INTRODUCTION:

Arthitis is a term often used to mean any disorder that affects joint. Symptoms generally include joint pain and stiffness. Different types of arthritis exists (i) rheumatoid arthritis (ii) osteoarthritis, each with different causes including wear and tear, infections and underlying diseases.

Various type of symptoms are include in arthritis like inflammation, stiffness and pain. For the treatment of arthritis Indomethacin is choice of drug. It’s a non-steroidal anti-inflammatory drug, it comes under class acetic acid derivative and it’s a poorly water soluble anti-inflammatory agent. It is used in the symptomatic management of painful and inflammatory conditions such as rheumatoid arthritis and osteoarthritis. It has a short biological half-life of 4.5hrs. Various types of dosage form available for Indomethacin like oral, topical, rectal, IV. The traditional dosage forms of Indomethacin such as tablets and capsules have to be taken 3 or 4times/day at a dose of 25mg and it is reported that 75mg of extended release Indomethacin is clinically more effective.^5,9,15

Control Drug Delivery is that type of system which release the medicaments from the dosage form at a predetermined specified rate for locally or systemically for a specified period of time. It maintains constant drug level in the blood target tissue usually by releasing the drug in a zero order pattern. Controlled release, prolonged action, sustained release, extended release, depot dosage forms are terms used to identify these drug delivery systems that are designed to achieve prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.^1,6,10

Several new modifications are being introduced of sustained release preparations. Sustained release (SR) dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systemically or to a specified target organ. They are also referred to as “long acting” or “delayed release” when compared to “rapid” or “conventional” release preparations.^4,16Advantages associated with sustained release product are the frequency of drug administration is reduce, patient compliance, more convenient, conventional dosage forms is reduced, minimize the fluctuation of in plasma level, better control of drug absorption, minimize side effects, minimize drug accumulation, less adverse effects, improve efficiency in treatment, improve bioavailability and economy. Sustained release dosage form also shows some disadvantages like probability of dose dumping, reduced potential for dose adjustment, cost of single unit is higher, increase potential for first pass metabolism, poor in-vitro and in-vivo correlation.^{3, 7, 11}

Oral drug delivery is the most preferred administration route for decades due to noninvasive, high patient compliance, convenient to handle and does not require any specific sterile conditions.^6,8,14

Polymers are utilized in drug delivery to provide drug release, enhanced bioavailability and patient compliance. Polymers are broadly classified as natural polymers and synthetic polymers.^{2, 17} Natural polymers are materials of large molecular weights from natural origins such as plants, micro-organisms and animals. In comparison to natural and synthetic polymers remain attractive primarily because they are compatible, economic, easily available and potentially biodegradable.^1,11,18 In present study xanthum gum and guar gum is selected for sustained release. Molecular weight of xanthan gum is high and it’s obtained from the fermentation of Xanthomonas campestris. Xanthan gum and hydroxyl propyl methyl cellulose were used as hydrophilic matrixing agents for preparing modified release tablets.^6,
18Guar gum is galactomannam, derived from guar (cyamopsistetragonolobus) kernels which belong to family Leguminosae. It is hydrophilic in nature and swells in cold water, forming viscous colloidal dispersion or sols. The bio adhesive and biodegradable property of guar gum make it the first choice for developing controlled and targeting drug delivery systems for colon. Guar gum is also used as a controlled release agent for the drug due to high hydration rate.^4,14,
19

Administration of Indomethacin in sustained release tablet dosage form greatly reduces the incidence of side-effect and provide prolong drug release with the help of guar gum and xanthan gum.^10,11,14 Both the polymers are natural, biogenic and biodegradable. Developing sustained release dosage forms for poorly soluble drugs is challenging but in present study the release of the drug from the matrix system of tablet occurs from the drug dissolution up to 12 hrs.^5,8,15

MATERIALS AND METHODS:

Chemicals:

All materials used in the present research were of analytical grades. Indomethacin was a gift sample from Merk Pharmaceutical Pvt. Ltd. Buddy. Xanthan gum, guar gum, lactose, sodium hydroxide, potassium hydrogen phthalate and potassium di-hydrogen phosphate purchased from Molychem, Mumbai. Talc, magnesium stearate and acetone purchased from SDFCL, Mumbai.

