INTRODUCTION:

Diclofenac sodium is used as anti-inflammatory drug. It is used for the treatment of chronic disease like rheumatoid arthritis and gout; it requires the frequent administration of drug. So in order to decrease the dosing frequency sustained release dosage forms of Diclofenac sodium tablets are proposed to be developed. The sustained release dosage form of diclofenac sodium is proposed to develop as a matrix tablets by employing guar gum, xanthangum, kondagogu, almond gum.

In this present work matrix tablets of diclofenac sodium are proposed to be formulated using guar gum, xanthan gum, kondagogu, almond gums as rate retarding materials¹.

Oral drug delivery remains the most preferred route for administration of various therapeutic agents. The direct compression process is highly influenced by powder characteristics such as Flowability, compressibility and dilution potential^[2]. Most formulations (70-80%) contain excipients at a higher concentration than the active drug ^[3].Ideal directly compressible adjuvant must exhibit good Flowability and compatibility. No single adjuvant is likely to possess all the ideal characteristics. For this reason, the current trend in industry is to use multifunctional co-processed excipients^[4]. Excipients with improved functionality can be obtained by developing new chemical excipients, new grades of existing materials and new combination of existing materials ^[5]. New combinations of existing excipients are an interesting option for improving excipient functionality because all formulations contain multiple excipients. Many possible combinations of existing excipients can be used to achieve the desired set of performance characteristics. A much broader platform for the manipulation of excipient functionality is provided by co-processing or particle engineering of two or more excipients ^[6].

Co-processing is based on the novel concept of two or more excipients interacting at the sub particle level, the objective of which is to provide a synergy of functionality improvement as well as masking the undesirable properties of individual ^[7].Co-processing excipient leads to the formation of excipients granulates with superior properties compared with physical mixtures of components or individual components. Major limitation of co-processed excipients mixture is that the ratio of the excipients in a mixture is fixed and in the developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the Active Pharmaceutical Ingredient (API) and the dose per tablet under development ^[8].

Usually a combination of plastic and brittle materials is used for co-processing. This combination prevents storage of too much elastic energy during the compression, which results in a small amount of stress relaxation and a reduced tendency of capping and lamination thereby optimum tableting performance ^[9].Hence, co-processing these two kinds of materials produces a synergistic effect in terms of compressibility by selectively overcoming the disadvantages and can help improve functionalities such as compaction performance, flow properties, strain rate sensitivities, lubricant sensitivity or sensitivity to moisture. Because of their high aqueous solubility and sweetness, which imparts a pleasing mouth feel and good taste masking, nearly all formulations for rapidly dissolving tablets contain sugar based materials. Guar gum is found to have poor flow properties, poor compressibility and uneven particle size and is to be incorporated in the matrix tablets in large proportion (30 to 90%), and tablets containing guar gum are typically prepared by wet granulation technique. While guar gum is a well accepted pharmaceutical excipient used in low proportions as a binder, disintegrant or carrier in conventional dosage forms. Xanthan gum is used as Suspending agent, emulsifier, stabilizer in toothpaste and ointments, sustained release agent. Gum kondagogu is a good emulsifying even at low concentrations. Almond gum is used as emulsifier, thickener, suspending agent, adhesive, glazing agent and stabilizer. Gum obtained from Almond as a binder in tablet formulations.

Hard compacts of microcrystalline cellulose disintegrate rapidly due to the rapid passage of water into the compact and the instantaneous rupture of hydrogen bonds ^[10].Higher concentration of microcrystalline cellulose may slow the disintegration of tablet due to physical entrapment of small particles between deformed MCC which delays wetting and dissolution.

