CHAPTER 19 PARACETAMOL + IBUPROFEN

CHAPTER 19 PARACETAMOL + IBUPROFEN

SUMMARY 246 A combination of paracetamol and ibuprofen is marketed in India. Literature survey indicated that one titrimetnc-1-** and one HPLC193 methods are reported for this combination. The HPLC method reported involves diode array detection. A new HPLC method was developed for the simultaneous determination of paracetamol and ibuprofen in combined dosage forms. A Phenomenex ODS column and a mobile phase consisting of methanolwater-acetic acid (80 : 20 : 1) were utilized. The flow rate used was 1.5 ml/min. UV detection at 235 nm was carried out. The retention times of paracetamol and ibuprofen were 2.3 and 6.4 min. respectively. The sensitivity ranges were 0.43-4.33 mcg/ml of paracetamol and 15.02-120.16 mcg/ml of ibuprofen. The new HPLC method was utilized for the assay of commercial tablets and suspension containing the two drugs. Precision and recovery studies were also carried out. The method is simple, rapid and precise.

EXPERIMENTAL Chemicals Used : Paracetamol was supplied by SIGMA Chemical Company, St. Louis, U.S.A. Ibuprofen was a gift sample provided by the Central Indian Pharmacopoeia Laboratory, Ghaziabad. Methanol and Acetic Acid (HPLC grade) were supplied by Spectrochem Pvt. Ltd., Bombay, India. Double distilled water was used for the HPLC studies. Ingtruroentatibn : The chromatographic system consisted of a ERC-8710 pump (Erma Optical Works, Japan), a degasser (model : ERC-3310) with a variable wavelength UV detector and a Chromatocorder 11 Integrator (Alphatech Corporation Ltd., Japan). A Phenomenex ODS (5/i) column (250 mm x 4.6 mm i.d.) was utilized. All spectrophotometric measurements were made using a Shimadzu spectrophotometer (model : UV-260). All weighings were performed on a Sartorius single pan balance. The mobile phase was methanol-water-acetic acid (80 : 20 : 1), filtered through a 0.45 m membrane filter and pumped at a flow rate of 1.5 ml/min. (pressure = 2800 p.s.i.). The UV detector was operated at 235 nm at a sensitivity of 0.005 A.U.F.S. The attenuation and chart speed of the integrator were set at 512 and 5 mm/min. respectively. Preparation of standard curves : Paracetamol : A stock solution (86.5 mcg/ml) of the drug in methanol was first prepared. From the stock solution, various concentrations were prepared ranging from 0.4325-4.3250 mcg/ml. Hundred microliters of each sample was injected three

times and the mean peak heights were utilized for linear regression analysis. Ibuprofen : A stock solution (300.4 mcg/ml) of the drug in methanol was first prepared. From the stock solution, various concentrations were prepared ranging from 15.02-120.16 mcg/ml. Hundred microliters of each sample was injected three times and the mean peak heights were utilized for linear regression analysis. The results obtained are presented in Tables 75, 76 and Figures 47 and 48. Sample Preparation : 1) Tablets : Twenty tablets were weighed and powdered. A quantity of the powder equivalent to 5 mg of ibuprofen was taken, dissolved in 10 ml of the mobile phase and filtered through Whatman No.44. The filtrate was diluted with the mobile phase to provide an approximate concentration of 50 mcg/ml of ibuprofen (Sample 1). Hundred microliters of this sample was injected three times and the mean peak height was utilized for the calculation of the concentration of ibuprofen from the regression equation. Sample 1 was further diluted with the mobile phase to provide an approximate concentration of 2 mcg/ml of paracetamol (Sample 2). Hundred microliters of Sample 2 was injected 3 times and the mean peak height was utilized for the calculation of paracetamol concentration from the regression equation. 2) Suspension : A volume equivalent to 5 mg of ibuprofen was diluted to 5 ml with methanol and filtered through Whatman No.44 filter paper. It was further diluted to provide two solutions as described under tablets.

