INTRODUCTION:

Binding agents are used to impart cohesive qualities to the powdered material during the production of tablets. Binders are added to tablet formulation to impart plasticity and thus increase the inter-particulate bonding strength within the tablet. Most commonly used binders are natural and synthetic gums. A number of plant gums or mucilage’s have been used as binding agents in tablet formulations. They have been found useful in producing tablets with different mechanical strength and drug release properties for different pharmaceutical purposes^1-4.

Gums are the by products obtained as a result of metabolic mechanisms of plants. Natural gums are either water soluble or absorb water to form a viscous solution. They are non-toxic and there wide availability has made them of continuing interest.

They impart cohesiveness to the tablet formulation, which ensures that the tablet remains intact after compression as well as improving the free flowing quality. Binders have been used as solutions and in dry form, depending on the other ingredients in the formulations and the method of preparation^1-3.

Oral route of drug administration is the most appealing, convenient, significant and popular route for the delivery of drugs owing to ease of swallowing, self medication, and most economic. Tablets are the most popular and preferred oral formulation available in the market because of its ease of manufacturing, convenience in administration, accurate dosing, stability compared with oral liquids and because it is more tamperproof than capsules^5-8.

Over the past two decades, sustained release drug delivery systems have made significant progress in terms of clinical efficacy and patient compliance. The primary benefits of a sustained release dosage forms compared to a conventional dosage forms, is maintenance of constant plasma drug concentration and therefore maintains uniform therapeutic effect. Drug-release-retarding polymers are the key performers in such systems. Regarding this, researchers investigated various natural, semi-synthetic and synthetic polymeric materials^9-11. Matrix system is most commonly used method for modulating the drug release in oral controlled drug delivery to obtain a desirable drug release profile, cost effectiveness and broad regulatory acceptance. Matrix devices, due to their chemical inertness, drug embedding ability and drug release character, have gained steady popularity for sustaining the release of a drug^{9, 12, 13}.

Drug products designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available for many years. Number of natural, semi synthetic and synthetic polymer materials are used in the sustained or controlled delivery of drugs. Regular research is going on in the field of use of natural occurring biocompatible polymeric material in designing of dosage form for oral controlled release administration. Natural polymers have gained the attention for their use in drug delivery systems due to their easy availability, non-toxic, cost effectiveness, ecofriendliness, biocompatible, capable of chemical modifications, potentially biodegradable and degradation under natural and physiological conditions^14-16.

Prunus persica gum is obtained from the injured or incised portion the trunk of Prunus persica trees belonging to family Rosaceae. The study was undertaken to evaluate the release modifying potential of Prunus persica gum in diclofenac sodium matrix tablets.

MATERIALS AND METHODS:

Materials:

Diclofenac sodium was purchased from Yarrow Chem Products, Mumbai, India. Microcrystalline cellulose, magnesium stearate and talc were procured from Central Drug House, New Delhi, India. Prunus persica gum was collected from the trunk of Prunus persica trees in a nearby locality of Dehradun, Uttarakhand. Plant sample was authenticated from Botanical Survey of India, Dehradun, Uttarakhand, India. One set of the sample was deposited in the herbarium of Botanical Survey of India, Northern regional Centre, Dehradun, Uttarakhand, India. All the other chemicals used were of analytical grade.

Isolation and Purification of Prunus persica Gum:¹⁷^{, 18}

The Prunus persica gum was collected from the trunk of Prunus persica trees from an injured or incised portion. Sometimes, it may get oozes out from its trunk itself. The crude form of gum collected was washed for impurities and then dissolved in distilled water. The supernatant was filtered through buckner funnel. The residue was again washed with distilled water 2-3 times and combined the filtrate. The gum was precipitated from combined filtrate using acetone. The precipitate was separated and dried below 60ºC. The dried gum was powdered and stored in tightly closed container.

