‫ العدد‬/ ‫ العلوم الصرفة والتطبيقية‬/ ‫مجلة جامعة بابل‬
2010 : )18( ‫ المجلد‬/ )2(
The Variation Of The In Vitro Antibacterial
Activity Of Common Antibiotic Generic Names
With Different Trade Names For Each In Iraqi
Local Markets
Senan A. Almashta
Department of Biology, College of Science for Women, University of Babylon
Abstract
Thirty antibiotics belong to nineteen pharmaceutical industries found in nine countries around
the world were collected from Iraqi local markets. Antibacterial activity for each type of antibiotics
manufactured in certain industry was studied to detect the difference in an effectiveness for each
product toward six species of bacteria: Pseudomonas aeruginosa, Streptococcus pyogenes,
Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Klebsiella pneumoniae in the method of
agar disk diffusion in which the diameter of inhibition zone was measured.
The product that gave the least inhibition values was determined, then confirmation of its
inactivity against the applied bacterial species was made.
‫الخالصة‬
،‫تم قياس الفعالية المضادة للبكتريا لثالثين مضادا ً حيويا ً صنع في تسعة عشر مصنعا ً دوائيا ً تابعة لتسع دول مختلفة حول العالم‬
‫ درست فعالية كل نوع من هذه المضادات الحياتية المنتجة من‬.‫حيث جمعت هذه المجموعة من المضادات من االسواق المحلية العراقية‬
:‫مصانع دوائية مختلفة للتعرف على اختالف التأثير لكل منتج في ست أنواع من البكتريا هي‬
Pseudomonas aeruginosa, Streptococcus pyogenes, Staphylococcus aureus, Bacillus subtilis,
Escherichia coli , Klebsiella pneumoniae.
‫ حدد المنتج الذي أعطى أقل نتيجة تثبيط لكل‬.‫ حيث تم قياس قطر منطقة التثبيط بالمسطرة‬،‫وذلك بطريقة االنتشار في الوسط الصلب‬
.‫نوع من هذه المضادات حيث تم التأكد من عدم فاعليته تجاه األنواع البكتيرية المدروسة‬
Introduction
Antibiotics are the low molecular weight secondary metabolites of
microorganisms, with moll mass of < 2000 Dalton, which, in small quantities(< 200
µg/ml), inhibit the growth of other microorganisms, without affecting the producers
themselves (Smelcerovic and Djordjevic, 2000). They are chemical substances that
can inhibit the growth of, and even destroy, harmful microorganisms. They are
derived from special microorganisms or other living systems, and are produced on an
industrial scale using a fermentation process. Although the principles of antibiotic
action were not discovered until the twentieth century, the first known use of
antibiotics was by the Chinese over 2,500 years ago. Today, over 10,000 antibiotic
substances have been reported. Currently, antibiotics represent a multibillion dollar
industry that continues to grow each year.
The commercial development of an antibiotic is a long and costly proposal. It
begins with basic research designed to identify organisms, which produce antibiotic
compounds. During this phase, thousands of species are screened for any sign of
antibacterial action. When one is found, the species is tested against a variety of
known infectious bacteria. If the results are promising, the organism is grown on a
large scale so the compound responsible for the antibiotic effect can be isolated
(Stacey et al., 2002).
The current era of antimicrobial chemotherapy began in 1935 with the
discovery of the sulfonamides. In 1940, it was demonstrated that penicillin,
discovered in 1929, could be an effective therapeutic substance. During the next 25
years, research on chemotherapeutic agents centered largely around substances of
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microbial origin called antibiotics. The isolation, concentration, purification, and mass
production of penicillin were followed by the development of streptomycin,
tetracyclines, chloramphenicol, and many other agents. These substances were
originally isolated from filtrates of media in which their respective molds had grown.
Synthetic modification of previously described drugs has been prominent in
the development of new antimicrobial agents. Antimicrobial drugs act in one of
several ways: by selective toxicity, by inhibition of cell membrane synthesis and
function, by inhibition of protein synthesis, or by inhibition of nucleic acid synthesis.
Antimicrobial activity is measured in vitro in order to determine (1) the
potency of an antibacterial agent in solution, (2) its concentration in body fluids or
tissues, and (3) the susceptibility of a given microorganism to known concentrations
of the drug (Brooks et al., 2007).
Antibiotic resistant pathogens have been widely and continuously reported. In
consequence, novel antibiotics have been investigated intensively (Miyadoh, 1993).
Most of the antibiotics are extracellular-secondary metabolites which are
normally secreted in culture media and serve as intermediates from primary
metabolisms as precursors for their biosynthetic process (Vilches et al., 1990).
The goal of this work is to evaluate the antibacterial activity of the common
antibiotics toward selected species of bacteria and to assess the difference in the
efficiency for each type of antibiotic manufactured in several pharmaceutical
industries export their products to Iraqi local markets during the second half of the
year 2008. Few of review articles was found around the world covering this subject
during the work time.
