In Vitro Dissolution Testing of Ibuprofen Using

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In Vitro Dissolution Testing of Ibuprofen Using Compendial and. Biorelevant Dissolution Media. Gitika Dhingra1*, Brinda Sreelesh1, Manju Nagpal2, Pankaj ...
Research J. Pharm. and Tech. 3(3): July-Sept. 2010

ISSN 0974-3618

www.rjptonline.org

RESEARCH ARTICLE

In Vitro Dissolution Testing of Ibuprofen Using Compendial and Biorelevant Dissolution Media Gitika Dhingra1*, Brinda Sreelesh1, Manju Nagpal2, Pankaj Rakha3, and BP Nagori4 1

NCRD’s Sterling Institute of Pharmacy, Nerul, Navi Mumbai-400706. Chitkara School of Pharmacy, Chitkara University, Solan-174103 (HP) 3 Rajendra Institute of Technology and Sciences, Sirsa-125055 (Haryana) 4 Lachoo Memorial College of Science and Technology, Jodhpur (Rajasthan) *Corresponding Author E-mail: [email protected] 2

ABSTRACT:

In present study, the performance of biorelevant and compendial dissolution media was compared to test dissolution of drugs belonging to class II according to Biopharmaceutic Classification Scheme (BCS). The solubility of Ibuprofen, a weakly acidic drug, was determined in various media (water, Phosphate buffer pH 7.2, FaSSIF and FeSSIF) having different pH to calculate D/S values in different media. Invitro dissolution of marketed tablets was studied in compendial media (water, phosphate buffer pH 7.2) and biorelevant media (FaSSIF and FeSSIF). Dissolution of Ibuprofen was found to be dependent upon pH. In all cases, the mean dissolution profiles in biorelevant media were in concordance with in vivo findings published earlier. The method was validated in terms of linearity and precision. The similarity factor in different media was also evaluated.

KEYWORDS: Biorelevant Dissolution Media, Biopharmaceutics Classification System, Dissolution Test, FaSSIF, FeSSIF.

INTRODUCTION:

BCS Class II drugs exhibit low solubility and good permeability and a strong correlation between in vitro dissolution and in vivo absorption can be established for these drugs if the in vitro dissolution simulates the GI physiology4, 5.

The goal of in vitro dissolution testing is to produce the data that can be used in the assessment of overall absorption of drugs and simultaneously to demonstrate bioequivalence from batch to batch. For these purposes, it is crucial to know whether 100% of dose can be released from dosage form or not. So, the most part of the compendial dissolution tests have been designed in such a manner that they ensure sink conditions for the dissolution of active ingredients during the test1. Pharmaceutical quality does not only mean the ability to manufacture the product reproducibly and to ensure that it maintains its release properties throughout its shelf life, but also includes the biopharmaceutical characteristics, such as rate and extent of absorption, can be relied on. Due to higher costs and ethical issues of invivo studies, there is increasing interest in the development of dissolution tests that can establish invitro invivo correlations in more logical manner. Compendial dissolution media (water, SGFSP and SIFSP) are best suited for quality control purpose but can not be used for IVIVC in all cases2,3.

‘Biorelevant medium’ is a term used to describe a medium that has some relevance to the in vivo dissolution conditions for the compound. These media reflect changes in pH, bile concentration, and osmolarity before and after meal intake3. Based on physiological parameters the composition of biorelevant media has been suggested to simulate gastric and small intestinal conditions in fasted and fed state conditions6. The invitro dissolution testing of BCS class II drugs in biorelevant dissolution media determine qualitative aspects of formulation and food effects on absorption of these drugs. The invivo profile from invitro data can be predicted if drug exhibits dissolution rate limited absorption and absolute bioavailability of drug is known. The present study deals with comparison of invitro dissolution behaviour of ibuprofen in various compendial and biorelevant media.

