International Journal of Current Pharmaceutical Research

ISSN- 0975-7066 Vol 3, Issue 1, 2011

Research Article
PHARMACEUTICAL EVALUATION OF DIFFERENT BRANDS OF LEVOFLOXACIN TABLETS
(250MG) AVAILABLE IN LOCAL MARKET OF KARACHI (PAKISTAN)

RAHEELA BANO1, SHAHNAZ GAUHAR*2, SYED BAQIR SHYUM NAQVI2 AND SHOUKAT MAHMOOD1
1Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, Karachi, 2Department of Pharmaceutics, Faculty of Pharmacy,
University of karachi. Email: [email protected]
Received: 04 July 2010, Revised and Accepted: 31 July 2010
ABSTRACT
Purpose: Main purpose of the present study is to minimize health risk factors while maximizing the safety of the people of Karachi to maintain and
improve their health. The present study is concerned to investigate and compare the physicochemical equivalence, in‐vitro activity of drug against
hospital isolates of bacteria and efficacy of different brands of tablets containing Levofloxacin prepared by various Pharmaceutical industries under
different trade names.
Methodology: The assessment included the evaluation of physical parameters i.e. weight variation, thickness, hardness, friability, disintegration
time, dissolution test as well as chemical assay. The susceptibility test of drug was also carried out using agar dilution method on standard strains of
E. coli (ATCC‐25922) and Staphylococcus aureus (ATCC ‐ 25923) along different isolates obtained from health care setups.
Result: Weight variation of the tablets proved statistically that all of the tablets were in accordance to the required limits that is not more then ±5%
deviations. Dissolution test was carried out; none had potency less than 85% within 45minutes the required specification, not less than Q+5%.
Pharmaceutical assay was carried out none had potency less than the required specification (95.00% ‐ 105.00%).Levofloxacin had MIC90;
0.03µg/mL against E.coli standard and MIC90; 0.12µg/mL against Staphylococcus aureus that are similar to previous studies. Conclusion: In
conclusion, this study will help in the availability of economical and Quality products in the market, whether they are manufactured by local or
Multinational Pharmaceutical companies – resulting in a better health care of our country. Promoting conditions that enable people to make healthy
choices and providing information so that they can make appropriate decisions about their health.
Keywords: Levofloxacin; Antibacterial activity; Pharmaceutical quality; Comparative evaluation; Physiochemical property.

INTRODUCTION administration. Therapeutically it is used for urinary tract infection,

