIONS AS A FUNCTION OF TIME
|
TIME HRS |
C1 |
C2 |
C3 |
D1 |
D2 |
D3 |
E1 |
E2 |
E3 |
|
0.5 |
91.67 |
41.67 |
50 |
66.67 |
43.75 |
45.83 |
137.50 |
79.17 |
73.61 |
|
1 |
187.50 |
100.00 |
86.11 |
100.00 |
83.33 |
59.72 |
191.67 |
114.58 |
101.39 |
|
2 |
445.83 |
225.00 |
172.22 |
391.67 |
225.00 |
180.56 |
337.50 |
235.42 |
211.11 |
|
3 |
570.83 |
291.67 |
220.83 |
462.50 |
297.92 |
205.56 |
500.00 |
333.33 |
261.11 |
|
4 |
695.83 |
350.00 |
262.50 |
608.33 |
341.67 |
254.17 |
712.50 |
375.00 |
316.67 |
|
5 |
812.50 |
450.00 |
325.00 |
675.00 |
414.58 |
291.67 |
775.00 |
452.08 |
338.89 |
|
6 |
908.33 |
495.83 |
352.78 |
858.33 |
458.33 |
313.89 |
916.67 |
500.00 |
368.06 |
|
8 |
1020.83 |
547.92 |
429.17 |
920.83 |
497.92 |
379.17 |
1037.50 |
568.75 |
451.39 |
|
10 |
1191.67 |
652.08 |
516.67 |
1045.83 |
610.42 |
444.44 |
1137.50 |
666.67 |
562.50 |
|
12 |
1312.50 |
772.92 |
602.78 |
1237.50 |
735.42 |
527.78 |
1333.33 |
833.33 |
590.28 |
TABLE 4.
DEGREE OF SWELLING OF DIFFERENT FORMULATIONS AS A FUNCTION OF TIME
|
TIME HRS |
C1 |
C2 |
C3 |
D1 |
D2 |
D3 |
E1 |
E2 |
E3 |
|
0.5 |
18.33 |
15.75 |
28.57 |
22.50 |
15.75 |
28.57 |
27.05 |
30.4 |
44.17 |
|
1 |
37.50 |
37.80 |
49.21 |
45.83 |
37.80 |
49.21 |
37.70 |
44 |
60.83 |
|
2 |
89.17 |
85.04 |
98.41 |
95.83 |
85.04 |
98.41 |
66.39 |
90.4 |
126.67 |
|
3 |
114.17 |
110.24 |
126.19 |
122.50 |
110.24 |
126.19 |
98.36 |
128 |
156.67 |
|
4 |
139.17 |
132.28 |
150.00 |
145.83 |
132.28 |
150.00 |
140.16 |
144 |
190.00 |
|
5 |
162.50 |
170.08 |
185.71 |
185.83 |
170.08 |
185.71 |
152.46 |
173.6 |
203.33 |
|
6 |
181.67 |
187.40 |
201.59 |
204.17 |
187.40 |
201.59 |
180.33 |
192 |
220.83 |
|
8 |
204.17 |
207.09 |
245.24 |
225.00 |
207.09 |
245.24 |
204.10 |
218.4 |
270.83 |
|
10 |
238.33 |
246.46 |
295.24 |
266.67 |
246.46 |
295.24 |
223.77 |
256 |
337.50 |
|
12 |
262.50 |
292.13 |
344.44 |
315.00 |
292.13 |
344.44 |
262.30 |
320 |
354.17 |
TABLE
5. DISSOLUTION PARAMETERS OF DIFFERENT
FORMULATIONS
|
Formulation
Code |
Release at 12
hr |
n |
Degree of Swelling (%) |
Percent of water uptake |
|
C1 |
97.14 |
0.512 |
262.5 |
1312.5 |
|
C2 |
84.87 |
0.461 |
292.13 |
772.50 |
|
C3 |
75.6 |
0.452 |
344.44 |
602.78 |
|
D1 |
104.6 |
0.559 |
315.00 |
1237.5 |
|
D2 |
103.33 |
0.555 |
292.13 |
735.42 |
|
D3 |
86.6 |
0.467 |
344.44 |
527.78 |
|
E1 |
93.65 |
0.516 |
262.30 |
1333.33 |
|
E2 |
75.59 |
0.452 |
320.00 |
833.33 |
|
E3 |
64.1 |
0.439 |
354.17 |
590.28 |
Swelling studies reveals an inverse relationship
between swelling and drug release in the sustained release diclofenac
sodium matrices. The rational combination of different grades of HPMC can be
used satisfactorily to regulate the release of drug for extended period of time
in such matrices.
1 Khan M.A. Studies on the effect of pH over dissolution
profile of diclofenac sodium sustained release
tablets, Journal of Drug Delivery and Therapeutics (JDDT), 2 (5), 2012,65-66.
2 Khan MA, and Maheshwari RK,
Studies of relationship between swelling and drug release in the sustained
release hydrophilic matrices containing different grades of hdroxypropylmethyl
cellulose, Research Journal of Pharmaceutical, Biological and Chemical Sciences
(RJPBCS), Vol. 2, Issue- 4 (2011),970-975.
3 Khan
M.A. Studies of swelling effect and drug release in hydrophilic matrices
containing different grades of polymers, Research J. of Pharm. Biological and
Chemical Sci. (4)1,2013, 1241-1247.
4 Khan M.A. , Chaturvedi
S C.,Swelling and Drug Release Studies from
Hydrophilic Matrices Containing Combination of Different Grades of Hydroxyl Propyl Methylcellulose, Asian Journal of Chemistry, Vol.
22,Issue 6(2010), 3566-3568.
5 Wan, L. S. C., and Wong, L.F., Drug Dev.
Ind. Pharm., 19(10), (1993).
6 Efentakis M, Vlachou M, Choulis N.H, Drug Dev.
Ind. Pharm, 23: (1997), 107-112.
7 Khan
M.A. Enhancement of solubility of poorly water soluble drugs diclofenac sodium by mixed solvency approach, Research
Journal of Pharmaceutical Dosage Forms and Technology 4(6),2012,40-42.
8 Liberman H, Lachman L and
Schwartz J, Pharmaceutical Dosage Forms: Tablets, vol.1, 2nd edition
revised and expanded , Dekker, New York, 2005.
9 Goodman and
Gilman’s: The Pharmacological basis of therapeutics. 10th edition
. Mc-Graw Hill 2001: 709-710pp.
Received on 31.05.2013
Modified on 04.07.2013
Accepted on 15.07.2013
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage
Forms and Technology. 5(4): July-August, 2013, 232-236