Instruments:

Electronic weighing balance, UV-visible spectrophotometer (Shimadzu, Japan) and Fourier transform infrared spectrophotometer Shimadzu, Japan were used. Hot air oven, Melting point determining apparatus, hardness tester, tablet punching machine, friability tester, vernier caliper and fluidized bed dryer were also used.

METHODS:

Preformulation studies of pure drug:

Identification of drug sample using Fourier transform infrared spectrophotometer (FTIR):

10mg of drug sample and 100mg KBr were taken in mortar and triturated. A small amount of the triturated sample was taken and kept onto the sample holder and scanned from 4000cm^-1to 400cm^-1 in FTIR Spectrophotometer.^6,20,21

Melting point:

Take a small amount of drug sample in capillary tube which was one sided closed and placed in a melting apparatus and the temperature which drug melts was noted.^{5, 21}

Solubility analysis:

A semi quantitative determination of the solubility was made by adding various solvents in small amount to a test tube. After each addition, examined visually for any undissolved solute particles.^3,16

Determination of λ max:

By appropriate dilution of drug solutions with phosphate buffer pH 7.2, solutions containing 10µg/ml of Indomethacin were scanned separately in the range of 200-800nm to determine the wavelength of maximum absorption for the drugs.^1,13

Preparation of calibration curve:

An accurately weighted amount of Indomethacin equivalent to 100mg was dissolved in small amount of pH 7.2 Phosphate Buffer in 100ml volumetric flask and volume made up to 100ml with the same pH 7.2 Phosphate Buffer. From this stock’s solution 10ml was withdrawn and diluted up to 100ml with Phosphate Buffer (pH 7.2) in 100ml volumetric flask to get concentration of 100µg. Now from this solution again 10ml was withdrawn and diluted up to 100ml with pH 7.2 Phosphate Buffer in same 100ml volumetric flask. Now from this solution 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml was withdrawn and diluted up to 10ml with pH 7.2 Phosphate Buffer in 10ml of volumetric flask to get concentration (μg) of 1, 2, 3, 4, 5, 6, 7, 8. The absorbance of each solution was measured by UV-Visible Spectrophotometer at 320nm using pH 7.2 Phosphate Buffer as blank.^{2, 19}

Preparation of granules of Indomethacin by wet granulation technique:

Granules of Indomethacin were prepared by wet granulation method. Drug, polymer and lactose were weighed accurately and mixed thoroughly in a mortar and pestle. Then wet mass passed through sieve no. 16 for preparation of granules. Granules were dried in a tray dryer at 45-50ºC at 2-3 hours. Then, granules were sized by using sieve having mesh number 16. It is shown in (Table 1).^4,13

Table 1. Formulation Chart for the preparation of Tablet

Ingredients (milligram)	F1	F2	F3	F4	F5	F6
Indomethacin	75	75	75	75	75	75
Xanthan gum	75	125	----	----	37.5	62.5
Guar gum	----	----	75	125	37.5	62.5
Lactose	310	260	310	260	310	260
Talc	20	20	20	20	20	20
Magnesium Stearate	20	20	20	20	20	20

Evaluation of Pre-Compression Characteristic of granule:

Powder blend prepared were evaluated for various rheological properties like bulk density, tapped density, angle of repose, carr’s index, hausner’s ratio by using standard procedures.^5,12,20

Bulk density:

Bulk densities of powders are determined by using digital weighing machine and measuring cylinder. Bulk density is calculated using the following formula.^{2, 7, 12}

Weight of powder

Bulk density = -––––––––––––––––––

Volume of powder

Tapped density:

Tapped density is determined by taking the dried powders in a measuring cylinder and measures the volume of powders after 300 tapping’s and take weight of the total powders.^4,20

Weight of the powder

Tapped Density = ––––––––––––––––––––––––––

Tapped volume of the powder

Angle of repose:

Angle of repose is determined by measuring the height and radius of the granular bed. Granules are poured in the tube and slowly removed the tube vertically. With the help of scale the height and radius of the heap were measure and note.^6,18

θ= tan -1 h/r

Where,

h = Height of granular bed

r = Radius of granular bed

Carr’s index:

The percentage compressibility of the powder mixture was determined by the following formula.²¹

Carr’s index=

(Tapped density-Bulk density)/(Tapped density)×100

Hausner’s Ratio:

It is expressed by-

Hausner' s ratio = Dt/Db

Where, Dt is the tapped density of the granule and Db is the bulk density of the granule.

Compression of granules into Tablets:

After adding Lubricant (talc) and glidant (magnesium stearate) to the prepared powder, they were compressed into tablets on a tablet rotatory compression machine, one side concave and one side flate punches.^{3,
9, 10}

Evaluation of tablets:

The prepared tablets were evaluated for their thickness, friability, hardness, weight variation, drug content and dissolution test by using standard procedures.^{3, 17}

Weight variation test:

20 tablets were taken and their weight was determined collectively and individually on digital weighing machine. The average weight of one tablet was calculated from collective weight of all the tablets. Not more than two tablets of the individual weight may deviate from the average weight.^4,11,15

Thickness test:

The tablets were evaluated for their thickness using a vernier caliper’s measured in terms of (mm) micrometer.^{10, 20}

Hardness test:

Hardness was evaluated by using Monsanto hardness tester for prepared tablets. The hardness was measured in terms of 7-8 kg/cm².^1,
21

Friability test:

For this test 20 tablets were weighted accurately and placed in the friabilator chamber and rotated at 25 rpm for a period of 4min. The Tablets were weighted again and loss percentage was determined.^1,14,20

% Friability = ([(W1-W2)100])/W1

Where, W₁= Weight of tablets

W₂= Weight of tablets (After test)

In-vitro drug release study:

The in- vitro drug release study was carried out using USP dissolution rate test apparatus (Apparatus II, 50 RPM, 37˚C ±1˚C) for 12 hrs in phosphate buffer pH 7.2 . Sample was withdrawn in every single hour time intervals. One ml of the sample was withdrawn and the sink condition of dissolution medium was maintained to 1 ml of fresh media. The sample were analyzed at 320 nm using UV- Spectrophotometer.^5,21

Preparation of sustained release tablet of Indomethacin by wet granulation method:

Formulation of Indomethacin tablet was prepared by wet granulation method. Xanthan gum and Guar gum used as natural polymer, Lactose as diluent, water and isopropyl alcohol as wetting property, Talc and Magnesium stearate used as Glident and Lubricant respectively.

RESULT AND DISCUSSION:

Identification of Indomathacin by FTIR:

It was found that the peaks obtained by performing FTIR of pure drug were found to be in (Fig 1) between the range of main principle peaks recorded previously as theoretical range; observed in (Table 2) hence this indicates that the drug is pure.

Fig 1. IR Spectra of pure drug Indomethacin

Table 2. IR peak Table with Principle Peaks of Indomethacin

S. No.	Functional Group	Reported IR band of Indomethacin (cm^-1)	Obtained Peak (cm^-1)
1.	CH Stretching (Aromatic)	2983-2930	2975
2.	CH Stretching (Aliphatic)	2891	2891
3.	C=O	1717-1692	1684
4.	CH-CH₃	1456	1456
5.	Ar-CH	926-692	753

Melting point:

Melting point of the drug was found to be in the range of 152⁰C - 159⁰C. Average melting point of pure drug was found to be 155^oC, which complies with Indian Pharmacopoeia specification so it was conformed that gift sample obtained was Indomethacin.