sinusitis, and chronic bronchitis.
The oral route is most frequently used for introducing drugs into the
body, and in fact the vast majority of drug dosage forms are The prime objective of the present study was to evaluate and
designed for oral ingestion, primarily for ease of administration, it compare the physicochemical equivalence of different tablets, of
should be recognized that this mode of administration may result in different brands that are available in local market of Karachi
inefficient and erratic drug therapy. Whenever a drug is ingested (Pakistan). In the present era where more than 85% of drugs can be
orally, one would like to have that drug absorbed into the obtained from more than one sources; for example Levofloxacin
bloodstream rapidly and completely (1). tablets that manufactured by more than 15 companies only in
Karachi (Pakistan) there might be chance of presence of some
Tablets are the most frequently administered oral solid dosage form. superiors along with sub‐standard drugs, that makes the patients
The increase in the number of generic drug products from multiple conscious about the selection of safest, effective as well as
sources has placed people involved in the delivery of health care in a economical medicine. The proposed study has been performed to
position of having to select one from among several seemingly provide the guideline to the physicians and pharmacists on the bases
equivalent products. For instance, in 1975 approximately 9% of all of which they can select the drugs for their patients. The physical
prescription drugs dispensed in the United States were generic parameters i.e. weight variation; thickness, hardness, friability,
versions (2). This figure rose to 20% in 1984 and 40% in 1991. Over disintegration, dissolution as well as chemical assay were
80% of the approximately 10,000 prescription drugs available in considered during the present study. This study was also conducted
1990 were obtained from more than one source and variable clinical to determine the in­vitro activity of Levofloxacin against common
responses to these dosage forms supplied by two or more drug and important bacterial isolates i.e E.coli and S. aureus because these
manufacturers was documented (3). These variable responses may be Gram ‐ve and Gram +ve organism are present in the environment
due to formulation ingredients employed, methods of handling, every where due to which human come in direct contact with these
packaging and storage and even the rigors of in‐process quality organism and suffering from respiratory tract, gastrointestinal tract
control. Thus, Michael, et al., 2003 suggested that there is need to and urinary bladder infection (10).
determine their pharmaceutical and therapeutic equivalence in
order to ensure interchangeability (4). MATERIAL AND METHOD
Antibiotics are among the most frequently prescribed medications in Instrumentation
modern medicine, they cure disease by killing or inhibiting bacteria.
With the increasing number of available antibiotics, prescribing For the analysis of Levofloxacin content in their dosage form a
these drugs has become a challenge. Levofloxacin is the optical S‐ (‐) Shimadzu UV‐1601 spectrophotometer was utilized.
isomer of ofloxacin which has been developed by the Daiichi Seiyaku Spectrophotometer system was integrated via Shimadzu model to P‐
Pharmaceutical Co. Ltd, in Japan. Ofloxacin is a racemic mixture, but III computer loaded with Shimadzu 1601 software for data
the S‐isomer has antibacterial activity 32‐ to 128‐fold more potent acquisition and mathematical calculations. Analytical balance,
than the R‐isomer – hence most of the antibacterial activity of Dissolution test apparatus, Disintegration test apparatus, sonicator,
ofloxacin is due to the S‐isomer. Levofloxacin has been developed to pH meter, autoclave, and micropipette.
take advantage of this antibacterial potency while requiring only Materials and reagents
about half the usual dose of ofloxacin to achieve similar efficacy, but
potentially with an improved toxicity profile (5‐9). Levofloxacin is Reference Levofloxacin was a kind gift sample from Aventis
rapidly and essentially completely absorbed after oral Pharmaceutical (Private) Limited. Six different brands of
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Int J Curr Pharm Res, Vol 3, Issue1, 15­22

Levofloxacin were obtained from different retail pharmacies of Drug cost and quality are the major component of the total cost of
Karachi (Pakistan) market. Representative Gram positive (S. aureus, the National Health Services (NHS) which is constantly rising. As the
ATCC= 25923) and Gram‐negative (E.coli, ATCC = 25922) standard resources of the NHS are limited, so it is the need of time to keep eye
organism obtained from Brookes Pharmaceutical (Pvt) Ltd. The on the quality and cost of the drugs that are available in the markets.
bacterial isolates of these organisms obtained from Liaquat National There are a number of companies that manufactures levofloxacin
Hospital, Karachi. Mueller Hilton broth (Merck Germany), Ethanol tablets 250mg. The label information of six different brands of
(Merck, Germany), hydrochloric acid, and Distilled water were tablets is presented in Table 1.
prepared freshly to prepare different dilution.
Uniformity of weight
Spectrophotometric condition
Tablet is designed to contain a specific amount of drug in a specific
Base line was adjusted to zero by using blank solvent (0.1N HCl).
Standard and test sample were analyzed (the result was based on amount of tablet formula. To check whether tablet contain a proper
three average readings). amount of drug, weight of tablet should be routinely measured.

Physiochemical parameters The tablets were examined for their uniformity of weight and for
tablet to tablet variations that should be within the limits of the
Rational use of medicines requires that "patients receive percentage deviation allowed by USP (generally ±10% for tablets
medications appropriate to their clinical needs, in doses that meet weighing 130mg or less, ±7.5%for tablet weighing more than 130mg
their own individual requirements, for an adequate period of time,
to 324mg and ± 5%for tablet weighing more than 324mg (11).
and at the lowest cost to them and their community".

Table 1: Label information of six different brands of levofloxacin tablets (250MG)

S.No Product code Manufactured by Batch No. Mfg. date Exp. Date Price/10 units
Rs
1. LEVO–1 Wilson’s Pharmaceutical Islamabad 7032 March March 99.00
2004 2007
2. LEVO–2 Werrick Pharmaceutical 4557 February February 99.00
Islamabad 2004 2007
3. LEVO–3 Getz Pharma 049‐D4 April April 170.00
Pakistan (Pvt) Limited 2004 2007
4. LEVO–4 S.J. & G Fazul Ellahi (Pvt) Ltd 026 May May 75.00
2004 2006
5. LEVO–5 Aventis Pharma (Pakistan) Limited D002 June May 417.00
2004 2007
6. LEVO–6 Bosch Pharmaceutical (Pvt) Ltd. E45156 July June 143.00
2004 2007

