Formulation of Sustained Release Matrix Tablets of Diclofenac Sodium Using New Hydrophilic Gum Blends

 

Gupta Khemchand*, Singhvi I., Ashawat M.S. and Gupta Santosh Kumar

Pacific College of Pharmacy, Pacific Hills, Pratap Nagar Ext., Airport Road, Debari, Udaipur (Raj.) -313003.

*Corresponding Author E-mail: khem_pharma@yahoo.co.in

ABSTRACT:

The major objective of this study was to use pectin (high methoxylated) in combination with guar gum to control the burst effect by promoting gelation and also to examine the release pattern of guar-pectin matrices. Guar gum has long been used to prepare matrix tablets. But its uncontrolled rate of hydration and initial slow gelling results into undesirable burst effect. Various combination of drug: polymer ratios were tried, out of which the ratio 1:0.5 yielded best results. The ratio of gaur: pectin in the polymer blend which gave best results was found to be 1:1.The effects of various diluents on the drug release were also determined at the same polymer level. The matrix tablet were prepared by wet granulation method using distilled water, were subjected to physical characterization and in vitro release studies. Release kinetics was evaluated by using USP apparatus type II at 75 rpm in 900 ml of phosphate buffer (pH 6.8).The in-vitro drug release study revealed that (batch F3) combining pectin with guar gum sustained the drug release for 10 hours (81.24%). The kinetic treatment showed that the release of drug follows zero order kinetic (r ² = 0.9943). Korsmeyer and Peppas equation gave value of n = 0.9898 indicating that the drug was released by zero order kinetic. Stability studies (40±2ºC/75±5%RH) for 3 months indicated that Diclofenac sodium was stable in the matrix tablets. The DSC and FTIR study revealed that there was no chemical interaction between drug and excipients. At the same polymer level the order of release fell in the following manner lactose, starch, avicel pH 101, and Emcompress®. So, the combination of pectin and guar gum shows better prosperity for preparation of sustained release tablets as compare to individual gums.

 

KEYWORDS: Diclofenac sodium, Pectin, Guar gum, In-vitro release, Zero order

 

INTRODUCTION:

Diclofenac sodium is sodium 2- [(2, 6- dichlorophenyl) - amino] phenyl acetate and is an acetic acid nonsteroidal anti- inflammatory drug (NSAID) with analgesic and antipyretic properties. It is also used to treat, dysmenorrhea, ocular inflammation, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and actinic keratosis^1,2. The biological half life of Diclofenac sodium is about 1.2-2 hours; therefore it requires multiple dosing to maintain therapeutic drug blood level. The development of sustained release formulation of Diclofenac sodium is therefore therapeutically relevant and can be used to provide a consistent dosage through sustaining an appropriate level of the drug over time³.

 

Hydrophilic polymer matrix systems are widely used in oral sustained drug delivery because of their flexibility to obtain a desirable drug release profile, cost effectiveness, and broad regulatory acceptance⁴. The ability of the hydrophilic polymer matrices to release entrapped drug in aqueous medium and to regulate the release of such drug by control of swelling and cross linking makes them particularly suitable for sustained release application^5,6. Natural polysaccharide and their derivatives (like sodium alginate, agar beads, carrageenan, chitosan, pectin, guar gum, karaya gum etc.) represent a group of polymer widely used in pharmaceutical dosage forms⁷.

 

Pectin (high methoxylated) is important ionic polysaccharides found in plant cell walls. They contain linear chains of (1-4)-linked α-D galacturonic acid residues. Its gelling ability and solubility strongly depends upon the pH of the surrounding media. The nontoxicity and the low production cost of pectin make them of great interest for the formulation of controlled release dosage forms⁸.

 

Guar gum is an interesting polymer for the preparation of hydrophilic matrix tablets because of its high water swellability, nontoxicity and low cost. Various groups of workers have used guar gum as a controlled release carrier^9,10. In different formulations guar gum has been used as binder and disintegrant¹¹. In spite of the wide pharmaceutical application of guar gum, its use in sustained release dosage form is limited due to uncontrolled rate of hydration and initial slow gelling, resulting into burst effect.  Thus, the main objective of this work was to use high methoxylated pectin in combination with guar gum that control the burst effect by promoting gelation (radial-axial expansion) and also to examine the release mechanism of guar-pectin combination  matrix system.