Physicochemical Properties of Prunus persica Gum:¹⁷^-20

Macroscopic properties of the gum were evaluated by observation of the colour, taste and odour of the powdered gum. The gum was evaluated for solubility in water, ethanol, acetone and chloroform in accordance with the standards. Other physicochemical properties were also determined for the gum like loss on drying, total ash, pH, angle of repose, bulk density, tapped density, hauser’s index and carr’s index.

Preparation of Diclofenac Sodium Matrix Tablets:¹⁸^{, 21}

Oral matrix tablets each containing 100mg of Diclofenac sodium were prepared by wet granulation method using different drug: gum ratios viz. 1:0.25, 1:0.5, 1:1 and 1:2 for various formulations containing Prunus persica gum. Microcrystalline cellulose was used as filler to maintain the tablet weight. The compressed tablets were stored in a closed container for 15 days, no significant evidence of chemical change was observed.

Evaluation:

The prepared formulations were evaluated for the following parameters:

1. Pre-compression evaluation^{18, 20, 21}

i. Angle of Repose:

The angle of repose of granules was determined by the funnel method. The accurately weight granules were taken in the funnel. The granules were allowed to flow through the funnel freely on to the surface. The diameter of the granules cone was measured and angle of repose was calculated using the following equation:

tan θ = h/ r or θ = tan^-1 (h/ r)

Where, θ = angle of repose,

h = height of the cone, and

r = radius of the cone base

ii. Bulk Density:

Bulk density (D_b) was determined by measuring the volume (V_b) of known weighed quantity (W) of granules using bulk density apparatus and can be calculated by using the formula:

D_b= W/ V_b

iii. Tapped Density:

Tapped density (D_t) was determined by measuring the volume (V_t) of known weighed quantity (W) of granules using bulk density apparatus and can be calculated by using the formula:

D_t= W/ V_t

iv. Hausner’s Index:

The Hausner’s index was calculated by dividing the tapped density by the bulk density of the granules.

Hausner’s index = D_t / D_b

Where, D_t is the tapped density and D_b is the bulk density.

v. Carr’s Index:

The Carr’s index (% compressibility) of the granules was calculated from the difference between the tapped and bulk densities divided by the tapped density and the ratio expressed as a percentage.

Carr’s Index (%) = {(D_t - D_b) / D_t} x 100

Where, D_t is the tapped density and D_b is the bulk density.

2. Post-compression evaluation^{19, 20}

i. Tablet Thickness:

The thickness of the tablets was determined by using vernier caliper. Three tablets were used, and average values were calculated.

ii. Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm². Three tablets were randomly picked and hardness of the tablets were determined.

iii. Weight Variation:

To study weight variation twenty tablets of the formulation were weighed using a digital balance and the test was performed according to the official method. Twenty tablets were selected randomly and weighed individually to check for weight variation.

iv. Friability:

The friability of tablets was determined using Roche Friabilator. It is expressed in percentage (%). Ten tablets were initially weighed and transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes. The tablets were weighed again. The % friability was then calculated by:

% Friability = {(Initial Weight – Final Weight)/ Initial Weight} x 100

% Friability of tablets less than 1% are considered acceptable.

v. Content Uniformity:

Five tablets were weighed individually and powdered. The powder equivalent to average weight of tablets was weighed and drug was extracted in acetone, the drug content was determined measuring the absorbance at 276 nm after suitable dilution using Elico SL210 UV-Visible double beam spectrophotometer. The drug content was estimated from the standard curve of diclofenac sodium.

vi. Disintegration Time:

Disintegration time test was carried out according to USP specification. 6 tablets were placed in a disintegration tester filled with distilled water at 37±0.20C. The tablets were considered completely disintegrated when all the particles passed through the wire mesh.

vii. Swelling Behaviour of Formulations:

The swelling index of all the tablet formulations was studied. The extent of swelling was measured in terms of percent weight gain by the tablet. To study the swelling behavior, one tablet from each formulation was kept in a petri dish containing 20 ml phosphate buffer pH 7.4. At the end of 1 hr, the tablet was withdrawn, kept on tissue paper and weighed. The process was continued for every 2 hr, till the end of 12 hr.

