Quality of Marketed Ranitidine hydrochloride tablets in Bangladesh-An Analytical Overview

Abu Taher Azad1, Md. Abdul Motaleb Bhuiya2*, Irfan Newaz Khan2, Mir Monir Hossain2 and Kishor Mazumder3

1. Student Department of Pharmacy University of Science & Technology Chittagong (USTC) Foys Lake, Chittagong-4202 2. Lecturer Department of Pharmacy University of Science & Technology Chittagong (USTC) Foys Lake, Chittagong-4202 3. Assistant Professor Department of Pharmacy University of Science & Technology Chittagong (USTC) Foys Lake, Chittagong-4202

*Corresponding Author: Md. Abdul Motaleb Bhuiya Department of Pharmacy, USTC Mobile: 01818-104698 E-mail: motaleb.bd@gmail.com _________________________________________________

Department of Pharmacy University of Science & Technology Chittagong (USTC) Foys Lake, Chittagong-4202

ABSTRACT Ranitidine is a H2-receptor blocker, which is widely used for the treatment of peptic ulcer disease (PUD).The marketed sample of ten brands of Ranitidine hydrochloride tablets were collected from different Retail Pharmacy shops at Chittagong in Bangladesh. The standard sample was collected from United chemicals & Pharmaceuticals Limited, Chittagong.Various parameters such as weight variation, thickness, hardness, disintegration, dissolution, potency etc. Were analyzed according to the official (BP/USP) pharmacopoeial methods to evaluate their quality. The result showed that, 8 brands of Ranitidine hydrochloride tablets meet the USP specification of potency & the remaining two were less potent. All brands tested, showed a good result for weight variation, hardness, and disintegration time & dissolution rate. But one brand of tablets exceeded the specification of Hardness & two brand of tablets showed slightly slow dissolution rate as compared to USP specification. . It is evident from the study that most of the brands tested showed good results but a few of them failed to meet the specification. Keywords: Quality, Ranitidine hydrochloride, Bangladesh ________________________________________________________________________

1. Introduction

Ranitidine is a competitive, reversible inhibitor of the action of histamine at histamine H2-receptors, including receptors on gastric cells with a minimal effect on H1- receptors. It is one of the drugs of choice for the treatment of active duodenal ulcers, gastric ulcers, ZollingerEllison syndrome, gastroesophageal reflux disease, and erosive esophagitis. The indicated oral dosage of ranitidine is 150 mg twice daily or 300 mg once daily. In the treatment of endoscopically diagnosed erosive esophagitis, the dosage is 150 mg ranitidine 4 times a day [Morrill et al, 1996, St Louis, et al, 2002]. It has been found that the conventional dose of 150 mg can inhibit gastric acid secretion up to 5 h. [Somade et al, 2002] The drug has a short biological half-life of approximately 23 h, an absolute bioavailability of only 50%, and it is absorbed only in the initial part of the small intestine [Ravala et al,2007]. Because of the increasing complexity of modern pharmaceutical manufacture arising from a variety of unique drugs and dosage forms, complex ethical, legal and economic responsibilities have been placed on those concerned with manufacture of modern pharmaceuticals. An awareness of these factors is the responsibility of all those involved in the development, manufacture, control and marketing of quality products. The major causes that lead to substandard drugs are given below: Addition of incorrect quantity of active ingredient or date expired sub-potent materials. Non-uniform distribution of active ingredients and Poor stability of active ingredients in the finished product. [Ahmed et al, 2003] Substandard or spurious drugs could endanger patient's life. After the

implementation of the National Drug Policy in 1982 the quality of marketed drug, no doubt, improved, but not as expected. This realization influenced to evaluate the ranitidine preparations available in the market. The major purpose of this study is to investigate the overall quality of the marketed ranitidine (tablets and suspensions) preparations available in Bangladesh. We hope that the findings of this study will help to make awareness both in physicians and consumers to select quality products. The investigation was performed in "Pharmaceutics Laboratory" of Pharmacy Discipline, University of Science & Technology Chittagong, Bangladesh during October 2008 to April 2009. 2. Materials and Methods: Instruments Name of the Instruments
Analytical balance Digital Slide calipers Monsanto tablet hardness tester Disintegration test apparatus Dissolution test apparatus UV spectrophotometer pH Meter Mortar and Pestle

Manufacturer
Mettler,Toleds,B303-S Shanghai, China. India. India. USP XXIV Paddle apparatus, India. Shimadzu Switzerland China