Uniformity of thickness Disintegration

Thickness of tablet can vary without any change in its weight Disintegrations are required to break up tablets, capsules and
because of difference in the density of the granulation and the granules into primary powder particles in to order to increase
pressure applied to the tablets as well as speed of tablet surface area of the drugs exposed to gastrointestinal fluids. The
compression. The thickness variation limits allowed are ± 5% of the disintegration test was carried out by using Erweka ZT 3
size of the tablet (12). Disintegrator. A 1000 ml beaker was filled with distilled water
(approx. 900ml), equilibrated to 37±0.5ºC. Six tablets from each
Length and diameter brand were subjected to the test. Time required for the last tablet to
BP (2002) (13) introduced a standard for tablet diameter to reduce disintegrate was recorded.
patient confusion over generic equipments. The stated diameter can Dissolution
deviate by + 5% up to 12.5 mm and by + 3% above 15mm.
Dissolution testing is the most important way to study, under in
Hardness vitro conditions, the release of a drug from a solid dosage form and
The resistance of the tablet to chipping, abrasion, or breakage under thus represents an important tool to assess factors that affect the
condition of storage, transportation and handling before usage bioavailability of a drug from a solid preparation. During dissolution
depends on its hardness (11). The hardness of tablet depends on the test the cumulative amount of drug that passes into solution is
weight of the material used space between the upper and lower studied as a function of time. The test thus describes the over all rate
punches at the time of compression and pressure applied during of the processes involved in release of the drug into a bioavailable
compression. In 1993, Gupta investigated that hardness also depends form. Dissolution test was carried out by using an Erweka
on the nature and quantity of excipients used during formulation (14). dissolution instrument. Paddle method (apparatus‐2; USP‐27) (15)
was used at 50 rpm. Hydrochloric acid 0.1N (900ml) prepared as
Friability test for tablets dissolution medium, was poured into the vessel and equilibrated to
37±0.5ºC. Six tablets from each brand were tested. 5ml of aliquot
The friability test is closely related to tablet hardness and is was withdrawn at the intervals of 15, 30 and 45min, and the
designed to evaluate the ability of the tablet to withstand abrasion in volumes withdrawn, replaced with fresh dissolution medium. The
packaging, handling and shipping. sample was filtered, using Whatman filter paper and 3ml of filtrate
Ten tablets were weighed and placed in the apparatus where they was further diluted as working solution (16µg/ml). The absorbance
were exposed to rolling and repeated shocks as they fall 6 inches in was measured at 294 nm against dissolution medium.
each turn within the apparatus. After four minutes of this treatment Standard preparation
or 100 revolutions, the tablets were weighed and the weight
compared with the initial weight. The loss due to abrasion was a For the standard solution, 20 mg Levofloxacin was weighed and
measure of the tablet friability. A maximum weight loss of not more dissolved in 50ml 0.1N HCl suitably diluted to produce a
than 1% of the weight of the tablets being tested (BP‐2002) (12). 0.016mg/ml (16µg/ml) final concentration of working solution.

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Int J Curr Pharm Res, Vol 3, Issue1, 15­22

Content assay Where, W = Weight of antibiotic to be dissolved in volume

(v).
Every tablet contains the amount of drug substance intended, with
little variation among tablets within a batch. Analysis of drug P = Potency given by the manufacturer.
potency in tablets not only indicating the presence of drug in dosage
form but also requisite for the establishment of stability data. V = Volume required.

Preparation of standard solution C = Final concentration of solution.