The % weight gain by the tablet was calculated by formula:

S.I. = {(Mt-M0) / M0} x 100

Where,

S.I. = swelling index

Mt = weight of tablet at the time (t)

Mo = weight of tablet at time 0.

viii. In-Vitro Drug Release Profile Studies:

Release of Diclofenac sodium from the matrix tablets was studied using a six basket USP dissolution apparatus taking 900 mL of 0.1 N HCl (pH 1.2) solution for first 2 hrs and phosphate buffer (pH 7.4) for next 10 hrs. The dissolution media were maintained at a temperature of 37°± 0.5°C. The speed of rotation of basket was maintained at 50 rpm. Aliquot equal to 10 ml sample was withdrawn at specific time intervals and the dissolution media volume was complimented with fresh and equal volume of phosphate buffer. The samples were filtered and suitably scanned with appropriate dilution and amount of Diclofenac sodium released from the tablet samples was determined spectrophotometrically at a wavelength of 276 nm by comparing with the standard calibration curve.

RESULTS AND DISCUSSION:

Preformulation studies of Prunus persica gum was performed for determining the macroscopic properties, solubility, pH, moisture content, total ash and flow properties. Macroscopic properties showed that Prunus persica gum obtained after purification was a free flowing light yellow colour powder with no taste and odour. The gum was found to be soluble in water but practically insoluble in ethanol, acetone and chloroform. It has pH around 4.0-5.0 with acceptable limit loss on drying (5.85%) and total ash (4.20%). Flow properties of gum was determined in terms of angle of repose (23.54º), bulk density (0.58g/cc), tapped density (0.79g/cc), hausner’s index (1.36) and carr’s index (26.58%). All these physicochemical properties were tabulated in Table 1.

Table 1: Physicochemical Properties of Prunus persica Gum

S.No.	Parameters		Results
1.	Macroscopic Property	Colour	Light Yellow
		Taste	Tasteless
		Odour	Odourless
2.	Solubility	Water	Soluble
		Ethanol	Insoluble
		Acetone	Insoluble
		Chloroform	Insoluble
3.	Loss on Drying (%)		5.85
4.	Total Ash (%)		3.20
5.	pH		4.0-5.0
6.	Angle of Repose (º)		23.54
7.	Bulk Density (g/cc)		0.58
8.	Tapped Density (g/cc)		0.79
9.	Hauser’s Index		1.36
10.	Carr’s Index (%)		26.58

Preformulation studies of Diclofenac sodium was performed for determining the solubility, melting point and λmax. The results showed that the drug was found to freely soluble in ethanol, acetone and methanol, sparingly soluble in distilled water and glacial acetic acid while practically insoluble in ether. Melting point of Diclofenac sodium was found to be 170°C approx. The λmax of Diclofenac sodium was found to be 275 nm in Figure 1 and standard calibration curve of Diclofenac sodium was prepared as showed in Figure 2.

Table 2: Formulation of Diclofenac Sodium Tablets

Ingredients	Formulations (mg/tablet)
Ingredients	PP-1 D:G (1:0.25)	PP-2 D:G (1:0.5)	PP-3 D:G (1:1)	PP-4 D:G (1:2)
Diclofenac Sodium	100	100	100	100
Prunus persica Gum	25	50	100	200
Microcrystalline Cellulose	360	335	285	185
Magnesium Stearate	10	10	10	10
Talc	5	5	5	5
Total	500	500	500	500