MATERIALS AND METHODS:

Materials Used:

Diclofenac sodium was obtained as a gift sample from Yarrow Chem. Products ltd., Dombivli. Guar gum, Xanthan gum, Micro crystalline cellulose were procured from S.D. Fine chemicals, Mumbai. Gum kondagogu, Almond gum were procured from Yarrow Chem. Products ltd., Dombivli. All materials used in the study complied with pharmaceutical and analytical standards .A multi-station tablet press (CDM-3-16, Cadmach machinery Co. Pvt. Ltd., Ahmadabad); dissolution test apparatus (DT 03071009, lab India- Mumbai, 2000); and UV-visible spectrophotometer (SL159, Elico Ltd., Hyderabad) Hot air oven (Thermolab, Mumbai) Fourier transform infrared spectrophotometer ( Bruker, Germany) were used in research work.

Methods Used:

To study the influence of co-processed excipient on flow and dissolution rate of Diclofenac sodium and to select the composition of co processed excipient, the tablets were formulated using co-processed excipient prepared with the technique granulation technique. Initially the co-processed excipients were prepared with granulation technique.

Preparation of co-processed excipients ^[4]

Co-processing excipients are prepared by granulation method. Co-processed excipient of Microcrystalline cellulose and Guar gum are prepared in the ratios 1:1, Microcrystalline cellulose and Xanthangum 1:1, Microcrystalline cellulose and Gum kondagogu 1:1, Microcrystalline cellulose and Almond gum1:1, Microcrystalline cellulose and Guar gum 1:2, 1:2.5,1:3 and which were prepared using water as binder. The damp mass was passed through mesh no 10.The granules were dried in hot air oven maintained at 60^◦c for 12hrs.The dried granules were subjected to sieving and granules that were retained on sieve no 16/24 were collected.

Studies on Pre- compression parameters:^[4]

The following micromeritic properties of the blend containing the drug and co-processed excipients were studied.

Bulk and Tapped densities: Granules were carefully poured into 50 ml graduated cylinder. The volume occupied by the granules was observed and the bulk density was calculated in gm/ml. the cylinder containing granules was tapped until constant volume was obtained, using bulk density apparatus from height of 2 cm and tapped density was calculated in gm/ml.

Percentage compressibility (Carr’s index) and Hausner’s ratio: The percentage compressibility (CI) was calculated from the difference between the tapped (Td) and the bulk densities (Bd) divided by the tapped density and the ratio expressed as a percentage. The Hausner’s ratio (HR) is the ratio between the tapped and bulk density

CI= (Td - Bd)/ Td

HR= Td/Bd

Preparation of tablets: ^{[4, 5]}

The tablets were formulated with the direct compressible diluents such as microcrystalline cellulose separately and with the co-processed excipient containing microcrystalline cellulose: guar gum in ratios 1:1, microcrystalline cellulose: xanthangum 1:1, microcrystalline cellulose: gum kondagogu 1:1, microcrystalline cellulose: almond gum1:1, microcrystalline cellulose and guar gum 1:2, 1:2.5 and 1:3. The composition of prepared tables was shown in table: 1.The tablets were compressed by direct compression technique. Prior to compression, the blends (F1 to F7) were evaluated for various micromeritic properties. Diclofenac sodium was mixed separately with the selected ratio of co-processed excipient (microcrystalline cellulose: guar gum xanthan gum, gum kondagogu, almond gum). The resulting blend was compressed to form a tablet by using 12mm round shaped tablet tooling.

Post – compression studies:

The following post – compression parameters were studied^:

Hardness:

The hardness of the prepared tablets was measured using Monsanto hardness tester. The hardness was measured in terms of kg/cm².

Weight variation:

20 tablets were collected randomly and weighed individually. The individual weights were compared with the average weight for the determination of weight variation. The percentage deviation was calculated.