The standard was prepared in the same concentration as for the

dissolution testing. After preparing the stock solution, preparing a series of varying
Preparation of sample solution concentrations, usually two fold serial dilutions (0.0625, 0.125, 0.25,
0.5, 1, 2, 4, 8, 16, 32, and 64 µg/ml), Equal volume of inoculums were
Sample was prepared by weighing and crushing 20 tablets and added in each.
transferring amount of drug substance equivalent to 20mg of
standard substance of levofloxacin in 50ml of volumetric flask Spectrophotometric condition
dissolved in 0.1N HCl. Portion of solution was filtered and the filtrate
Before performing the sample, adjusted the base line on zero by
was further diluted to obtain the final working dilution of 16µg/ml.
using blank solvent (broth dilution). The broth dilution method was
Antibacterial activity used to determine the levofloxacin MICs against the pathogens.
To evaluate the activity of an antibacterial drug product against the RESULTS
microorganisms and their isolates need to be tested for determining
the spectrum of antimicrobial activity either by dilution or disk In the present study, quality of the branded product Levofloxacin
diffusion tests. (250mg) tablets was evaluated through weight variation, diameter,
thickness, hardness, friability disintegration time, dissolution and
In the present study an economical method was performed for the chemical assay. It helps to recognize the comparative difference of
determination of resistance pattern and activities of levofloxacin quality control test / parameters of levofloxacin and the effect of
standard with different commercial brands (available in the local these differences on the release of drug from the formulation and
market) by using agar dilution method that was developed by also performed the microbial susceptibility test against E.coli
Rammel kamp in 1942 (16). The Organisms used were: (standard ATCC‐25922 and its isolates) and S. aureus (standard
ATCC ‐ 25923 and its isolates).
1. E.coli (ATCC‐25922).
2. Five isolates of E.coli of different sources. Any changes in these characteristics may significantly affect the
3. S. aureus (ATCC ‐ 25923), and. safety and efficacy of the product. Therefore it is very important to
4. Five isolates of S. aureus of different sources. keep a check on each and every step during the formulation and
Stepwise considerable points were as: manufacturing of a drug product. A wide range of literature (17‐ 24) is
available regarding the comparative study of different brands of the
1. Preparation of the Mcfarland Standard same generic. Which indicated that the pharmaceutical equivalency
2. Preparation of Inoculums of different brand is as important as the biological and clinical
3. Preparation of Antibiotic Stock Solution equivalency?
Suitable ranges of antibiotic concentrations were selected for the Price fluctuation
organisms to be tested. Standard antibiotics powder (Reference
levofloxacin and different brands) weighed accurately for the As the variation in the price has been observed from as much as 7.5
preparation of stock solutions by using the formula. to 41.7pak rupees per unit (Fig: 1) while there was no significant
variation in the quality of the tested drugs. Hence it may be
W= 1000 x V x C suggested that the most economically available drug should be used
as the pharmaceutical outcomes are promising too.
P

price fluctuation levo-5

40

30

unit cost
levo-3
in Rs 20 levo-6
levo-1 levo-2 levo-4

10

0
1

Fig. 1: Price fluctuation among different brands of levofloxacin available in local market of Karachi

Weight variation that weight uniformity can be achieved due to proper care &
continuous monitoring of each batch.
It was found that the different brands tablets were of an average
weight of 300mg to 750mg ± 5%. Fig: 2 indicated that two brands levo‐1 and levo‐2 comprises on
750mg weighed that is too large as compare to levo‐5, 309.50mg but
Table: 2 shows weight variation and their standard deviation results the thickness was 5.73mm and 6.10mm that make it in acceptable
were highly significant with the limits given + 5%. The result shows volume range.

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Table 2: Physical parameters of six different brands of levofloxacin tablets 250mg with its standard deviation
Brand name Average weight Mg±SD Average thickness MM±SD Average hardness±SD
LEVO‐1 752.65 ± 18.41 5.73 ± 0.11 20.36 ± 0.01
LEVO‐2 766.05 ± 6.95 6.14 ± 0.07 20.43 ± 0.31
LEVO‐3 399.30 ± 10.43 4.61 ± 0.12 11.76 ± 0.62
LEVO‐4 362.00 ± 3.57 4.53 ± 0.08 16.34 ± 0.78
LEVO‐5 309.50 ± 2.06 4.11 ± 0.03 11.52 ± 0.34
LEVO‐6 405.45 ± 8.10 10.11 ± 0.02 11.22 ± 1.95
An even distribution of the force is required to reduce the weight variation problem.