Solubility analysis:

The solubility profile of drug was observed in (Table 3).

Table 3. Data for solubility of drug:

S. No.	Solvents	Solubility
1.	Distilled water	Insoluble
2.	Ether	Soluble
3.	Acetone	Soluble
4.	Ethanol	Soluble
5.	Castor oil	Soluble

Determination of λ^max:

The absorption spectrum of pure drug was scanned 200-800nm with 10µg/ml prepared in phosphate buffer pH 7.2. The λ^maxof pure Indomethacin was to be found to be 320nm.

Standard Curve of drug:

Standard calibration curve of Indomethacin was carried out in a pH 7.2 Phosphate buffer at 320nm. The absorbance value obtained is shown in (Fig 2). The Beer and Lambert’s plot was obtained between the absorbance and concentration. The plot is given the figure. The R² value of pH 7.2 Phosphate Buffer was found to be 0.998.

Fig 2. Standard calibration curve of Indomethacin

Evaluation of pre-compression characteristics of granules:

The pre-compression evaluations of prepared granules were shown below (Table 4). The powders were evaluated for Angle of repose, Bulk density, Carr’s index, Hausner’s ratio, Tapped density, and consistency in data obtained as indicated by their standard deviation value.

Table 4. Pre-compression characteristics of standard deviation value

S. No.	Bulk Density (g/ml±SD)	Tapped Density (g/ml±SD)	Angle of repose (Ө±SD)	Carr’s Index (%±SD)	Hausner’s ratio (g/ml±SD)
F1	0.3833±0.02	0.4059±0.03	28.096±0.291	12.2949±0.76	1.14±0.05
F2	0.3129±0.02	0.3978±0.026	30.32±0.09	14.3423±1.063	1.15±0.03
F3	0.4120±0.02	0.4380±0.023	29.74±0.215	11.9360±1.509	1.18±0.047
F4	0.3646±0.013	0.4003±0.03	30.18±0.061	17.1928±0.98	1.16±0.055
F5	0.3679±0.018	0.3992±0.031	26.63±0.223	10.1764±0.87	1.12±0.03
F6	0.3821±0.016	0.4106±0.009	30.26±0.344	11.9947±0.45	1.14±0.06

Table 5. Data of sustained release tablet of Indomethacin

Formulation No.	Thickness (mm±SD)	Hardness (Kg/cm²±SD)	Friability (%±SD)	Weight variation (mg±SD)
F1	3.0±0.014	7.5±0.37	0.29±0.02	501±1.06
F2	3.1±0.004	7.5±0.26	0.25±0.005	498±1.004
F3	3.5±0.002	8.0±0.36	0.50±0.005	495±1.01
F4	4.3±0.02	8.5±0.32	0.41±0.01	500.3±1.08
F5	3.0±0.01	7.4±0.305	0.35±0.011	497.2±1.01
F6	3.7±0.01	8.5±0.25	0.95±0.01	504.7±1.08

Table 6. Cumulative percentage Drug Release Profile

Time (hrs)	Cumulative Percentage of Drug Release (C%DR±SD)
Time (hrs)	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
1	15.32±1.27	10.05±0.01	26.30±2.61	12.34±3.15	19.34±3.31	21.93±3.15
2	21.70±3.15	16.98±2.04	32.90±3.10	22.81±1.70	27.74±1.2	26.73±1.70
3	25.50±1.70	38.61±2.91	43.37±2.18	34.10±1.25	39.68±2.34	31.25±1.25
4	28.83±1.25	49.59±3.23	54.30±1.27	42.92±2.13	44.31±2.62	35.90±2.13
5	33.97±2.13	65.72±3.10	69.42±1.13	49.30±2.74	52.25±3.42	43.70±2.74
6	40.20±2.74	78.20±2.35	83.50±3.21	58.41±2.75	59.66±2.53	49.50±2.75
7	46.17±2.75	85.91±2.18	90.23±2.15	67.14±2.33	68.51±1.82	57.20±2.33
8	50.27±2.33	90.40±1.0	95.32±2.63	77.72±2.10	80.57±1.43	64.64±2.10
9	57.30±2.06	95.67±2.18	97.31±3.21	86.25±2.05	89.70±1.11	68.80±1.81
10	62.10±3.01	98.61±3.10	97.90±1.0	93.10±2.75	92.50±1.04	71.7±1.50
11	67.21±3.07	98.65±1.0	98.12±1.12	96.25±2.33	95.70±1.12	73.31±1.23
12	75.20±2.61	98.81±1.0	98.32±1.21	99.29±2.01	98.79±2.13	82.44±1.43