249 TABLE 75 : STANDARD CURVE FOR PARACETAMOL No. Concentration mcg/ml Mean Peak Height*, cm. SD CV(%) 1 0.4325 1.0333 0.06 5.59 2 0.8650 2.1333 0.06 2.71 3 1.7300 4.2667 0.06 1.35 4 2.1625 5.3000 0.10 1.89 5 3.0275 7.4333 0.06 0.78 6 4.3250 10.2333 0.15 1.49 *=Mean of 3 readings LINEAR REGRESSION ANALYSIS RESULTS Peak Height = 2.3740 x Concentration + 0.1041 n = 6( r = 0.9995

250 STANDARD CURVE FOR PARACETAMOL FIGURE 47 CONCENTRATION (megm) (mb) IKOflH XV3d NV3H

251 TABLE 76 : STANDARD CURVE FOR IBUPROFEN No. Concentration mcg/ml Mean Peak Height*, cm. SD CV(%) 1 15.02 1.2000 0.10 8.33 2 30.04 2.4333 0.06 2.37 3 45.06 3.6333 0.06 1.59 4 75.10 6.0667 0.06 0.95 5 105.14 8.5333 0.06 0.68 6 120.16 9.7333 0.06 0.59 *=Mean of 3 readings LINEAR REGRESSION ANALYSIS RESULTS Peak Height = 0.0812 x Concentration - 0.0178 n = 6, r = 0.999995

252 STANDARD CURVE FOR IBUPROFEN 0 20 40 60 SO 100 120 F IG U R E 48 CONCENTRATION (mca/ml) («U9) 1H0I3H XV3d NV3H

253 RESULTS AND DISCUSSION The proposed assay method uses a mobile phase comprising of methanol - water - acetic acid in the ratio 80 : 20 : 1 (v/v) which gives a good resolution between paracetamol and ibuprofen. The addition of acetic acid in the mobile phase helps in improving the peak shape. Thus the mobile phase preparation in the proposed method is easy a«td also economic as it does not employ any costly solvents. The chromatogram obtained is shown in Figure 49. The retention times of paracetamol and ibuprofen were 2.3 and 6.4 min. respectively. The standard curves were linear over the entire concentration ranges of the two drugs (r = 0.9995 for paracetamol and r = 0.999995 for ibuprofen ). Precision studies were performed by injecting 1.73 mcg/ml of paracetamol and 75.1 mcg/ml of ibuprofen, six times. The coefficients of variation (CV) obtained were 1.21% and 1.24% respectively for the two drugs. Recovery studies were performed by taking known amounts of the two drugs and analyzing them by the proposed HPLC technique. Each sample was injected three times and the mean peak height was utilized for the recovery study. The results obtained are presented in Tables 77 and 78. Few market samples were analyzed by the proposed method. The results obtained are presented in Table 79. A high attenuation (512) was chosen in order to minimize the dilutions. The sensitivity can be further increased by decreasing the attenuation. The precision of the proposed method is good and

254 FIGURE 49 1 1 = Paracetamol (2.2 min.) 2 = Ibuprofen (6.4 min.)

255 TABLE 77 : RECOVERY OF PARACETAMOL NO. Amount Taken mcg/ml Amount Found mcg/ml % Recovery 1 0.4325 0.4336 100.2 2 0.8650 0.8548 98.8 3 1.7300 1.7253 99.7 4 2.1625 2.1747 100.6 5 3.0275 3.0312 100.1 6 4.3250 4.2949 99.3 Mean = 99.8 SD =0.66 CV(%) = 0.66

TABLE 78 : RECOVERY OF IBUPROFEN No. Amount Taken mcg/ml Amount Found mcg/ml % Recovery 1 15.0200 14.9991 99.9 2 30.0400 29.7791 99.1 3 45.0600 44.5590 98.9 4 75.1000 74.1188 98.7 5 105.1400 104.9104 99.8 6 120.1600 120.9220 100.6 Mean =99.5 SD = 0.73 CV(%) 0.73

257 TABLE 79 : ANALYSIS OF COMMERCIAL DOSAGE FORMS NO. Dosage Form Labelled Amount of paracetamol %Label Claim Labelled Amount of ibuprofen %Label Claim 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Tablet 500 mg 93.7 400 mg 97.1 -do- 97.3 -do- 98.1 400 mg 96.1 -do- 103.3 333 mg 97.3 -do- 95.0 325 mg 98.6 -do- 90.9 -do- 103.1 -do- 97.1 -do- 101.9 -do- 105.4 -do- 94.9 -do- 99.2 -do- 91.4 -do- 97.1 -do- 101.9 -do- 100.2 -do- 97.3 -do- 95.0 -do- 99.6 -do- 96.1 -do- 100.8 -do- 99.2 -do- 99.6 -do- 94.0 -do- 99.6 200 mg 96.2 Suspension 162.5 mg/5 ml 102.4 100 mg/5 ml 95.0 125 mg/5 ml 102.7 -do- 101.2

258 an internal standard is therefore not very essential. The proposed method is simple, specific and accurate and can be conveniently adopted for the routine analysis of paracetamol and ibuprofen in combined dosage forms. =====*=====*=====