Weight difference in different brands

a) b)
752.65 766.05 Thickness variation
800
12
700 10.11

10
600
Different
8
brand's 500 399.3 405.45 Different 5.73 6.14
362 brand's
weight 400 309.5 6 4.61
4.53
thickness in 4.11
in mg
300 mm
4
200
2
100
18.41 6.95 10.43 3.57 2.06 8.1 0
0.11 0.07 0.12 0.08 0.03 0.02
Standard deviation Standard deviation

Fig. 2: A) Comparison of different brands weight variation b) thickness variation due to weight variation

The thickness of six different brands of Levofloxacin including its Dissolution

Mean + Standard deviation (5%) was in accordance with B.P/U.S.P
(Table 2). Levo‐6 has more thickness as compare to other five The present investigation showed that almost all the 6 brands
brands that make it difficult for patient’s points of view. dissolved 55% in 15minutes, 80% in 30minutes and 90% in
45minutes (Table:3) indicating that the release pattern of drugs
Hardness is an important parameter which helps to assess the were same either the brands manufactured by different companies
resistance of the tablet to breakage under condition of storage, by using different excipients in different ratio but on the bases of
transportation and handling. Before use this parameter should be releasing factor it can be used interchangeably. The statistical
evaluated. It was found that 6 different brand of Levofloxacin tablet evaluation (ANOVA) of dissolution test also indicated that there was
were in accordance with the stated B.P/U.S.P guideline (Table 2). no significant variation found between and within different brands
of Levofloxacin tablets (Table: 4).
Disintegration
Chemical assay
Disintegration test was conducted on the six different brands of
Levofloxacin tablet 250mg. In present investigation all the six tablets Every unit of tablet should contain the amount of drug substance
of each brand disintegrated within the range of 5.84 –10.55minutes equivalent to its label amount. For the evaluation of content, assay
(Fig: 3). should be performed. The results of the assay of chemical content of
Levofloxacin tablets (Table 5) showed that the active content of all the
Fig: 3 indicates that product levo‐3 has shown a maximum average brands were between 95% and 105% of the labeled amount specified
disintegration time about 10.55 ± 0.60 minutes and product levo‐4 for levofloxacin. The results indicated that although different
has shown minimum disintegration time about 5.48 ± 0.58minutes, manufacturer formulates the different brands by different method of
which is best as compare to other products. The disintegration tests formulation but all are under the BP/USP specification. The statistical
do serve as a component in the overall quality control of tablets evaluation (ANOVA) also indicated that there was no significant
manufacturing. variation in content of active moiety in their dosage form (Table: 6).

Comparison of Disintegration time

12

10

8
Disintegrati
on time 6
(min)
4

0
levo-1 1 levo-22 3
levo-3 4
levo-4 5
levo-5 6levo-6

differents brands of tablets

Fig. 3: Mean disintegration time for 6 different brands of levofloxacin tablets 250mg

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Int J Curr Pharm Res, Vol 3, Issue1, 15­22

Table 3: Rate of % dissolution (mean + sd) of the six brands of levofloxacin tablets 250mg.
Name of brand Average dissolution at 15min ± SD Average dissolution at 30 Min ± SD Average dissolution at 45 Min ± SD
LEVO‐1 57.25 ± 5.48 75.78 ± 3.35 91.17 ± 3.06
LEVO‐2 56.88 ± 6.17 79.32 ± 4.60 94.53 ± 1.41
LEVO‐3 56.92 ± 3.62 79.07 ± 7.36 94.57 ± 3.77
LEVO‐4 59.73 ± 6.17 79.00 ± 3.74 94.80 ± 4.35
LEVO‐5 52.73 ± 1.51 83.55 ± 3.04 94.60 ± 3.78
LEVO‐6 58.92 ±1.37 83.47 ± 6.57 94.88 ± 4.43

Table 4: Anova for extant of dissolution (%) of different brands of levo

[

Source of Variation SS Df MS F P­value F crit

Between Groups 62.17916667 5 12.4358 0.95102 0.46297 2.5336
Within Groups 392.2883333 30 13.0763
Total 454.4675 35

a) Reference absorbance b) Sample absorbance at 45min

Table 5: Comparison of content assay (%) of different brands of levofloxacin

S.No. LEVO 1 LEVO 2 LEVO 3 LEVO 4 LEVO 5 LEVO 6
1 99.4 98.8 99.7 98.9 99.4 99
2 97.4 96.3 98.1 97.4 96.3 98.1
Mean 98.4 97.55 98.9 98.15 97.85 98.55
± SD 1.41 1.76 1.13 1.66 2.19 0.63