MATERIALS AND METHODS

Received on 27.03.2010 Accepted on 19.04.2010

Ibuprofen was kindly gifted from Sanchez Pharmaceuticals Pvt. Ltd. Bombay, Brufen 600 and Brufen 400 Tablets was procured from Briocia Pharma (I) Pvt. Ltd. Ibuprofen Tablets was procured from Arbro Pharmaceuticals Ltd.

Modified on 09.04.2010 © RJPT All right reserved

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 470-473

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Research J. Pharm. and Tech. 3(3): July-Sept. 2010

Soya Lecithin was purchased from Ases Chemicals, Jodhpur, Sodium Taurocholate was purchased from CDH, New Delhi. Another chemicals used were of AR grade. Determination of D/S value: The solubility was determined in compendial and biorelevant media by adding known amount of drug (10, 20, 30, 40 and 50 mg) in different volumes (100,500 and 1000ml) of dissolution media and incubated in shaker incubator at 37±0.5oC. The ionic strength of all media was adjusted to 0.15 N using sodium chloride. The D/S values for each media were obtained from solubility corresponding to highest absorbance in the range of 0.2-0.8 (Table 1). These solutions also served as stock for the preparation of calibration curve. The weighted regression was used to derive the coefficients (slope and intercept) of calibration curve7. b = { WXY-( WX* WY/ W)}/{ WX2-( WX* Figure 1: Mean dissolution time profile of Brufen 600 in different WY/ W)} media. a = YW -bXW Where, YW = WY/ W, XW = WX/ W and Weight (W) = 1/ (concentration)2, X= conc., Y= Abs In vitro dissolution test: The USP apparatus II (paddle method) containing 500 ml of dissolution media (both compendial and biorelevant), maintained at 37±0.5oC and stirred at 100 rpm, was used to analyze 12 units per test. The aliquots were withdrawn at different intervals up to 2 hrs and filtered through whatmann filter paper. The drug content was measured spectrophotometrically at 221 nm in all dissolution media. The experiment was repeated for three formulations. The process was validated by checking linearity of absorption curve, intraday, interday and intermediate precision for whole experiment. The f2 factor was calculated from the following equation8: f2 = 50 log [{1 + 1/n (T1- T2)2}0.5 *100] Where, T1 and T2 = percent drug dissolved at each time point in two different dissolution media and n = number of observations. An f2 value less than 50 indicate different Figure 2: Mean Dissolution time profile of Ibuprofen 400 in dissolution profiles. different media.

RESULT AND DISCUSSION:

Solubility studies of pure drug and invitro dissolution behavior of three marketed formulations was studied in compendial medium and two biorelevant media. The solubility of ibuprofen was found to be maximum in phosphate buffer, followed by FaSSIF, FeSSIF and water. The concentration of bile salts is more in FeSSIF than in FaSSIF, but the solubility pattern didn’t followed the same pattern. This suggests that solubility of ibuprofen is not dependent on the presence or absence of surfactant. Ibuprofen has pka value in the physiological range, so the solubility may change greatly with changes in pH of the environment (Table 1). Table 1: Solubility values of ibuprofen in different media. S. No. Dissolution Medium Solubility (mg/ml) 1. Water 0.01 2. Phosphate buffer 3.70 3. FaSSIF 2.10 4. FeSSIF 1.50

Figure 3: Mean dissolution time profile of Brufen 400 in different media

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Research J. Pharm. and Tech. 3(3): July-Sept. 2010 Table 2: Summary of validation parameters of calibration curve. Drug Medium Linearity range (ppm) Correlation coefficient Ibuprofen

