BILAYER TABLET TENDERED IMMEDIATE RELEASE OF PARACETAMOL AND SUSTAINED RELEASE OF IBUPROFEN FOR QUICK ONSET OF ACTION AGAINST PAIN AND FEVER

Objective: The objective of this research was to formulate bi-layer tablet which contains immediate-release layer of Paracetamol for quick onset of action and sustained release of Ibuprofen for prolonging long period. Materials and Methods: The following chemicals were used: Paracetamol (Combiotic Global Pvt. Ltd., India), Ibuprofen (Combiotic Global Pvt. Ltd., India), microcrystalline cellulose (MCC) (Avicel), and Polyvinylpyrrolidone (PVP) K-30 (Loba Chem). Wet granulation method was adapted to formulate the bilayer tablets. The immediate-release layer of Paracetamol was prepared using sodium starch glycolate as superdisintegrants, MCC as diluent, starch as binder. The sustained release layer of Ibuprofen was prepared using high-performance liquid chromatography E50LV and ethyl cellulose as binder along with other excipients such as MCC, PVP, and magnesium stearate by wet granulation technique. Result and Discussion: The release rate of Paracetamol from Formulations 1 was more than 80% at 40 min. In case of Ibuprofen, sustained-release polymers such as HPMC E50 LV were used to increase the release time. Conclusion: The bilayer tablets were prepared and show good release rate.


Chauhan and Kaushik
Standard graph of Paracetamol: Form this standard stock solution, a series of dilution (10,20,30,40, and 50 µg/ml) were prepared using mobile phase.

• Standard stock solution of Ibuprofen
Accurately weighed 100 mg of Ibuprofen and was dissolved in 100 ml of mobile phase. 1 ml pipette out from above solution and taken in 10 ml volumetric flask and volume make up with mobile phase. A standard stock solution contains 100 µg/ml. Standard graph of Ibuprofen: Form this standard stock solution, a series of dilution (10,20,30,40, and 50 µg/ml) were prepared using the mobile phase [21].

Fourier transform infrared spectroscopy (FTIR)
The selected drug and polymers were characterized by FT-IR spectroscopy and the FTIR spectra of the pure drug Paracetamol with used excipients such as MCC, PVP K-30, starch, and sodium starch glycolate and Ibuprofen with excipients such as HPMC E50LV, ethylcellulose, PVP K-30, magnesium stearate, and talc were recorded to know the drug excipient interactions. The spectrum was recorded for pure drug, physical mixture of combination of all the excipients and drugs. The scanning range was 4000-500 cm −1 [15].

Formulation of bilayer tablets
The proposed bilayer tablets contain two layers.

Formulation of Paracetamol granules
Different formulations of immediate-release tablets of the Paracetamol layer (F1-F5) were prepared by wet granulation method using different excipients such as MCC, starch, and PVP K-30 as a binder and sodium starch glycolate were used as disintegrants.

Procedure
Appropriate quantities of Paracetamol and excipients such as MCC, Starch, PVP K-30, and sodium starch glycolate were measured accurately, and all the measured powders were sifted through Sieve no # 40. The above-sifted materials were mixed rapidly for 5 min and again passed through sieve no 40. Isopropyl alcohol having (2%) w/v amount of starch and PVP K-30 was used as the granulating solution and the solution was added to the mixture in step 2 and was kneaded for 2-5 min, then the kneaded mass was passed through sieve no # 16 to obtain the granules. The granules obtained in step 3 were dried in a tray drier at 50°C for 2 h. The dried granules were lubricated uniformly with weighed quantities of magnesium stearate. The above granules were compressed into tablets by CADMACH multi-station tablet compression machine using 19.1 × 8.75 mm punch.

Formulation of Ibuprofen granules
Different formulations of sustained-release tablets of Ibuprofen layer (F1-F5) were prepared by wet granulation method using different excipients such as MCC, HPMC E50 LV, and ethyl cellulose used as sustained release polymer, PVP K-30 as a binder, and magnesium stearate as a lubricant.