* PP- Prunus persica * D: G = Drug: Gum ratio

Table 3: Pre-Compression Evaluation of Diclofenac Sodium Granules

S.N.	Parameters	Formulations
S.N.	Parameters	PP-1	PP-2	PP-3	PP-4
1.	Angle of Repose (º)	26.12±0.66	24.60±0.30	24.82±0.44	23.68±0.34
2.	Bulk Density (g/cc)	0.49±0.03	0.43±0.02	0.51±0.01	0.46±0.02
3.	Tapped Density (g/cc)	0.61±0.04	0.56±0.01	0.65±0.02	0.58±0.01
4.	Hausner’s Index	1.24	1.30	1.27	1.15
5.	Carr’s Index (%)	19.67	23.21	21.54	20.69

*Values are in mean±s.d. (n=3) (s.d.= standard deviation)

Table 4: Post-Compression Evaluation of Diclofenac Sodium Tablets

S.N.	Parameters	Formulation
S.N.	Parameters	PP-1	PP-2	PP-3	PP-4
1.	Tablet Thickness (mm)	4.11±0.05	4.10±0.24	4.15±0.18	4.20±0.02
2.	Hardness (Kg/cm³)	6.38±0.64	6.20±0.93	6.17±0.82	6.82±0.54
3.	Weight Variation	495±0.01	498±0.02	503±0.22	497±0.03
4.	Friability (%)	0.56±1.23	0.43±0.29	0.76±1.11	0.54±1.02
5.	Content Uniformity (%)	100.2±0.03	99.6±0.04	100.5±0.05	100.4±0.05
6.	Disintegration Time (min)	8.33±0.72	11.74±0.01	16.48±0.86	20.85±1.02

*Values are in mean±s.d. (n=3) (s.d. = standard deviation)

Figure 3: Swelling Behaviour of Diclofenac Sodium Tablets

Table 5: In Vitro Release Data of Diclofenac Sodium Tablets

Time (hr)	% Cumulative Drug Release
Time (hr)	PP-1	PP-2	PP-3	PP-4
1	7.52±1.73	13.87±1.01	12.92±1.25	16.38±1.54
2	25.54±1.44	34.84±1.02	32.80±1.38	30.67±1.09
3	46.81±1.10	46.73±1.52	41.31±1.45	40.43±1.79
4	79.19±1.04	64.52±1.32	62.68±1.81	59.32±1.81
5	92.27±1.81	87.15±1.61	78.81±1.01	71.61±1.20
6	97.39±1.06	98.91±1.59	89.72±1.09	84.03±1.37
7	-	-	96.32±1.61	91.90±1.74
8	-	-	98.15±1.25	96.35±1.61
9	-	-	-	98.63±1.02
10	-	-	-	99.61±1.16
11	-	-	-	-
12	-	-	-	-

*Values are in mean±s.d. (n=3) (s.d. = standard deviation)

CONCLUSION:

The study revealed that Prunus persica gum appears to be suitable for use as a release modifier in the preparation of matrix tablets of diclofenac sodium because of its properties to give excellent and better results by evaluating the pre-compression and post-compression parameters for different formulations containing variable ratios of drug and gum. By observing the good swelling index and appropriate drug release pattern in tablet formulations, it was revealed from the study that among all the formulations, PP-4 was found to release the drug in a slow, controlled manner with maximum drug release of 99.61% over a period of 10 hr.

All the formulations follow zero order kinetics as correlation coefficient (R²) values are higher than other kinetic models. The kinetic treatment showed that PP-2 preferentially follows zero order kinetics while PP-4 follows Higuchi kinetics indicating that the drug diffuses at a comparatively slower rate. Hence it can be concluded that, the Prunus persica gum can be used as a promising drug release retardant in a particular concentration range.

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Received on 22.10.2013 Modified on 20.11.2013

Res. J. Pharm. Dosage Form. and Tech. 6(1): Jan.-Mar. 2014; Page 18-25

Formulations	Zero order	First order	Higuchi	Koresmayer-Peppas
Formulations	R2	R2	R2	R2
PP-1	0.968	0.893	0.856	0.837
PP-2	0.995	0.759	0.899	0.727
PP-3	0.969	0.920	0.935	0.745
PP-4	0.943	0.908	0.957	0.718