 

MATERIALS AND METHODS:

The drug Diclofenac sodium was procured as gift sample from Zim Labs, Nagpur, Pectin and Guar gum was procured from TIC Gums, USA. Lactose, Starch and Emcompress® was procured from S. D. Fine Chemicals, Mumbai. All other chemicals were procured locally and were of analytical grade.

 

Preparation of Matrix Tablets:

Matrix tablets were prepared by wet granulation method using pectin and guar gum as per the formula given in the table 1. Diclofenac sodium, pectin and guar gum were mixed in a poly bag and the mixture was passed through mesh #60. Granulation was done using sufficient quantity of granulating agent (distilled water) to get wet mass. The wet mass was passed through mesh #14. The wet granules were dried at 60 ^oC for 2 hours in an oven. The dried granules were then sized by mesh #18 and mixed with magnesium stearate. The granules of Diclofenac sodium were compressed by a single punch tabletting machine (Kilburn-manestry) with 8 mm flat shaped punches. Seven different formulas, having different diluents (F1, F2 and F3 without diluents) at same concentration were developed to study the effect of diluents on drug release.

 

Evaluation of Tablets:

Evaluation of physical properties:

The prepared matrix tablets were evaluated for uniformity of weight, hardness, friability and thickness. Uniformity of weight was performed according to official method¹². Hardness of the tablets was tested using a Monsanto hardness tester and the friability of the tablets was determined in a Roche friabilator¹³. Thickness was measured by Vernier caliper as per USP XXIV monograph. The readings were carried out in triplicate and average value was noted¹⁴. The physical properties are shown in table 2.

 

Determination of drug content:

Twenty tablets from each formulation were accurately weighed and average weight per tablet was determined. The tablets were powdered and powder equivalent to 50 mg of Diclofenac sodium was shaken with 60 ml of methanol in a 200 ml volumetric flask and diluted to volume with methanol. 5 ml of this solution was diluted to 100 ml with methanol and analyzed against blank (methanol) for the drug content by double beam UV/Visible spectrophotometer at 276 nm. Results are shown in table 2.

 

In vitro drug release studies:

The in vitro drug release studies were carried out using USP XXIV dissolution apparatus type II (paddle) at 75 rpm. The dissolution medium consisted of the 900 ml phosphate buffer pH 6.8, maintained at 37°C±0.5°C. 10 ml of samples were withdrawn every one hour interval and analyzed spectrophotometrically at 276 nm using a UV-visible double beam spectrophotometer (Shimadzu, Japan, Model-1701) after suitable dilution. Fresh dissolution medium was replaced after each withdrawal. The study was performed in triplicate.

 

FTIR studies:

The drug and polymers must be compatible to produce a stable product. Drug and polymer interaction were studied by using FTIR (Shimadzu, Japan, Model-8001). IR spectral analysis of pure Diclofenac sodium, pectin, guar gum, and Diclofenac sodium with pectin and guar gum were carried out by KBr pellet method. The peaks and pattern produced by the pure drug were compared with combination of polymer¹⁵.

 

DSC studies:

Thermal study of Diclofenac sodium, pectin, guar gum and Diclofenac sodium with pectin and guar gum were assessed by DSC using DSC Q10 V9 and Mettler-Toledo DSC 821 instrument. Heating of sample was done from 100 to 500°C at rate of 10°C/min.

 

 

 

 

 

 

Table 1: Tablet composition (%w/w) of different formulations of Diclofenac sodium sustained release matrix tablets

S. No.	Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7
1.	Diclofenac sodium	100	100	100	100	100	100	100
2.	Pectin	50	--	25	25	25	25	25
3.	Guar gum	--	50	25	25	25	25	25
4.	Lactose	--	--	--	15	--	--	--
5.	Avicel pH 101	--	--	--	--	15	--	--
6.	Emcompress®	--	--	--	--	--	15	--
7.	Starch	--	--	--	--	--	--	15
8.	Magnesium Stearate (2 %)	3	3	3	3	3	3	3
	Total	153	153	153	168	168	168	168