Friability:

The friability of the tablets was determined by using Roche friabilator. Five tablets were weighed (W_O) and put into the friabilator and set to rotate at 25 rounds per minute for about four (4) minutes. The tablets were then removed and weighed again (W). The friability (F) is given by the formula

F= (1-W/Wo)*100

In-vitro dissolution studies:

In-vitro dissolution studies were performed for all the prepared tablets by using USP dissolution apparatus II. The dissolution test was carried for a period of 12hrs at 50 rpm using 900ml of 6.8 phosphate buffers as the dissolution medium at 37±0.5⁰c. At appropriate time intervals (30minutes), 5ml of the sample was withdrawn and replaced with the same volume of dissolution medium. The absorbance of the samples was measured at 275 nm against blank using UV spectrophotometer to determine the amount of drug release.

Determination of similarity factor:

The similarity factor is determined by comparing the dissolution profile of tablets formulated using different binders with the marketed formulation. The similarity factor was computed using the following equation,

f₂ = 50 + log {[1+ (1/n) ∑ⁿt₌₁ * n (R_t-T_tw)²]^-0.5 *100}

Where, f2 similarity factor, n= number of dissolution sampling times and R_tand T_t₌ individual or mean percent dissolved at each time-point for reference and test dissolution profiles respectively.

Infrared spectroscopy:

Infrared spectroscopy is one of most powerful analytical technique when it comes to the determination of presence of various functional groups involved in making up the molecule. It provides very well accountable spectral data regarding any change in the functional group characteristics of a drug molecule occurring while in the processing of a formulation. IR spectral of Diclofenac sodium and its formulation were obtained by KBr pellet method using Bruker FT-IR spectrometer in order to rule out drug-excipient interaction occurring during the formulation process.100mg of potassium bromide powder was mixed with 2mg of each sample, thoroughly triturated in motor and pestle. A portion of mixture was compressed using IR pelletizing press. Then the KBr pellets were placed in sample holder of FT-IR spectrophotometer. The spectra were recorded in the wave number of 3500-1000cm^-1. In each case the spectra was compared with the pure drug spectrum to detect the interaction between drug and excipients.

RESULTS AND DISCUSSION:

The present investigation was carried out on the design and development of sustained release tablets of Diclofenac sodium. For this investigation polymer like, guar gum, xanthan gum, gum kondagogu, almond gum and diluents is micro crystalline cellulose were selected.

Pre formulation studies:

Micromeritic properties Diclofenac sodium:

Diclofenac sodium was evaluated for flow properties such as angle of repose, Carr’s index and Hausner’s ratio. The results of angle of repose, Carr’s index and Hausner’s ratio of the Diclofenac sodium were 30.76, 22.56 and 1.53 respectively. From the above results it reveals that, Diclofenac sodium exhibited poor flow properties.

Micromeritic properties of Diclofenac formulations:

The results of Carr’s index of the Diclofenac sodium formulations F_1-F7were found to be 10, 8.62, 13.4, 17.1, 13.8.1, 11.3 and 12 respectively. The results of Hausner’s ratio of the Diclofenac sodium formulations F_1-F7 were found to be 0.916, 0.913, 0.86, 0.82, 0.86, 0.88 and 0.86 respectively. From the above results, it was observed that all the formulations exhibited good flow properties (Table no-2).

Physical characteristics of diclofenac sodium tablets:

Post compression parameters like weight variation, thickness, hardness and friability were found to comply with the pharmacopoeial standards and results were shown in the table no-3, 4.The hardness of all the batches was found to be in the ranges of 4-6kg/cm². The friability of all the formulations was found to be less than 1% and drug content of all the formulations was in between 95-98% that meets the official specifications (90-110%)

In-vitro drug release studies:

The in-vitro release of Diclofenac sodium matrix tablets were studied for first two hours in P^H 1.2 and for subsequent 10 hours in phosphate buffer of P^H6.8.It is reasonable to conclude that the release profile of Diclofenac sodium from the matrix tablets showed two distinct phases. An initial burst release phase occurs in the first two hours, followed by gradual release phase.

The formulations were subjected to in-vitro dissolution studies and corresponding data were shown in the figure 1-6 Formulations F1, F2, F3, F4 F5, F6 and F7sustained the drug release up to 12 hours respectively.