Materials and Methods
1- Bacterial Species:
Six bacterial species were studied (Pseudomonas aeruginosa, Streptococcus
pyogenes, Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Klebsiella
pneumoniae), were isolated from patients suffering from urinary tract infection and
bacteremia at Babylon maternity and children hospital, Hilla, Iraq, and identified
according to the diagnostic procedures recommended by Bergy’s manual for
determinative bacteriology (Holt et al., 1994).
2- Antibiotics:
Thirty antibiotics from different pharmaceutical industries were examined for
their antibacterial activity, their generic names, trade names, state of origin, name of
industry and packaging formulas shown in table (1).
3- Antibiotic Concentrations:
All antibiotic concentrations were made according to (Sambrook and Russell,
2001), 10 mg/ml for Ampicillin, Amoxicillin and Cephalexin, while the final
concentration for (Amoxicillin+Clavulanic acid), (Ampicillin+Cloxacillin),
Ciprofloxacin, Tetracycline and Chloramphenicol was 5 mg/ml.
4- Antibiotic Sensitivity Test:
Three replicates were made by using small disks (6 mm in diameter) from
Wattman filter paper No.1, saturated in each antibiotic concentration left for 30
minutes(Williamson et al., 1985), then dried and tested against the bacterial species
by method of agar disk diffusion (Bauer et al., 1966), the concentration of bacterial
growth was 1.5*108 cell/ml (tube number 0.5 McFarland standard), the average of
inhibition zone diameter was taken.
5- Confirmation of Antibiotic Activity:
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Member of some types of antibiotics showed the least antibacterial values was
examined to confirm the weakness of this activity, nutrient agar media in conical
flasks were autoclaved and cooled to 50°C, each generic name of antibiotic was added
in certain concentration as follow: Ampicillin and Cephalexin (100 µg/ml),
Ciprofloxacin and Tetracycline (20 µg/ml) and 50 µg/ml for Chloramphenicol, then
poured into Petri dishes and left to solidify, the applied bacterial species were cultured
by picking and patching method, dishes incubated under 37°C for 24 hours and the
results were recorded (Miniatis et al.,1982).
Table 1. Antibiotic generic names and their basic informations.
No.
1
2
3
4
Antibiotic Generic
Name
Ampicillin 250 mg
Ampicillin 500 mg
Ampicillin 500 mg
Ampicillin 500 mg
5
6
7
------------------------------------PAN AMPICILLINE
-------------------
Packaging
Formula
Capsules
Vials
Vials
Vials
State of
Origin
Iraq
Germany
France
Eygpt
Amoxicillin 250 mg
Amoxicillin 500 mg
Amoxicillin 500 mg
-----------------EMBAMOX
-------------------
Capsules
Capsules
Capsules
Iraq
India
China
8
9
Amoxicillin 500 mg
Amoxicillin 500 mg
Capsules
Vials
China
France
10
11
12
Amoxicillin 500 mg
Amoxicillin 500 mg
Amoxicillin 250 mg
+ Clavulanic Acid
125 mg
Amoxicillin 250 mg
+ Clavulanic Acid
125 mg
Ampicillin 250 mg +
Cloxacillin 250 mg
Ampicillin 250 mg +
Cloxacillin 250 mg
Ampicillin 250 mg +
Cloxacillin 250 mg
Cefalexin 500 mg
Cephalexin 250 mg
Cefalexin 500 mg
Ciprofloxacin 500 mg
Ciprofloxacin 500 mg
Ciprofloxacin 500 mg
-----------------PAN
AMOXICILLINE
Glomox 500
Neomox
Clavoxil375
S.D.I
Troge Medical. GMBH
PANPHARMA
Chemical Industries
Development
S.D.I
Laborate Pharmaceutical
Harbin Pharmaceutical Group
Co., LTD
Sishui Pharmaceutical Co., LTD
PANPHARMA
Capsules
Capsules
Tablets
U.A.E
U.A.E
Syria
global pharma
neopharma
Elsaad Pharma
Bactoclav-375
Tablets
India
Micro Labs Limited
--------------------
Vials
Germany
Troge Medical. GMBH
Ampicloxacillin 500
Vials
China
Sishui Pharmaceutical Co., LTD
Amicloxan
Capsules
Syria
Cefex-500
----------------------------------CIPROXENE 500
IFICIPRO 500
-----------------
Capsules
Capsules
Capsules
Tablets
Tablets
Tablets
India
Iraq
China
Syria
India
China
TYFLOX -500
Bactiflox- 500
SAMACYCLINE
APCYCLINE-250
---------------------------------------
Tablets
Tablets
Capsules
Capsules
Capsules
Capsules
India
Portugal
Iraq
India
Germany
China
Barakat Pharmaceutical
Industries
Micro Labs Limited
S.D.I
ZMC
Medical Bahry Company.
Unique Pharmaceutical Labs
Shijiazhuang Taihang Medicines
Co., LTD
Ajanta pharma limited
Sofarimex Lda
S.D.I
Ajanta pharma limited
Troge Medical. GMBH
ZMC
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Ciprofloxacin 500 mg
Ciprofloxacin 500 mg
Tetracycline 250 mg
Tetracycline 250 mg
Tetracycline 250 mg
Chloramphenicol
250 mg
Trade Name
430
Industry
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2010 : )18( ‫ المجلد‬/ )2(
29
30
Chloramphenicol
1 g.