 

Table 2: Physical properties of compressed tablets

Batch No.	Weight Uniformity ( mg)* (Mean ± S.D.)	Hardness (Kg/cm2)** (Mean ± S.D.)	Friability (%) *	Thickness (mm)** (Mean ± S.D.)	Drug content ( %)** (Mean ±S.D.)
F1	152.1 ± 3.11	3.66 ± 0.53	0.83	2.87 ± 0.02	98.34 ± 1.10
F2	154.6 ± 2.44	4.33 ± 0.42	0.98	2.89 ± 0.03	99.63 ± 1.27
F3	151.5 ± 1.63	5.33 ± 0.67	0.59	2.90 ± 0.03	100.33 ± 1.62
F4	165.7 ± 3.19	4.66 ± 0.52	0.73	3.22 ± 0.04	96.24 ± 0.81
F5	163.0 ± 4.54	3.33 ± 0.57	0.66	3.18 ± 0.01	100.54 ± 1.35
F6	170.2 ± 2.89	4.80 ± 0.83	0.64	3.25 ± 0.03	97.90 ± 1.92
F7	167.6 ± 2.35	3.66 ± 0.57	0.78	3.20 ± 0.02	99.09 ± 2.41

* n = 20,    ** n = 3

 

Table 3: In-vitro dissolution Profile of F1 to F7 formulations

Time (Hrs.)	Cumulative % drug release (Mean ± S. D; n = 3)
	F1	F2	F3	F4	F5	F6	F7
1	21.46 ± 0.64	28.62 ± 1.33	12.64 ± 1.33	12.37 ± 0.60	10.17 ± 0.53	7.90 ± 0.70	11.76 ± 1.14
2	35.73 ± 1.29	37.54 ± 0.92	18.66 ± 1.12	22.65 ± 0.61	18.01 ± 0.62	13.86 ± 0.73	18.89 ± 1.53
3	53.03 ± 1.60	46.78 ± 1.84	23.93 ± 1.28	35.12 ± 1.01	30.0 ± 0.61	24.69 ± 0.82	26.60 ± 1.25
4	68.36 ± 1.42	53.69 ± 0.76	33.74 ± 1.14	44.52 ± 1.16	38.23 ± 0.42	31.71 ± 1.08	39.22 ± 0.95
5	87.76 ± 1.69	60.24 ± 1.43	45.25 ± 0.99	57.02 ± 0.81	49.47 ± 0.47	48.74 ± 1.47	46.32 ± 1.12
6	99.40 ± 1.25	66.45 ± 1.22	50.42 ± 1.26	68.92 ± 1.41	58.86 ± 0.58	53.54 ± 0.64	56.18 ± 1.03
7	----	72.08 ± 1.12	59.84 ± 1.43	77.58 ± 0.79	66.39 ± 0.68	61.20 ± 0.62	68.94 ± 1.44
8	----	76.37 ± 0.48	64.22 ± 0.33	85.52 ± 0.86	75.02 ± 0.52	69.87 ± 1.08	79.52 ± 1.21
9	----	79.46 ± 1.72	73.65 ± 1.37	92.12 ± 1.66	86.46 ± 1.67	76.28 ± 2.06	88.78 ± 0.82
10	----	84.62 ±  0.75	81.24 ± 1.22	98.57 ± 0.82	96.04 ± 0.86	82.36 ± 1.54	97.45 ± 1.32

 

 

Drug release kinetics:

In vitro drug release data for the most compromising formulation batch (F3) was explored for the type of release mechanism followed. The data were treated with zero order rate, first order rate, Higuchi matrix rate, Korsmeyer –peppas equation and Hixon crowell equations. The coefficient correlation of kinetics was calculated by specified equations and compared. Zero order (% released) = k.time, first order (log fraction of unreleased) = k/2.303.time, Higuchi matrix equation (% released) = k.time ^0.5, Korsmeyer –peppas equation (% released) = k.time ⁿ, and Hixson crowell equation (fraction unreleased) ^1/3=1-k.time^{16, 17}.

