INTRODUCTION:

Bi-layer tablets are prepared with one layer of drug for immediate release while second layer designed to release drug, later, either as second dose or in an extended release manner. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose¹.

Paracetamol an N-(4-hydroxyphenyl) ethanamide¹¹ used as analgesic and antipyretic agent. Paracetamol active metabolite of phenacetin, responsible for its analgesic effect^2,3. Paracetamol a weak prostaglandin inhibitor in peripheral tissues and possesses no significant ant inflammatory effects. Its one of the most important drugs used for the treatment of mild to moderate pain when an anti inflammatory effect is not necessary. Paracetamol preferred over aspirin as an analgesic antipyretic for patients in whom aspirin is contraindicated, such as those who have a history of gastric ulcer or a coagulation disorder^4,5.

Ibuprofen (IB), 2-(4-Isobutyl-phenyl)-propionic acid, is one of the nonsteroidal anti-inflammatory agent with analgesic and antipyretic properties. The anti-inflammatory effects of IB, and most of its other pharmacological effects, are generally thought to be related to its inhibition of cyclooxygenase and consequent decrease in prostaglandin concentration. After oral administration of IB, well over 80%of the dose is absorbed from the GI tract (mainly the intestine) ⁶. IB has shorter plasma half-life (t1/2=2 h), thus sustained release formulation is suitable to prevent frequent administration.

The literature survey revealed that there is no simultaneous estimation for dissolution profile of conventional release paracetamol and sustain release Ibuprofen. This present work describes an absorption ratio method for simultaneous determination of these drugs.

MATERIALS AND METHODS:

Paracetamol, Ibuprofen, microcrystalline cellulose (Avicel PH 102), Starch, crosspovidone (XL) and hydroxypropylmethylcellulose (HPMC K4M), Magnesium stearate, talc were received from JCPL Pharma Pvt. Ltd. Jalgaon.

The excipients considered are microcrystalline cellulose (filler), starch (binder), crospovidone XL (superdisintegrant), hydroxypropylmethylcellulose (HPMC K4M)

Preparation of Paracetamol Tablets:

Paracetamol, microcrystalline cellulose, and fraction of crospovidone were granulated by starch solution which was prepared by adding 60°C water. Then the wet mass was passed through 20# sieve to obtain granules at 75°C for 40min. Then the granules obtained are blended with crospovidone, talc, magnesium stearate⁷. The tablets are made from each group of formulation then they are evaluated for weight variation, friability, hardness, disintegrating time and dissolution^8.Composition of all batches was represented in Table I.(.Evaluation results show in Table. IV )

TABLE-I: FORMULATION OF PARACETAMOL GRANULES

Ingredient	PF1	PF2	PF3	PF4
Paracetamol	325	325	325	325
Starch	50	—	50	66
MCC	-	75	75	80
Crospovidone	3	3	--	3
Talc	5	5	5	5
mg.stearate	5	5	5	5

Preparation of Sustained Release Tablets Of IB:

IB and HPMC K4M were mixed with other excipient for 15 min in porcelain mortar except magnesium stearate, and the mass was prepared by starch solution which was prepared by adding 60°C water. Then passed the mass through 16 # sieve and granules were allowed to dry in oven at 40 °C for 30 min. Dried granules passed through 12 # sieve. Then 10% fine was added in the granules and mixed with magnesium stearate for 5 min. The tablets are made from each group of formulation then they are evaluated for weight variation, friability, assay, and dissolution Composition of all batches was represented in Table II. (Evaluation results show in Table.V )

TABLE III: FORMULATIONS OF IBUPROFEN SUSTAIN RELEASE GRANULES

Ingredients (mg)	IF1	IF2	IF3	IF4
IB	400	400	400	400
HPMC K4M	100	100	125	125
Sod.Bicarbonate	30	20	-	10
PVP	50	50	5	25
MCC	12	22	62	32
IPA	Q.S.	Q.S.	Q.S.	Q.S.
Mg stearate	8	8	8	8

IB-Ibuprofen, HPMC-hydroxy propyl methylcellulose, PVP-polyvinylpyrollidone, MCC- microcrystalline cellulose, Q.S.-quantity sufficient.

Preparation of Bilayer Tablets

For the preparation of bilayer tablets the optimized batch of paracetamol and Diclofenac sodium were taken. Bilayer tablet press (Cadmatch & Co.) with D tooling of punch size 19.2mm was used. The first layer was sustained release diclofenac sodium and second layer was conventional release paracetamol. Then the tablets were evaluated for weight variation, friability, hardness, and invitro dissolution ^9,10.