Procedure
Appropriate quantities of Ibuprofen and excipients such as MCC, HPMC E50 LV, and Ethyl Cellulose were measured accurately, and all the measured powders were sifted through Sieve no # 40. The above-sifted materials were mixed rapidly for 5 min and again passed through sieve no 40. Isopropyl alcohol having 2% w/v amount of PVP K-30 was used

Chauhan and Kaushik
as the granulating solution and the solution was added to the mixture in step 2 and was kneaded for 2-5 min, then the kneaded mass was passed through sieve no # 16 to obtain the granules. The granules obtained in step 3 were dried in a tray drier at 50°C for 2 h. The dried granules were lubricated uniformly with weighed quantities of magnesium stearate. The above granules were compressed into tablets by CADMACH multi-station tablet compression machine using 19.1 × 18.75 mm punch.

Angle of repose (θ)
Angle of repose is an indication of fractional forces existing between granules particles. The maximum angle possible between the surface of the pile of granules and the horizontal plane gives the angle of repose.
Where (θ) = angle of repose h = height of heap of granules r = radius of heap

Bulk density
Bulk density of the powder is the ratio of the mass of an untapped powder sample and its volume indicating the contribution of the intraparticulate void volume. The bulk density is expressed in grams per ml (g/ml). Bulk density is determined by weighing powder into a dry graduated 250 ml cylinder. The powder was carefully leveled without compacting, volume (V o ) was recorded, and bulk density g/ml was calculated using the following formula.

Tapped density
Tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing a powder sample. After observing the initial powder volume to weight, the measuring cylinder or vessel is mechanically tapped, and volume readings are taken until little less than 1% further volume change is observed. The mechanical tapping is achieved by raising the cylinder or vessel and allowing it to drop under its own weight at specified distance. Secure the cylinder in the holder of the apparatus with weighed powder sample. Measure 100-200 taps and observe the corresponding volumes to the nearest graduated unit [16].

Carr's index
The Carr's Index and Hausner's ratio are measures of the porosity of a powder to be compressed. They measure the relative importance of interparticle interactions. For poor flow materials, there are frequently greater interparticulate interactions and a greater difference between the bulk and tapped densities. These differences are reflected in the compressibility index and Hausner's Ratio. Carr's index was calculated using the following formula.
Hausner's ratio The Hausner's ratio is a number that is correlated to the flowability of a powder or granular material. Hausner's ratio is calculated using the following formula [17]:

Evaluation of tablets
The formulation tablets were evaluated for the following physical parameters.

Thickness
Thickness depends on the die filling, physical properties of the material to be compared. It is possible of small variation in the thickness of individual tablets in a batch. However, it should not appear to the unaided eye. The thickness and diameter can be measured by Vernier caliper [18].

Weight variation test
Twenty tablets were selected randomly and weighed individually. Calculate average weight compare the individual tablet weight to the average. Not more than two of the individual weights derivate from the average weight by more than percentage is shown in tablet and none derivate by more than twice the percentage.

Hardness
Tablets must possess sufficient strength or hardness and can be measured by Monsanto Hardness Tester. Ten tablets were randomly picked from each formulation and were evaluated for hardness and can be expressed in kg/cm 2 .

Friability
Friability can be performed in Roche friabilator; preweighed ten tablets were introduced in the friabilator. Then, the machine was operated for 100 revolutions. Tablets were dropped from a distance of 6 in each revolution. Tablets were then dusted and reweighed. Loss of <1% in weight is considered to be within the specification and acceptable [19].

Mobile phase preparation
A mixture of 75 volumes of buffer solution prepared by dissolving 3.9 g of sodium dihydrogen phosphate dihydrate and 8.9 g disodium hydrogen phosphate dihydrate in water, adjust to pH 7.0 with orthophosphoric acid, dilute to 1000 ml with water and 24.5 volume of acetonitrile and 0.5 volume of methanol.