 

Stability studies ^[18]:

The optimized Diclofenac sodium formulation (batch F3) were packed and subjected to accelerated stability studies as per ICH guidelines (40°C±2°C/75%RH±5%RH). The sample were withdrawn periodically (0, 15, 30, 60, 90 days) and evaluated for the different physico-chemical parameters viz. appearance, weight variation ,thickness, hardness , drug content  and  in vitro drug release studies.

 

RESULTS AND DISCUSSION:

The physical properties of different batches of developed matrix tablet are given in table 2. The average percentage deviation of 20 tablets of each formulation was less than (7.5%), and hence all formulations passed the test for uniformity of weight as per official requirements (Pharmacopoeia of India 1996). The hardness of the tablets of all the formulations ranged from (3.33 ± 0.57 to 5.33 ± 0.67) kg/cm², friability (0.59 to 0.98 %), thickness (2.87 ± 0.02 to 3.25 ± 0.03 mm), and drug content (96.24 ± 0.81 to 100.54 ± 1.35 %). All were found within the acceptable official limits.

The data obtained from in-vitro release studies for formulation batches F1 to F3 and F4 to F7 are shown in the figure 1 and 2 respectively. The cumulative percentage drug release of formulation batch F1 (drug to pectin ratio, 1:0.5) was 99.40 % at the end of 6 hours. Initially pectin controlled the drug released rate due to its high gelling property but after 3-4 hours, due to its eroding property drug release reached the level of 99.40 % at the end of 6 hours. The cumulative percentage drug release of formulation batch F2 and F3 was 84.62 % and 81.24 % at the end of 10 hours respectively. In batch F2 (drug to guar gum ratio,1:0.5), an initial burst release may be due to uncontrolled rate of hydration and an initial slow gelling of guar gum but after 4-5 hours, released rate become slow due to high swelling of guar gum.  In batch F3, pectin was used in combination with guar gum that might control the burst effect by promoting gelation both in radial and axial expansion and after 4-5 hours, pectin maintained the release rate by acting as an eroding material and controlled the drug release up to 10 hours.

 

Figure.1: In-vitro drug release profile of F1 to F3 formulations

Effects of diluents on in-vitro drug release from Diclofenac sodium matrix tablet are shown in table 3 and fig. 2. The lowest release (82.36 %) was seen with tablets containing Emcompress® while tablets containing lactose showed high drug release rate (98.57 %). Lactose containing tablets exhibited a single crack on the sides of tablets during dissolution process and drug diffusion was promoted due to the pores and channels that were created following the solubilization of the lactose (batch F4). Emcompress® is insoluble, non-swelling and tablets are intact throughout the dissolution process and drug released through diffusion via small inter and intra granular spaces (batch F6). Tablets containing avicel pH 101 and starch absorbed water through the capillaries leading to swelling and disintegration (batch F5 and F7).

 

Figure.2: In-vitro release profile of F4 to F7 formulations

 

Drug release kinetics:

The goodness of fit for various models investigated for Diclofenac sodium tablets ranked in the order of Zero-order>Hixson-Crowell>Korsmeyer-Peppas>First-order>Higuchi. As shown in table 4, the Zero-order model gave the highest value of the squared correlation coefficient (r²) for the dissolution profile of Diclofenac sodium tablets (batch F3). The value of ‘n’ was found to be 0.9898 means it follows case-II transport (relaxation or swelling controlled system) mechanism. The achievement of zero order kinetics is due to the predictable swelling/erosion and final polymer chain deaggregation and dissolution that are regulated by the gelling characteristics of polymers in the formulation.

 

Table 4: Kinetic values obtained from most promising formulation (F3)

Values	Release Models
	Zero-order	First-order	Higuchi	Korsmeyer-Peppas	Hixson -Crowell
r2 values	0.9943	0.9870	0.9448	0.9901	0.9931
n value	0.9898	--	--	--	--

 

Stability studies:

According to ICH guidelines , three months accelerated study (40°C±2°C/75%±5%RH) for the optimized formulation ( batch F3) showed negligible change over time for the parameters like  appearance, weight variation, thickness, hardness , drug content and in vitro drug release. Results are shown in table 5.