Table 6: Anova single factor for content assay of levofloxacin

Source of Variation SS df MS F P­value F crit
Between Groups 2.38666667 5 0.47733 0.2248 0.9386 4.387374
Within Groups 12.74 6 2.1233
Total 15.1267 11

Standard Levofloxacin Sample Levofloxacin

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Int J Curr Pharm Res, Vol 3, Issue1, 15­22

Antimicrobial susceptibility test against standard E.coli (Fig: 4) were 0.03µg/ml, as that of the
reported value of E.coli (Drago et al., 2002; Fu et al., 1992) (25‐26).
The first significant susceptibility test to be developed was the broth
dilution test described by Rammel Kamp and Maxon in 1942. The The analysis of variance Table # 7 showed that there were no
broth dilution susceptibility test allows the determination of the MIC significant variations found in MIC values of different brands of
of an antimicrobial agent (16). Levofloxacin tablets (MIC =0.05µg/ml – 1.0µg/ml) which indicated
that the levofloxacin tablets are good choice of drug for E.coli
Resistance of common pathogens to Antimicrobial agents has emerged resistance.
as one of the most important problems in the field of infectious
diseases. As a matter of microbial evaluation of different brands of The Fig:5 represented the antimicrobial activity of standard
levofloxacin, broth micro‐dilution method was employed against E. levofloxacin against standard S.aureus (ATCC = 25923) with 5
coli plus its isolates and S. aureus plus its isolates. The experiment was different isolates. The susceptibility test indicated that the MICs of
carried out on standardized cultures and isolates. The results were standard levofloxacin (MIC = 0.12µg/ml) against standard S.aureus
observed visually and spectrophotometrically on λ = 546nm. were same as that of the reported value of S.aureus (Sariano et al.,
2005) (27) which showed that levofloxacin standard as well as its
The resisting pattern was assessed by their MICs (Fig: 4 and 5). The different brands have a significant resistance against S.aureus and its
susceptibility test indicated that the MICs of standard levofloxacin isolates.

MICs of Std. and brands against E.coli and isolates

1
0.9
0.8
0.7
0.6
MIC s 0.5
0.4
0.3
0.2
0.1
0
1 2 3 4 5 6
std-levo levo-1 levo-2 levo-3 levo-4 levo-5 levo-6

conc.(mcg/ml)

Fig. 4: Comparison of mics against e.coli among standar and different brands

Table 7: Analysis of variance (anova) for different brands of levofloxacin against e.coli
Source of variation SS df MS F P­value F crit
Between Groups 0.8110139 5 0.1622028 1.727348 0.1587514 2.5335538
Within Groups 2.8170833 30 0.0939028
Total 3.6281 35

Comparison of std levofloxacin and diff.brands

2
1.8
1.6
1.4
1.2
MICs 1
0.8
0.6
0.4
0.2
0
1 2 3 4 5 6

std-levo levo-1 levo-2 levo-3 levo-4 levo-5 levo-6

conc.(mcg/ml)

Fig. 5: Comparison of standard and different brands of levofloxacin against std. s.aureus & its isolates

Table 8: Analysis of variance (anova) for different brands of levofloxacin against s.aureus
Source of variation SS df MS F P­value
Between Groups 3.076619 5 0.6153238 2.3673527 0.0589224
Within Groups 9.3571429 36 0.2599206
Total 12.433762 41
The MIC values were also evaluated by statistical test (ANOVA) which concluded that no significant variation was found in different brands of
levofloxacin (Table: 8)
DISCUSSION implicated to be substandard (28‐29). For minimizing the health risk
factors and to maximizing the safety of health products and food; it
It was evaluated by literatures (Shakoor, et al. 1997; Arya, 1997) is necessary to monitor all the pharmaceutical services in a regular
that many drugs that are manufactured in developing countries are basis that promoting the conditions and providing information on

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Int J Curr Pharm Res, Vol 3, Issue1, 15­22

the base of which the people become enable to make healthy choices Sciences, Baqai Medical University and Department of
and they can make correct decisions about their health. Pharmaceutics, Faculty of Pharmacy, University of Karachi, Karachi,
Pakistan, for giving us moral and generous help in following up the
Price fluctuation in societies where there is no regulatory control research.
has been a severe problem related to the quality of the drug. Fig: 1
indicated that a significant variation in the cost of different brands of REFERENCES
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