Standard preparation
Weigh accurately 325 mg of Paracetamol into 50 ml volumetric flask and make up the volume with media. Take 2 ml from the above solution into 25 volumetric flasks and make up the volume with media.
Weigh accurately 400 mg of Ibuprofen into 50 ml volumetric flask and make up the volume with media. Take 2 ml from the above solution into 25 volumetric flasks and make up the volume with media.

Sample preparation
One tablet was taken from F1 batch and crushed in pestle mortar. Crushed powdered will be taken into 50 ml volumetric flask and make up the volume with media. Take 2 ml from the above solution into 25 volumetric flasks and make up the volume with media.

Procedure
Inject 5 μL portion of diluent as blank five replicate injections of standard preparation and one injection of each test preparation into the HPLC system record the chromatograms and measure the peaks response.

Mobile phase preparation
A mixture of 75 volumes of buffer solution prepared by dissolving 3.9 g of sodium dihydrogen phosphate dihydrate and 8.9 g disodium hydrogen phosphate dihydrate in water, adjust to pH 7.0 with orthophosphoric acid, dilute to 1000 ml with water, and 25 volume of acetonitrile.

Standard preparation of Paracetamol
Weigh accurately 28 mg of Paracetamol and transfer into a 100 ml volumetric flask, dissolve and dilute up to volume with dissolution media. Take 1 ml from the above solution and transfer into 10 ml volumetric flask, dissolve and dilute up to volume with dissolution media.

Standard preparation of Ibuprofen
Weigh accurately 35 mg of Ibuprofen and transfer into a 100 ml volumetric flask, dissolve and dilute up to volume with dissolution media. Take 1 ml from the above solution and transfer into 10 ml volumetric flask, dissolve and dilute up to volume with dissolution media.

Sample preparation
Take 2 ml from the above solution and transfer into 25 ml volumetric flask and volume make up with dissolution media.

Procedure
Inject 5 μL portion of diluent as blank, six replicate injections of standard preparation, and one injection of each test preparation into the HPLC system, record the chromatograms, and measure the peaks response [21].

Drug release kinetics
The release kinetics was studied by various kinetic models such as zero-order plot, first-order plot, Higuchi plot, and Korsmeyer-Peppas plot. To study the release kinetics of the nanoparticle gel data obtained from in vitro drug release studies was plotted in various kinetic models: Zero-order as cumulative amount of drug releases versus time, firstorder as long cumulative % of drug remaining versus time, Higuchi model as cumulative % of drug released versus square root of time, and Korsmeyer-Peppas model as log cumulative % drug release versus long time. The best fit model was confirmed by the value of correlation coefficient near to one [22].

Paracetamol Solubility
Paracetamol was found to be soluble in methanol, ethanol, acetone, 0.1 N HCL, and sparingly soluble in water.

Melting point
DSC curve of Paracetamol showed a sharp endothermic peak near 169°C that is indicative of its melting temperature. FTIR analysis FTIR spectroscopic analysis was carried out to characterize drug. The FTIR spectra obtained were compared with that given in pharmacopeia for Paracetamol. Diagnostic peaks and fingerprint regions were found identical. These characteristics peaks are useful in identification of drug.
The results obtained showed that there are no interactions between the components when taken together.

Linearity by HPLC method • Standard stock solution of Paracetamol
Accurately weighed 100 mg Paracetamol and dissolved in 100 ml of the mobile phase. 1 ml pipette out from above solution and taken in 10 ml volumetric flask and volume was makeup with mobile phase. A standard stock solution contains 100 µg/ml.
Standard graph of Paracetamol: Form this standard stock solution, a series of dilution (10,20,30,40, and 50 µg/ml) were prepared using mobile phase.

Evaluation of Paracetamol blended granules
The blended granules of different formulation were evaluated for angle of repose, bulk density, tapped density, Carr's index, and Hausner's ratio. The results of these evaluations were as follows:

Angle of repose
Angle of repose for the granules of F1-F5 was found to be 25.1-28.6, which indicates good flow property.  The Carr's index for the granules of F1-F5 was found to be 14.58-15.34%, which shows good flowing properties.