IR spectral analysis:

The FTIR studies of pure Diclofenac sodium, pectin, guar gum and formulations containing pectin and guar gum were carried out to study the interaction between the drug and polymers used (shown in figure 3, 4, 5 and 6 respectively).

-NH stretching, aromatic -CH stretching, -C-Cl stretching, esteric -CO stretching, Aromatic ring stretching of pure Diclofenac sodium and the Diclofenac sodium sustained release tablets formulations containing pectin and guar gum were almost in the same region of wave number ranging from 3350 cm^-1 to 740 cm^-1. The results proved that there were no significant interactions between the drug and polymers.

 

Figure 3: FTIR spectra of Diclofenac sodium

 

Figure 4: FTIR spectra of pectin

 

Figure 5: FTIR spectra of guar gum

Table 5: Stability studies data on selected formulation (F3) of Diclofenac sodium (40°C with 75% RH)

Time (Hrs.)	Cumulative % drug release (Mean ± S. D; n = 3)
	Initial Tablets	15(Days)	30(Days)	60(Days)	90(Days)
1	12.64 ± 1.33	13.02 ± 1.12	12.26 ± 0.88	12.32 ± 0.95	12.39 ± 0.39
2	18.66 ± 1.12	16.84 ± 1.81	17.34 ± 0.81	18.31 ± 0.98	17.53 ± 0.86
3	23.93 ± 1.28	24.42 ± 0.24	23.78 ± 1.26	25.32 ± 0.84	22.84 ± 1.02
4	33.74 ± 1.14	34.02 ± 1.19	32.12 ± 0.76	33.32 ± 0.36	35.22 ± 1.62
5	45.25 ± 0.99	46.24 ± 1.06	44.84 ± 1.22	47.34 ± 1.18	45.14 ± 1.02
6	50.42 ± 1.26	51.81 ± 1.18	50.02 ± 0.85	49.72 ± 1.02	49.31 ±  1.41
7	59.84 ± 1.43	58.02 ± 1.38	60.82 ± 1.16	61.74 ± 1.81	59.14 ± 1.22
8	64.22 ± 0.33	65.82 ± 1.02	66.14 ± 0.76	64.58 ± 1.12	64.18 ± 0.88
9	73.65 ± 1.37	73.86 ± 0.56	74.0 ± 0.86	72.63 ± 1.58	71.34 ± 0.52
10	81.24 ± 1.22	81.12 ± 1.26	80.78 ± 1.56	80.46 ± 0.84	80.18 ± 1.67
Drug content (%)	100.33 ± 1.62	99.84 ± 0.68	100.04 ± 1.74	99.53 ± 0.88	98.36 ± 1.26

 

 

 

Figure 6: Diclofenac sodium with pectin and guar gum

 

DSC studies:

DSC thermograms of pure drug Diclofenac sodium, pectin, guar gum and Diclofenac sodium sustained release tablets containing pectin and guar gum are shown in figure 7, 8, 9 and 10 respectively.

 

DSC thermograms of Diclofenac sodium showed sharp exothermic peak at 278.9°C, indicating the tranisition from amorphous solid to crystalline solid. However, the DSC thermograms of Diclofenac sodium sustained release tablets containing pectin and guar gum showed only a negligible shift in their position with some peak broadening in the latter (at 259.1°C). Therefore, this study revealed that there were no significant interaction between the drug and polymers.

 

Figure 7: DSC thermogram of Diclofenac sodium

 

Figure 8: DSC thermogram of pectin

 

Figure 9:  DSC thermogram of guar gum

 

Figure 10: DSC thermogram of Diclofenac sodium with pectin and guar gum

 

CONCLUSION:

Previous studies have shown that guar gum alone cannot efficiently control the drug release. This study demonstrates that its combination with pectin is synergistic in controlling the Diclofenac sodium release. Use of hydrophilic polymers like guar gum and pectin was successful in the formulation of matrix and at the same time it is effective in retarding the drug release. Among all the formulations, F3 shows 81.24% release at the end of 10 hours. Furthermore, mathematical modeling and statistical analysis proved that the zero order kinetic model can be described the dissolution profile. Stability studies shown that there was no significant change in appearance, weight variation, thickness, hardness, drug content, and in vitro drug release of selected formulation (F3). Thus, a suitable combination of two natural gums (pectin and guar gum) may be successfully employed for formulating sustained release matrix tablets of Diclofenac sodium.