Note: Value are mean value of 6 observation (n=6), and value in parenthesis are Standard deviation (S±D)

Comparison of release profile of tablets prepared by different ratio of polymer:

In all formulations F1 indicate best formulation was showing lowest percentage of drug release. Increasing the proportion of hydrophilic natural polymer concentration in the polymer matrix increase the % cumulative drug release.

DISCUSSIONS:

Sustained release tablets of Indomethacin using natural polymers like guar gum and xanthan gum were prepared by incorporating various drug polymer ratios and hence six different formulations were prepared by wet granulation method. All these formulations were than treated with different official test to check the physicochemical properties of these sustained release tablet formulations. After the preparation of granules angle of repose, bulk density, tapped density, Hausner’s ratio and compressibility index were determined and all were in official limits and were acceptable. Granulation is a basic process which plays a very important role in manufacturing of many dosage forms. The tablets each containing 75 mg of indomethacin were prepared employing the two selected natural polymers. Among the various sustained release formulation of tablet is a simple and feasible technique for obtaining sustained release. Hardness test, thickness test, weight variation and friability test were determined and were official limits and were acceptable.

Indomethacin release from the tablets was studied in phosphate buffer pH 7.2. The drug release pattern of six different formulations in which xanthan gum and guar gum were used as a retarding material in different proportions was shown in table no. 6. The formulation F1 releases (75.20%) upto 12 hrs whereas the formulation F2 releases the drug (98.81%) in same time. The formulations F3, F4, F5 and F6 release 98.32%, 99.29%, 98.79% and 82.40% respectively. The dissolution pattern of both gums was similar i.e. with drug to polymer ratio (1:1).

In present work F1 shows best sustained release upto 12 hrs in which Drug to Polymer ratio was 1:1:0 (Drug : Xanthan gum : Guar gum).

In formulation F2 drug release was not sustained and complete release occurs in 12 hrs where the Drug to Polymer ratio was 1:1.67:0 (Drug : Xanthan gum : Guar gum). It was found that on the concentration of xanthan gum decreases the release rate of the drug also decreases. For sustain release there is not much role of Guar Gum reported. The release of drug not only depends upon nature of matrix but also depends upon the drug polymer ratio.

CONCLUSION :

Indomethacin drug has been selected which has half-life 4.5 hrs. Hence the present work, an attempt has been made to provide sustained release drug delivery using polymers with Indomethacin as the model drug. When xanthan gum and guar gum, alone or in combination, were used as release retarding agents, rugged Indomethacin containing- granules that demonstrated good flow could be produced, and good physical properties of sustained release tablets. Xanthan gum was best able to retard Indomethacin release mechanism even in the presence of a polymer. Polymer can be used to formulate successful sustained release Indomethacin matrix tablets that have desirable characteristics.

ACKNOWLEDGEMENTS:

Authors express their sincere gratitude to Columbia Institute of Pharmacy, Raipur, for continuous motivation, support and guidance for research activity and for providing all required facilities to accomplish the entitled work.

ETHICS STATEMENT:

The paper reflects the author’s own research and analysis in a truthful and complete manner.

CONFLICT OF INTEREST:

The author declares no conflict of interest.

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Received on 05.12.2023 Modified on 01.01.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(1):35-41.

DOI: 10.52711/0975-4377.2024.00006