Hausner's ratio
Hausner ratio was found to be 1.12-1.15, it indicates good flow properties of the granules.

Ibuprofen Solubility
Ibuprofen was found to be freely soluble in methanol, ethanol, acetone, soluble in PBS of pH 6.8, 7.4, practically insoluble in water, and 0.1 N HCL.

Melting point
Melting point of the pure Ibuprofen was found to be 76°C which was within the limit as per the IP 2018. DSC curve of Ibuprofen exhibits endothermic peak at 76°C.

Linearity by HPLC method • Standard stock solution of Ibuprofen
Accurately weighed 100 mg Ibuprofen and dissolved in 100 ml of mobile phase. 1 ml pipette out from above solution and taken in 10 ml volumetric flask and volume was make up with mobile phase. A standard stock solution contains 100 µg/ml. Standard graph of Ibuprofen: RM this standard stock solution, a series of dilution (10,20,30,40, and 50 µg/ml) were prepared using mobile phase.

Evaluation of Ibuprofen blended granules
The blended granules of different formulation were evaluated for angle of repose, bulk density, tapped density, Carr's index, and Hausner's ratio. The results of these evaluations were as follows:

Angle of repose
Angle of repose for the granules of F1-F5 was found to be 25.0-39.9, which indicates good flow property.

Carr's index
The Carr's index for the granules of F1-F5 was found to be 11.49-16.66%, which shows good flowing properties.

Hausner's ratio
Hausner ratio was found to be 1.12-1.15; it indicates good flow properties of the granules.

Kinetic study for Paracetamol IR layer of bi-layer tablet
The data obtained for in vitro release were fitted into equations for zero-order, first-order, Higuchi, and Korsmeyer-Peppas release models. The interpretation of data was based on the value of the resulting regression coefficients.
From these values, it was observed that the first-order model was found to be best suited with R 2 value of 0.933.

Kinetic study for Ibuprofen SR layer of bilayer tablet
The data obtained for in vitro release were fitted into equations for zeroorder, first-order, Higuchi, and Korsmeyer-Peppas release models. The interpretation of data was based on the value of the resulting regression coefficients.
From these values, it was observed that the Higuchi model was found to be best suited with R 2 value of 0.994.

DISCUSSION
Paracetamol is also known as acetaminophen, centrally acting analgesic derivative of p-aminophenol. Commonly used for its antipyretic and analgesic effects, which has a biological half-life of 1-4 h. Ibuprofen is described as 2-(4-isobutylphenyl)propionic acid and is a nonsteroidal compound, which exhibits high levels of anti-inflammatory, analgesic, and antipyretic activities necessary for the effective treatment of rheumatoid arthritis and osteoarthritis. best formulation among them. Paracetamol release 97.87% after 40 min. Formulation F1 gave 97.65% drug release after 12 h. Therefore, F1 was selected as best formulation among F1-F5. The bi-layer tablets prepared formulated F1 shown good post-compression parameters such as hardness, and friability weight variation drug content which were within the limits. Both the drugs in bi-layer tablets are shown dissolution profiles within the limit. Since, HPMC E50LV is a good sustained release polymer. The combination of HPMC E50LV and CMC gave good sustained drug release for 12 h. From this study by preparing bilayer tablets, it was concluded that we could reduce the dosage frequency, dose-related side effects, and improve the bioavailability of drugs which in turn improves patient compliance. Thus, a fixed-dose combination tablet of Paracetamol and Ibuprofen were designed as bi-layer tablets which will have good patient compliance.

ACKNOWLEDGMENT
The author would like to thanks Dr. Dinesh Kaushik for providing a platform and facility to conduct research work. The authors would like to thanks Comboitic Global Pvt. Ltd. for providing a gift sample of Ibuprofen and Paracetamol.

AUTHORS' CONTRIBUTIONS
All the authors have contributed equally.

CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.