 

ACKNOWLEDGEMENTS:

The authors acknowledge the facilities provided at University Deptt. Of Pharmaceutical Sciences, Nagpur (M.S) in carrying out the work. The authors would like to thanks Zim Labs, Nagpur and TIC Gums, USA for providing gift sample of the drug and gums respectively.

 

REFERENCES:

1.       Sungthongjeen S, Pitaksuteepong T, Somsiri A, Sriamornsak P. Studies on pectins as potential hydrogel matrices for controlled-release drug delivery. Drug Dev Ind Pharm 1999; 25:1271-1276.

2.       Bravo SA, Lamas MC, Salamon CJ. In-vitro studies of diclofenac sodium controlled- release from biopolymeric hydrophilic matrices. J. Pharm. Pharmaceut. Sci. 2002; 5: 213-219.

3.       Tiwari SB, Murthy SK, Pai MR, Mehta PR, Chowdary PB. Controlled release formulation of tramadol hydrochloride using hydrophilic and hydrophobic matrix system. AAPS Pharm Sci Tech., 2003, 4(3): Article 31.

4.       Heller J, Helwing RW, Baker RW, Tuttle ME. Controlled release of water soluble macromolecules from bioerodible hydrogel. Biomaterials 1983; 4: 262-266.

5.       Graham NB, Mcneill ME. Hydrogels for controlled drug delivery. Biomaterials 1984; 5: 27-36.

6.       Bhardwaj TR, Kanwar M, Lal R, Gupta A. Natural gums and modified natural gums as sustained release carriers. Drug Dev Ind Pharm. 2000; 26(10): 1025-1038.

7.       Sungthongjeen S, Pitaksuteepong T, Somsiri A, Sriamornsak P. Studies on pectins as potential hydrogel matrices for controlled release drug delivery. Drug Dev Ind Pharm. 1999; 25(12): 1271-1276.

8.       Nakano M, Ogata A. Examination of natural gums as matrices for sustained release of theophyline. Chem. Pharm. Bull., 1984; 32: 782-785.

9.       Mishra AN, Baweja JM. Modified guar gum as hydrophilic matrix for controlled release tablets. Indian Drugs 1997; 34: 216-223.

10.     Duru C, Colombo P, Gaudy D, Massimo G, Barthelemy P. Comparative study of the disintegrating efficiency of polysaccharides in a directly tabletable formulation. Pharmaceut Technol Int 1992; 4:15-16, 20, 22-23.

11.     Baweja JM, Misra AN. Modified guar gum as a tablet disintegrant. Pharmazie 1997; 52:856-859.

12.     Indian pharmacopoeia, Vol. II, 4^th edition, the controller of publication, New Delhi, 1996:734-736.

13.     Chang R, Robinson JR. Sustained release from tablets and particles through coatin. In: Libreman HA, Lachman L, Schwartz JB (Eds). Pharmaceuticals dosage form tablets. 2^nd  Edn, Vol.3, Marcel Dekker; 1990: 199-302.

14.     Nokano M, Ogata A. In vitro release characteristics of matrix tablets: Study of karaya gum and guar gum as release modulators. Ind J Pharm Sci., 2006; 68(6): 824-826.

15.     Sharma YR. Elementary Organic Spectroscopy Principles and Chemical applications, S, Chand and Co., New Delhi. 2005; 65-133.

16.     Korsemeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanism of solute release from porous hydrophilic polymers. Int J Pharm. 1983; 15: 25-35.

17.     Siemann J, Peppas NA. Modeling of drug release from delivery system based on hydroxylpropyl methylcellulose (HPMC). Adv Drug Deli Rev. 2001; 48: 139-157.

18.     Mathews BR. Regulatory aspects of stability testing in Europe. Drug Dev Ind Pharm.1999; 25: 831-856.

 

 

 

 

Received on 21.04.2011       Modified on 19.05.2011

Accepted on 07.06.2011      © RJPT All right reserved