Water Phoshate buffer FeSSIF FeSSIF

1-7 16-40 9-17 4.5-9.0

0.9995 0.987 0.992 0.992

The percent dissolved after 2 hours was maximum in phosphate buffer, followed by in FaSSIF, then FeSSIF and minimum in water. The percent drug dissolved in mean dissolution time profile of tablet formulations in phosphate buffer (compendial media) was found to be 85 - 98% within 60 minutes. The in vivo data of eleven normal adult volunteers does not indicate this much high amount of plasma drug concentration even after 2 hours9. This suggests that in compendial medium, batch-to-batch consistency can be checked with greater accuracy but not the biopharmaceutical characteristics of drugs. In phosphate buffer (pH 7.2), the percent drug dissolved from marketed tablets was 90 folds higher than in water (97.46% Vs 1.25% (Brufen 600); 96.32% Vs 1.47% (Ibuprofen 400); 96.46% Vs 1.46% (Brufen 400) after 2 hours (Fig 1, 2 and 3). This difference in dissolution behavior of ibuprofen cannot be attributed solely to the pH difference between the two media. In the case of water, the lack of buffer capacity enables a microclimate pH close to the pka of ibuprofen to be established at the dissolving surface of drug particles, limiting further dissolution. FeSSIF is based on average pH and bile component concentrations in the fed state and doesn’t account for the presence of ingested lipids. This may underestimate fed state dissolution in some cases for highly lipophilic compounds. Although a forecast of the effects of food on oral absorption was successful in present study, one should keep in mind that in the in vivo food studies of ibuprofen, the dosage form was administered 30 min after meal intake9. It is known that luminal bile salt concentrations begin to fall towards the end of the first hour after food administration10. The concentration of bile salts / lecithin in FeSSIF is based on average peak values and may have, in the case of this particular study (in which the drug was administrated after peak bile output), offset the lack of dietary lipids in the medium.

Intra Day 0.364 0.420 0.209 0.420

Inter Day 0.292 0.397 0.564 0.549

standard deviation for precision values was found to be less than 1% in case of calibration data and less than 5% in case of dissolution data (Table 2 and 3). The dissolution profiles of three tablet formulations in water, phosphate buffer, FaSSIF and FeSSIF were found to be significantly similar (f2 > 50).

CONCLUSION:

A key difference between studies with biorelevant and compendial media is that, in the case of the biorelevant media, no attempt is made to adjust the composition to obtain sink conditions. So the data can be useful for qualitative forecasts, while on the quantitative basis, it may underestimate the dissolution rate in vivo. The study demonstrates the utility of biorelevant media for studying the biopharmaceutical characteristics of poorly soluble drug products. For the weakly acidic drugs belonging to BCS Class II, dissolution under intestinal conditions will be important in the fasted state. This can be modeled well with FaSSIF (However, the drug is recommended with meals as it may cause gastric irritation). Compendial medium, at a pH of 7.2, cannot be recommended for this purpose since the high pH results in an over prediction of the dissolution rate of weak acids. FeSSIF is a reasonable starting point for assessing dissolution in the intestine after administration with meals. Trends in bioavailability with formulation and food effects on bioavailability can be at least qualitatively demonstrated. Although biorelevant dissolution tests still have issues which will require further refinement, they offer nonetheless a promising in vitro tool for studying the biopharmaceutical characteristics of drugs with dissolution limited absorption. In conclusion, with the array of compendial and physiological media available, it is possible to design more meaningful in vitro dissolution tests to ensure quality of drug product.

Table 3: Summary of validation parameters of dissolution data. Tablet Medium Intermediate precision (%RSD) Brufen 600 Water 1.077 Brufen 600 Phosphatebuffer 0.481 Brufen 600 FeSSIF 0.788 Brufen 600 FeSSIF 0.880 Ibuprofen 400 Water 0.875 Ibuprofen 400 Phosphatebuffer 0.508 Ibuprofen 400 FeSSIF 0.662 Ibuprofen 400 FeSSIF 0.495 Brufen 400 Water 0.383 Brufen 400 Phosphatebuffer 0.494 Brufen 400 FeSSIF 0.580 Brufen 400 FeSSIF 0.794

The method was validated in terms of linearity and precision and these values were calculated for both calibration curve and dissolution data. The percent relative

Precision (%RSD) Repeati- bility(n=7) 0.309 0.315 0.151 0.809

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