Collection of sample: The marketed sample of 10 brands of Ranitidine hydrochloride tablet were purchased at M.R.P from different Retail pharmacy at Chittagong in Bangladesh. These tablets of 10 brands were coded as RT01..to RT10.The samples were properly checked for their physical

appearance, name of manufacturer, batch number, manufacturing date, expiry date, manufacturing license number, D.A.R. number & maximum retail price at the time of purchase. The standard sample was collected from United Chemicals & Pharmaceuticals Ltd, Chittagong, Bangladesh. None of samples were bought & analyzed which date of expiry had already been passed & both of these samples were stored under appropriate condition. Weight variation test of tablets: Procedure: Twenty tablets were taken and weighed individually by an analytical balance. The average weight of the tablets was calculated. Then % of weight variation is calculated by using the following formula: % of weight variation = {(Individual weight Average weight)/Average weight} 100 Hardness test of tablets: Tablet hardness is defined as the load required to crush or fracture a tablet placed on its edge. Sometimes it is also termed as tablet crushing strength. In this study, Ranitidine tablet was placed between fixed & moving jaw of Monsanto Hardness tester.[Ahmed et al 2003] Disintegration time test of tablets: Disintegration time is the length of time required for causing disintegration of tablet. This test is important to evaluate a tablet since it directly influences the onset of action. This test not only evaluates the quality but also the bioavailability and effectiveness of tablets. Procedure: USP disintegration apparatus contains 6 glass tubes that are 3 inches long, open at the top

and held against a 10-mesh screen at the bottom end of the basket rack assembly. About 900ml distilled water was taken in both 1000ml beaker & then these beakers were placed into the device. One Ranitidine tablet was placed in each tube of basket rack & a plastic disk is placed over each tablet & then the basket rack is accurately positioned into the beaker. The temperature was maintained as 372C.A motor driven device helps to move the basket up & down through a distance of 5-6cm at a rate of 28-32 cycles per minute. The time at which all the Ranitidine tablets passed through the sieve was the disintegration time & the average disintegration time were calculated. [Ahok K.Gupta] Dissolution of Ranitidine: Dissolution is the property or tendency of a drug to undergo solution, which affects the rate of drug absorption Procedure: About 900ml of distilled water was filled into 1000ml beaker of dissolution apparatus. One Ranitidine tablet was placed into each beaker. The dissolution medium was heated up to 370.5c by an autoheater & 50 r.p.m was adjusted.10ml solution were withdrawn from beaker at 15 minutes interval which was replaced with another 10ml distilled water & then withdrawn solution was immediately filtered through cotton.[ Ahok K.Gupta].The withdrawn solution of Ranitidine HCl tablet was suitably diluted & absorbance was measured at 229nm by using UV spectrophotometer. Finally the percent release of Ranitidine HCl tablet was determined by using these data. Preparation of standard sample curve: A series of standard solutions with different concentration of standard Ranitidine HCl e.g.,1g/ml, 2g/ml,

Weight variation number of tablet within USP range

Potency determination of tablets: At least 20 tablets of each brand were weighed & triturated to make powder. From which 100mg equivalent of active ingredient were calculated. The same procedures were followed for both marketed sample & standard sample. In 100ml volumetric flask; 100mg Ranitidine HCl powder was taken & few ml of distilled water was added & shaken. Then make the volume upto 100ml mark of volumetric flask with distilled water by filtering through cotton. From filtered solution, 1ml is taken in another 100ml volumetric flask. Then the volume was made upto 100ml mark of volumetric flask with distilled water by filtering through cotton. Then the absorbance of each solution was measured at 229nm by using UV spectrophotometer. (USP 23, 1995).The potency was calculated by following equation:

RT01 RT02 RT03 RT04 RT05 RT06 RT07 RT08 RT09 RT10

20 20 20 20 20 20 20 20 20 20

342.7 297 250.5 345.2 256.3 304.4 360.9 340 259.3 349.1

20 20 20 20 20 20 20 20 20 20

Table 1: Absorbence of different concentrations of standard Ranitidine HCl.

Hardness test: The hardness of 10 brands of Ranitidine HCl tablets (20 tablets from each brands) were measured & the observed results are shown in (table 3) BP/USP specification of hardness: not more than 7.0kg-cm-1.It was seen from the result (table 3) that RT08 brands exceeded the specification & remaining 9 brands of Ranitidine HCl tablet complied with the BP/USP specification for tablet hardness.
Concentration (g/ml) 1 2 3 4 5 6 7 8 Absorbance of standard sample 0.088 0.176 0.264 0.351 0.440 0.521 0.606 0.684

3. Results and Discussion Weight variation test of tablets The weight variations of 10 brands Ranitidine HCl tablets were determined & the observed results are shown in (table 2).The USP specification of weight

USP rangeNumber of tablet out of

tablets takenNumber of

Average weight (mg)

3g/ml,4g/ml, 5g/ml, 6g/ml, 7g/ml, 8g/ml, etc were prepared by dissolving 100 mg of standard Ranitidine HCl in a 100-ml volumetric flask and volume was adjusted by distilled water. Absorbance was taken at 229 nm against a blank for each solution and the average was calculated (table 1). The measured absorbances were plotted against the respective concentrations of the standard solutions which give a straight line (Fig.02).

variation: 7.5% for 130 to 324mg average weight of tablet & 5% for more than 324mg average weight of tablet. It was observed that all of the brands meet the USP specification. Table 2: Weight variation of 10 brands of Ranitidine HCl tablets
Sample code

