INTRODUCTION:

Sustained release dosage forms are dosage form designed to release drug at a predominant rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects. This can be achieved through a variety of formulations, including microbeads, liposomes and drug-polymer conjugates¹.

Ionotropic gelation is a technique used for the production of multi-unit polymeric systems. Such systems are generically spheroidal in shape, and are characterized by a diameter that can range between a few µm and some mm².

Ibuprofen (C₁₃H₁₈O₂) is a non-steroidal anti-inflammatory drug (NSAID) derived from propionic acid and it is viewed as the first of the propionic. The IUPAC name of Ibuprofen is 2-(4-isobutylphenyl) propionic acid and its underlying improvement was in 1960 while exploring for a more secure option for aspirin. It was the most readily available over-the-counter NSAID. Ibuprofen is an NSAID and non-selective COX inhibitor used to treat mild-moderate pain, fever, and inflammation.In this research Ibuprofen is used because its half-life is 1.8 to 2 hrs. And it has low gastrointestinal disturbance and also for the reduction of the multiple dosing. Metabolism of Ibuprofen occurs mainly in the liver and it is almost completely metabolized with the little to no unchanged drug found in the urine. The metabolism occurs due to enzyme cytochrome P450^3-6.

MATERIAL AND METHOD:

Ibuprofen was obtained as a gift sample from Unijules Pvt Ltd, Sodium Alginate was procured from Loba Chem, Mumbai, Hydroxyl Propyl Methyl Cellulose,and Calcium Chloride was procured from Avantor Performance Materials India Ltd. All other chemicals and reagents used were of analytical grade and were used as obtained.

Drug –Excipient Interaction Study:

Fourier Transform Infrared Spectroscopy:

Drug polymer interactions were studied by FT-IR spectroscopy. 1:1 ratio of drug and polymer was taken and the physical mixture of samples were weighed and mixed properly with potassium bromide to a uniform mixture. A small quantity of the powder was compressed into a small pellet by applying pressure⁷. The IR spectrum of the beads from 400-4000cm^-1 was recorded and compared with standard to study any interference.

Differential Scanning Calorimetry:

Drug and excipient was performed by employing DSC. 5mg of pure drug and the physical mixture of drug with the polymers were scanned in aluminum pans over a temperature range between 50 and 400˚C at a scanning rate of 10˚C/min. Nitrogen was used for purging the sample holder at a flow rate of 20 Ml/min⁸.

Standard Calibration Curve:

An accurately weighed quantity of 100mg of Ibuprofen was transferred into a 100 ml standard flask and volume was made up to the mark using 0.1N HCL.From solution having concentration 100μg/ml aliquots of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5ml were pipette out into 10ml volumetric flasks. The volume was made up to the mark with 0.1N HCLto get the final concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50μg/ml respectively⁹. The absorbance of each concentration was measured at 220 nm.

Preparation of Microbeads:

The Microbeads were prepared by employing Ionotropic gelation technique. The required amount of sodium alginate was dissolved in 5ml of water which was of low viscosity to this the required quantity of HPMC K15 was added and mixed well until a homogenous mixture was obtained. To this suspension the required amount of drug was suspended until a homogenous suspension was prepared. The prepared suspension was deaerated by keeping the suspension for 30 min so that the air bubbles can be removed. The deaerated suspension was then incorporated into the 4% solution of calcium chloride drop by drop with the help of syringe for the cross linking process. The prepared beads were then allowed to cure for 2 hrs. until complete rigidization. The beads were then filtered off and washed with distilled water. The washed beads were then allowed to dry at room temperature for 24 hrs.

Table 1: Formulation Chart of Microbeads

Batch	Drug (mg)	Sodium Alginate (mg)	HPMC K15 (mg)	Calcium Chloride (%)
B1	200	100	900	4%
B2	200	200	800	4%
B3	200	300	700	4%
B4	200	400	600	4%
B5	200	500	500	4%
B6	200	600	400	4%
B7	200	700	300	4%
B8	200	800	200	4%
B9	200	900	100	4%

Evaluation Parameters:^10-12

Micromeritics Properties:

The prepared microbeads were evaluated for their micromeretics properties such as Tap density, Bulk density, Carr’s index, Hauser’s ratio, Angle of repose.

Tap Density:

Tapped density of prepared microbeads was determined by the tapping method. Accurately weighed quantity of microbeads from each batch was transferred in to a 10 ml measuring cylinder. After observing the prevailing volume of microbeads, the tapping was continuing on a tough surface till no progressive modification in the volume was noted and therefore the tapped density was calculated.

Mass of microbeads

Tap Density: --------------------------------------------

Volume of microbeads after tapping

Bulk Density:

It is the quantitative relation between a given mass of a powder and its bulk volume. Bulk density of the formulated microbeads was calculated by pouring about 2 g of formulated microbeads in a clean measuring cylinder, and initial volume was measured. The bulk density was calculated by the following equation:

Mass of microbeads in gram

Bulk Density: -----------------------------------------------

Volume of microbeads in cm³

Carr’s Index:

Carr index is a specific measure of powder arch or bridge strength and durability. Calculated with the following formula:

Carr’s Index: Tap Density – Bulk Density × 100

---------------------------------------------------------------

Tap Density

Hauser’s Ratio:

It is associate degree indirect index of easy powder flow. It is calculated by the following formula:

Tap Density

Hauser’s Ratio: -----------------------

Bulk Density

Angle of Repose:

The flow property of floating microbeads is usually estimated by determining the angle of repose. The angle of repose of microbeads was determined by using a fixed funnel on a burette stand employing fixed funnel method. The microbeads were allowed to freely fall through the fixed funnel until apex of conical pile formed just touched the tip of the funnel. The angle of repose (θ) was determined according to the following formula:

Height of Pile

Tan θ = -------------------------------

Radius of Pile

Drug Entrapment Efficiency:

Accurately weighed beads (10mg) were transferred to a beaker containing 10ml 0.1N HCL pH 6.8 and the mixture was allowed to stand for 24 hours. The contents of the beaker were stirred for 1-2 hours using a magnetic stirrer for complete breakage of the beads, followed by filtration using what man filter paper. The amount of drug (x) in a single batch of beads was then estimated in the filtrate by measuring the absorbance at 215nm using U.V.-visible spectrophotometer. Drug Entrapment efficiency was then calculated by followingformulae:

% Entrapment efficiency = -------- X 100

Where,

x = Actual quantity of drug present in beads and

T=Theoretical quantity of drug added during preparation

Swelling Index:

Accurately weighed beads of each preparation were taken in a beaker containing 10 ml of 0.1N HCL of pH 7.4 and 0.1 N HCL, and then allowed to stand at room temperature for 6 hr. Excess fluid attached to the surface of the beads is removed by Whatman filtering paper and swollen beads are weighed. Each experiment was carried out in triplicate. The swelling index of the beads was calculated by using the formula:

SR= (Ws-Wd)/ Wd

Were, Ws= weight of swollen beads & Wd= weight of dried beads

Percentage Yield:

Percentage yield of prepared microbeads formulation was determined by weighing the microbeads after drying. The actual weight of microbeads was divided by the full weight of all the non-volatile parts used for the preparation of microbeads and is calculated by the subsequent formula:

Percentage Yield = Actual Weight of microbeads × 100

-------------------------------------------------------------------

Total Weight of microbeads

Bead Size Determination:

Beads size of the alginate beads was determined using an optical microscope using a compound microscope. A standard stage micrometer was used to align the optical micrometer.

Loose surface crystal study (LSC):

A study was conducted to estimate the amount of drugs present on the surface of microbeads that showed rapid release from dissolving sources. 100mg of microbeads was suspended in a 100ml 0.1N HCL (pH 7.4), modifying the dissolving media. Samples are shaken vigorously for 15min in a mechanical shaker ¹³. The amount of drug extracted from the surface was analyzed spectrophotometrically at 215nm.

Surface Morphology:

The surface morphology of the prepared microbeads was determined by the scanning electron microscopy (SEM). The samples for SEM were prepared by sprinkling the microbeads on a double adhesive tape which stuck to a stub. The stubs were then coated with platinum underneath an argon atmosphere employing a gold sputter module in an exceedingly high vacuum evaporator.

In vitro drug release:

In-vitro release studies of prepared beads were carried out to900 ml of 0.1 N HCl (pH 1.2). The test was carried out in 0.1 N HCl for 2 h, and then using phosphate buffer for the remaining time (pH 7.4) using USP- XXII apparatus at 100 rpm, maintained at a temperature of 37±5˚C for a period up to 12 hrs. At each time interval 5 ml of sample was withdrawn for the study and at the same time 5 ml of fresh dissolution media was added to maintain sink condition¹⁴. The withdrawn samples were suitably diluted and measured the absorbance spectrophotometrically at 220 nm.

RESULT AND DISCUSSION:

Standard Calibration Curve: From the calibration it was found that the drug shows linearity and obeys beer’s lambert law. The R² value was 0.995.

Figure 1: Standard Calibration Curve of Ibuprofen

Drug Interaction Study:

From the study of FTIR and DSC it was found that there was no chemical or physical interaction between the pure drug and polymer. Therefore the drug was compatible with the excipient.

Figure 2: FTIR of a) Pure Drug b) Optimized Formulation

Figure 3: DSC of a) Pure Drug b) Optimized Formulation

Table 2: Micromeritics Properties

Batch	Bulk Density (g/cc)	Tapped Density (g/cc)	Carr’s compressibility Index	Hausner’s ratio	Angle of repose (degree)
B1	0.302	0.352	16.88	1.16	29⁰16’
B2	0.309	0.344	11.32	1.11	30⁰82’
B3	0.389	0.425	8.47	1.09	30⁰82’
B4	0.467	0.528	11.55	1.13	28⁰24
B5	0.481	0.525	9.14	1.09	30⁰82’
B6	0.386	0.442	12.66	1.14	29^O72’
B7	0.489	0.547	10.60	1.11	30⁰82’
B8	0.584	0.638	8.46	1.09	30⁰82’
B9	0.504	0.549	8.19	1.08	27⁰45

Table 3: Evaluation Parameters

Batch	% Yield	Drug content	% DEE	Particle Size (µm)
B1	65.23	54.15	64.21	509
B2	72.41	59.21	72.16	517
B3	68.57	55.64	66.43	421
B4	78.59	62.79	68.38	463
B5	74.63	60.42	71.06	409
B6	72.98	56.83	63.78	486
B7	79.45	64.83	73.45	426
B8	67.51	51.13	61.37	461
B9	73.42	57.94	63.52	487

Figure 4: SEM Study of B7

Figure 5: Swelling Index of Prepared Batches at Different Time Intervals in 0.1N HCL

Percent Drug Release:

From the study of percent drug release it was found that the batch B7 was having the highest amount of drug release in the predicated time period. Therefore, B7 can be concluded as the optimized formulation.

Figure 6: Percent Cumulative Drug Release

CONCLUSION:

From the current study it was seen that the prepared Microbeads can be a better alternative for the sustain release dosage form. The prepared Microbeads were shown to have a better drug release within a predicated time period. Due to this the multiple dosing can be avoided which will not disturb the GIT. From this study the aim of reducing the dosage can be achieved.

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Received on 06.07.2021 Modified on 11.01.2022

Asian J. Pharm. Tech. 2022; 12(2):91-95.

DOI: 10.52711/2231-5713.2022.00015