The cumulative percentage of drug release from different formulations was given in the following order.

F1 > F2> F3> F4 F5 > F6 > F7.

Formulation F1, F2, F3 and F4 showed rapid drug release may due to small amount of gums present in the tablets. Dissolution data were fitted to popular release kinetic equations. Drug release from all the formulations followed zero-order kinetics as shown in figure- and different in-vitro dissolution parameters such as dissolution rate constant (K), T50 and T90 were determined and presented in table -5,6.peppas plots were found to be linear (r²>0.997) in all the formulations indicating diffusion as the drug release mechanism.

The rate constants (K values) were 21.4, 19.5, 19.3, 19.06.64, 4.8, 4.38 and 7.12 mg/hr. The release exponents ‘n’ for formulations F_1,F2, F3 , F4,F5,F6 and F7 was found to be 0.59, 0.62, 0.629, 0.634,1.0, 1.05, 1.03, 1.04 mg/hr indicates super case transport diffusion.

From the in –vitro dissolution data it was found that formulations F1,F2,F3 and F4 release more than 90% of drug release at the end of 12 hours . The study indicating that the polymer amount is not sufficient to control the drug release.

The drug release studies, formulations F5, F6, F7 showed desired in-vitro drug dissolution at low concentration.

The drug release rate of Diclofenac sodium tablets were found to be affected by the concentration of guar gum polymer used in the formulation. As the concentration of the polymer was increased, the drug release was found to be retarded.

The evaluation parameters tested for all formulations and compared with in –vitro dissolution profile of marketed formulation Voveran SR-100.formulation F7show 53.5% release within in 12 hours, so it is better than Voveran –SR-100( fig 7-9).

Drug –excipient compatibility studies:

The spectrum of selected formulation, it was observed that the intensive absorption bands were noted around the same wave numbers. All the functional groups in Diclofenac sodium were maintained in the spectrum of selected formulation. The results indicate that no chemical interaction occurred between Diclofenac sodium and excipients in the selected formulation. The IR spectrum of pure drug, selected formulation and the excipient were shown in (fig: 10, 11).

Similarity factor:

The similarity factor (f₂₎ was found to be 50.21 and indicating good similarity between marketed tablet and selected tablet.

Statistical Evaluation:

The relevance of difference in the in-vitro diffusion rate profile was evaluated statistically. Statistical analysis by using One-way analysis of variance (P<0.05) proves that tablets prepared with various gums and its ratios, indicates that the dissolution rate constants were significantly differ with each other.

Figure -1: Drug release profile of Diclofenac sodium tablets formulated with guar gum, xanthan gum, gum kondagogu, almond gum1:1 ratio:

Table -1: Composition of Diclofenac sodium tablets:

S.NO	Ingredients	Quantity taken for tablet(mg)
S.NO	Ingredients	F1	F2	F3	F4	F5	F6	F7
1	Drug: Guar gum & MCC granules	1:1	-----	-----	-----	1:2	1:2.5	1:3
2	Drug: Xanthangum &MCC granules	-----	1:1	-----	------	----	----	----
3	Drug: Kondagogu &MCC granules	-----	-----	1:1	-----	-----	-----	-----
4	Drug: Almond gum &MCC granules	-----	-----	-----	1:1	----	-----	-----
Total		200	200	200	200	300	350	400

Table- 2: Micromeritic properties of the blends:

S.no:	Formulation	Bulk density(g/ml)	Tapped density(g/ml)	Carr’s index (%)	Hausner’s ratio
1	F1	0.60	0.55	10	0.916
2	F2	0.58	0.53	8.62	0.913
3	F3	0.483	0.418	13.4	0.86
4	F4	0.461	0.382	17.1	0.82
5	F5	0.413	0.356	13.8	0.86
6	F6	0.44	0.39	11.3	0.88
7	F7	0.50	0.43	12	0.86