0 0 0 0 0 0 0 0 0 0

Table 3: Hardness of 10 brands of Ranitidine HCl tablets sample code Average Hardness (kgcm-1) RT01 5.24 RT02 5.9 RT03 5.06 RT04 6.87 RT05 4.37 RT06 6.98 RT07 4.22 RT08 8.1 RT09 5.66 RT10 6.79 Disintegration test: The disintegration time of 10 brands of Ranitidine HCl tablets were measured & the observed results are shown in (table 4). The specification of disintegration time: 5 to 30 minutes. (Leon. Lachman, Industrial Pharmacy).It was seen from result (table 4) that none of the marketed Ranitidine HCl sample exceeded the specification & therefore it can be said that all the marketed sample complied with the specification for tablet disintegration time. Table 4: Disintegration time of 10 brands of Ranitidine HCl tablets Marketed Average Disintegration sample code time in minute RT01 7 RT02 10 RT03 11 RT04 13 RT05 6 RT06 15 RT07 11 RT08 14 RT09 19 RT10 17 Dissolution rate test: The dissolution rates of 10 brands of Ranitidine HCl tablets were determined &

the observed results are shown in table 5. The % of drug release was plotted against the times, which give a dissolution curve (Fig.01). USP specification: Not less than 80% of the labeled amount of Ranitidine (C13H22N4O3S) to be dissolved in 45 minutes. It is seen from the result (table 5) that RT03, RT10 shows slightly less percent of drug release within 45 minutes & the remaining 8 brands of Ranitidine HCl tablets meet the specification. Table 5: Dissolution rate of 10 brands of Ranitidine HCl tablets sampl % of % of % of % of e drug drug drug drug code releas releas releas releas e after e after e after e after 15 30 45 60 minut minut minut minut es es es es RT01 75.99 91.9 96.3 99.51 RT02 81.06 90.12 98.15 99.8 RT03 44.12 61.29 77.67 85.8 RT04 64.9 75.99 94.8 98.95 RT05 85.1 92.25 98.12 99.97 RT06 68.64 69.29 95.6 98.9 RT07 49.61 79.67 90.3 99.7 RT08 62.4 73.92 89.57 98.6 RT09 66.61 81.12 95.6 99.09 RT10 29.04 62.56 78.35 84.13

120 100 80 60 40 20 0 0 20 40 Tim e (m in) RT 01 RT06 RT02 RT07 RT03 RT08 RT04 RT09 RT05 RT10 60 80

0.8 0.7 Absorbence 0.6 0.5 0.4 0.3 0.2 0.1 0 0 0 2 4 6 8 10 Concentration(mcg/ml) 0.44 0.351 0.264 0.176 0.088 0.684 0.606 0.521

RT02 RT03 RT04 RT05 RT06 RT07 RT08 RT09 RT10

103.08 102.36 100.39 98.95 100.57 99.71 101.82 99.52 87.99

% of Drug release

4. Conclusions:
Ranitidine hydrochloride tablets have been analyzed to find their current Quality status. For this purpose, the marketed sample of 10 brands of Ranitidine hydrochloride tablets were analyzed by using established method & apparatus. All brands tested, showed a good result for weight variation, hardness, and disintegration time and dissolution rate. In this experiment, RT01, RT02, RT05 showed the best dissolution rate. But one brand of tablets exceeded the specification of Hardness & two brand of tablets showed slightly slow dissolution rate as compared to USP specification. Two brands of Ranitidine hydrochloride tablets also failed to meet the USP specification of potency. This may be due to the degradation of active ingredient or due to the addition of less amount of active ingredient at the time of manufacture. The present study, although performed on a limited scale yet on the basis of professional judgment the data reported in this study can help the Drug Control Authority to get an idea about the quality status of the marketed ranitidine hydrochloride preparations in Bangladesh. This study emphasizes the need of constant surveillance and continuous evaluation of marketed drug products by the governments, manufacturers and independent research group to ensure proper supply and availability of quality medicines

Fig 1:In vitro release of Ranitidine HCl Fig 2: Standard curve of Ranitidine HCl Potency test: The potency of 10 brands of Ranitidine HCl tablets were determined.The obtained results are shown in Table 10. USP specification: Ranitidine tablets contain an amount of Ranitidine hydrochloride (C13H22N4O3S) equivalent to not less than 90.0percant & not more than 110.0 percent of the labeled amount of Ranitidine. (USP 23, 1995) From the result (Table 10), it was evident that 8 out of 10 brands of Ranitidine HCl tablet meet the specification of potency whereas only RT01, RT10 was slightly less potent than the USP range. This may be due to the degradation of active ingredient or due to the addition of less amount of active ingredient at the time of manufacture. Table 10: Potency of 10 brands of Ranitidine HCl tablets
Marketed sample code RT01 Potency (%) 88.56

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