Dissolution Test

The in-vitro dissolution studies were carried out using USP apparatus type II at 50 rpm. The dissolution medium (900 mL) consisted of phosphate buffer (pH 5.8) was used for the first 2 h and then replaced with phosphate buffer (pH 7.2) for 3 to 10 h (900 mL), maintained at 37±0.5 °C. The drug release at different time intervals was measured by UV– visible spectrophotometer at 221 and 257 nm for IB and Paracetamol respectively. The release studies were conducted on (six tablets), and the mean values were plotted versus time with SD¹².( Show in Fig No. II & III )

Determination of Isobestic Point and Selection of Wavelength

Absorbance ratio method:

Absorbance ratio method of analysis is based on the absorbance at two selected wavelengths, oneof which is an isoabsorptive point and the other being the wavelength of maximum absorption of one drug. From overlain spectra , 222.4 nm (λmax of ibuprofen) and 226.4 nm

(Isoabsorptive point) are selected for the formation of Q absorbance equation. The absorptivity values determined for paracetamol are 0.0241 (ax1), 0.0295 (ax2) and for ibuprofen are 0.0353 (ay1), 0.0252 (ay2) at 222.4 nm and 226.4 nm respectively. These values are means of six estimations. The absorbances and absorptivity at these wavelengths were substituted in equation to obtain the concentration of drugs.

Cx= [(Qm-Q1)/(Q2-Q1)] x (A/a)

Cy = [(Qm-Q1)/(Q1-Q2)] x (A/a)

Where,

Cx and Cy - the concentrations of paracetamol and ibuprofen.

Qm - absorbance of mixture of paracetamol and

ibuprofen at isobestic point λmax to any of one component.

Q1 – Absorbance ratio of paracetamol

Q2 - Absorbance ratio of ibuprofen.

A - Absorbance of mixture at isobestic point.

a - Absorptivity value of mixture at isobestic point.

Analysis of the Tablet Formulations

Twenty tablets of marketed formulation were accurately weighed and powdered. A quantity of powder equivalent to 50 mg of paracetamol was transferred to 100 mL volumetric flask and dissolved in 0.1N NaOH and final volume was made up with 0.1N NaOH. The sample solution was then filtered through Whatman filter paper No.41. From the above solution 10 mL of solution was taken and diluted to 50 mL with 0.1N NaOH to get a solution containing 100 μg/mL of paracetamol and corresponding concentration of ibuprofen. From above, 0.65 mL of solution was diluted with same solvent in 10 mL volumetric flask to get final concentration of paracetamol 6.5μg/mL and ibuprofen 8μg/mL. Analysis procedure was repeated six times with tablet formulation^13,14. The results of tablet analysis are reported in Table III. show in fig No (i)

Method	Drug	Intraday	Precision (%COV)
	n=3		Interday*
			First day	Second day	Third day
Abs ratio method	PAR	0.702	0.944	0.613	0.584
	IBU	0.692	0.567	0.614	0.578

PAR: Paracetamol, IBU: Ibuprofen, COV: Coefficient of variation, *Average of six determination

RESULTS AND DISCUSSION:

Fig i : overlain spectra of paracetamol and ibuprofen.

FIG. II: DISSOLUTION PROFILE OF PARACETAMOL FORMULATIONS

TABLE NO IV: EVALUATION TEST OF PARACETAMOL

Evaluation test	PF1	PF2	PF3	PF4
Weight variation	-	-	-	-
Friability	1.02%	2.76%	0.25%	0.13%
Disintegrating time	12.2mins	10.3 mins	4.5 mins	2.8 mins
Dissolution time	30mins	45.59 mins	15.12 mins	12.25 mins

FIG III: DISSOLUTION PROFILE OF IB TABLET.

TABLE NO V -EVALUATION TEST OF IBUPROFEN

Evaluation test	PF1	PF2	PF3	PF4
Weight variation	-	-	-	-
Friability	0.014%	0.038%	0.032%	0.030%
Dissolution time	303 mins	314 mins	328 mins	364 mins
Drug content	101.75	100.93	101.40	100.58

Analysis Of The Tablet Formulations

Simultaneous estimation method of paracetamol and diclofenac was done by absorption ratio method. The prepared bilayer tablets were compared against the standard drug formulation in market.

Precision is determined by studying the repeatability and intermediate precision. Repeatability result indicates the precision under the same operating conditions over a short interval of time and inter assay precision. Intermediate precision study expresses within laboratory variation in different days. In both intra and inter day precision study for both the methods % COV are not more than 2.0% indicates good repeatability and intermediate precision.

Evaluation of Bi-Layer Tablet

Properties of bi-layer tablets such as weight variation, thickness, hardness and friability was checked. Weight variation of bi-layer tablet was found (1075.57±3.72 mg) within limit (100±5%). Friability of bi-layer tablet was found (0.45%) less than 1%. Hardness was found 5.65 Kg/cm2 and thickness variation was found (8.20±0.16) less than 5%. Content uniformity of Paracetamol and IB in bi-layer tablet was found 99.8±0.80 and 102.1±0.58 respectively. (Show in Fig No.IV )

FIG IV: Dissolution profile of bilayer tablet (conventional release paracetamol and sustain release ibuprofen)

CONCLUSION:

The dissolution profiling of bilayer tablet done by simultaneous estimation method was efficient and accurate. The formulations PF4 and IB1 release patterns were found to be similar to marketed product. By this type of formulations patient compliance will increase due to overcoming problems like dose missing, frequency of dosing. The spectrophotometric method was validated and showed to be specific, linear, precise and accurate.

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Received on 24.01.2012 Modified on 13.02.2012

Research J. Pharm. and Tech. 5(4): April 2012; Page 490-493