Table-3 :Physical properties of the Diclofenac sodium tablets formulated with guar gum, xanthan gum, gum kondagogu, almond gum 1:1 ratios by wet granulation method:

S.no:	Formulation F1,F2,F3,F4	Thickness (mm)	Average weight(mg)	Hardness (Kg/cm²)	Friability (%)	Drug content (%)
1	MCC & Guargum1:1	0.302±0.005	200±5.13	4.5±0.23	0.75	98
2	MCC& xanthan gum1:1	0.430±0.01	200 ± 4.53	5.33±0.57	0.459	96.27
3	MCC &Kondagogu1:1	0.445±0.01	200 ± 6.23	5.16±0.28	0.552	95.66
4	MCC& Almond gum1:1	0.450±0.011	200 ± 3.23	5.00±0.5	0.592	95.92

Table -4 Physical properties of the Diclofenac sodium tablets formulated with different concentrations of guar gum 1:2, 1:2.5, 1:3 prepared by wet granulation method:

S.no:	Formulation F5,F6,F7	Thickness (mm)	Average weight(mg)	Hardness (Kg/cm²)	Friability (%)	Drug content (%)
1	MCC& Guargum1:2	0.343±0.005	300±7.63	4.5± 0.57	0.8	96
2	MCC & Guargum1:2.5	0.403±0.005	350 ± 5.25	4.52 ± 0.28	0.72	97.20
3	MCC& Guargum1:3	0.453±0.005	400 ±4.65	5.4 ± 0.50	0.78	98.54

Table -5: In-vitro release kinetics of Diclofenac sodium tablets formulated with guar gum, xanthan gum, gum kondagogu, almond gum 1:1 ratio:

Formulation	Correlation coefficient (R²)				T₅₀ (hr)	T₉₀ (hr)	Exponential coefficient(n)	K (mg/hr)
Formulation	Zero order	First order	Higuchi-matrix	Peppa’s	T₅₀ (hr)	T₉₀ (hr)	Exponential coefficient(n)	K (mg/hr)
F1	0.95	0.85	0.98	0.99	5.6	10.1	0.590	21.42
F2	0.95	0.93	0.98	0.99	5.7	10.2	0.628	19.58
F3	0.98	0.95	0.98	0.99	5.7	10.3	0.629	19.3
F4	0.96	0.95	0.98	0.99	5.7	10.3	0.634	19.08

CONCLUSION:

The flow properties of the blend, the strength of the tablet and the dissolution properties were dependent on the composition of co-processed excipient. The co-processed excipient (microcrystalline cellulose: guar gum 1:3) prepared by granulation technique was found to be more suitable for preparing Diclofenac sodium tablets. Among the prepared ratios MCC and guar gum 1:3 was considered as a best formulation because of having retarded drug release properties and good micromeritic properties. The drug dissolution rate followed zero-order kinetics and mechanism of drug release was governed by peppas model. The dissolution exponent of release profiles (slope) has a value of 0.59-1.05 (n>1), which indicates super case ц transport diffusion. The results obtained in the present study thus indicate that the tablets prepared with co-processing technique using gums of various concentrations have shown significant influence on dissolution rate of tablets. The statistical analysis by one-way analysis of variance (p<0.05) indicated that the dissolution rate constants were significantly differs with each other. The similarity factor (f₂) was found to be 50.21 and indicating good similarity between marketed tablet and selected tablet. The drug and excipient interaction studies were conducted with IR spectral studies and drug and the selected excipient were found to be compatible.

ACKNOWLEDGEMENTS:

The author expresses sincere thanks to Yarrow Chem. Pharma limited, Dombivli for providing us gift sample and to Bapatla society for providing necessary facilities.

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Received on 10.04.2014 Modified on 15.06.2014

Res. J. Pharm. Dosage Form. & Tech. 7(1): Jan.-Mar. 2015; Page 51-58

DOI: 10.5958/0975-4377.2015.00008.7