Chloramphenicol
1 g.
------------------
Vials
China
ZMC
FENICOL 1000
Vials
Syria
Shifa Pharmaceutical Industries
Results
Assay revealed that there are many differences between each type of
antibiotics produced by several pharmaceutical industries in the efficiency toward the
applied bacterial species.
Ampicillin from S.D.I, Iraq showed highest values against bacteria whilst the
same antibiotic from Troge Medical, Germany gave the lowest values. At the same
time, this antibiotic from PANPHARMA, France and Chemical Industries
Development, Egypt had close results in general (table 2, figure 1).
Seven industries belong to five states produce the antibiotic (Amoxicillin)
between others that found in Iraqi local markets during the era of this work, the
interference of their antibacterial activity is confusive, amoxicillin from
PANPHARMA, France recorded its highest values against Streptococcus pyogenes,
but the one from Laborate Pharmaceutical, India and Harbin Pharmaceutical Group
Company, China showed their highest level of activity with Staphylococcus aureus, at
that time, another one from S.D.I, Iraq showed its highest value against Bacillus
subtilis and Escherichia coli, but amoxicillin from global pharma, U.A.E. had the
greatest effect against Klebsiella pneumoniae (table 2, figure 2).
Table 2, figure 3 showed that two types of the combination (Amoxicillin+
Clavulanic Acid) have been applied in this work, they were from Elsaad Phama, Syria
and Micro Labs Limited, India, both of them exhibited approximately the same results
against the tested bacterial species.
The combination (Ampicillin+ Cloxacillin) was effective against Bacillus
subtilis, Escherichia coli and Klebsiella pneumoniae especially the one from Barakat
Pharmaceutical Industries, Syria, but the combinations from Troge Medical, Germany
and Sishui Pharmaceutical Company, China were more effective against
Staphylococcus aureus and Streptococcus pyogenes. No inhibition have been recorded
with Pseudomonas aeruginosa (table 2, figure 4).
Biggest values of Cefalexin from Micro Labs Limited, India appeared with
Streptococcus pyogenes, Bacillus subtilis and Escherichia coli, it had the same effect
with the ones from S.D.I, Iraq and ZMC, China against Bacillus subtilis (table 2,
figure 5).
Moreover, Ciprofloxacin from five different industries exerted a huge activity
against the tested bacterial species including Pseudomonas aeruginosa, their results
approximately were the same, except the one from Sofarimex Lda, Portugal which
showed the lowest inhibitory effect in general (table 2, figure 6).
In the case of Tetracycline, table 2, figure 7 demonstrated that three different
origins were available, one from Ajanta pharma limited, India recorded the highest
inhibitory values when exposed to Streptococcus pyogenes, Staphylococcus aureus,
Bacillus subtilis and Klebsiella pneumoniae, whilst Troge Medical tetracycline came
at the end of the activity degree (table 2, figure 7).
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Finally, Chloramphenicol in the form of capsules created from ZMC, China
occupied the first position in its antibacterial inhibitory role, but the same antibiotic
from Shifa Pharmaceutical Industries, Syria came last (table 2, figure 8).
Confirmation of antibiotic activity showed that Ampicillin 500 mg, Troge
Medical GMBH; Ciprofloxacin 500 mg, Sofarimex Lda; Cefalexin 500 mg, ZMC
could not prevent the growth of Streptococcus pyogenes, also Tetracyclin 250 mg,
Troge Medical. GMBH was unable to eliminate the survival of Pseudomonas
aeruginosa; Streptococcus pyogenes; Staphylococcus aureus and Escherichia coli,
one other thing that Chloramphenicol 1 g., Shifa Pharmaceutical Industries was
ineffective to kill Streptococcus pyogenes; Staphylococcus aureus; Escherichia coli
and Klebsiella pneumoniae (table 3).
Table 2. Inhibition zone diameter (mm) of antibiotics versus bacterial species.
No.
Antibiotic Generic Name
Industry
1
2
3
4
Ampicillin 250 mg
Ampicillin 500 mg
Ampicillin 500 mg
Ampicillin 500 mg
5
6
7
Amoxicillin 250 mg
Amoxicillin 500 mg
Amoxicillin 500 mg
8
Amoxicillin 500 mg
9
10
11
12
17
18
19
20
21
Amoxicillin 500 mg
Amoxicillin 500 mg
Amoxicillin 500 mg
Amoxicillin 250 mg +
Clavulanic Acid 125 mg
Amoxicillin 250 mg +
Clavulanic Acid 125 mg
Ampicillin 250 mg +
Cloxacillin 250 mg
Ampicillin 250 mg +
Cloxacillin 250 mg
Ampicillin 250 mg +
Cloxacillin 250 mg
Cefalexin 500 mg
Cephalexin 250 mg
Cefalexin 500 mg
Ciprofloxacin 500 mg
Ciprofloxacin 500 mg
S.D.I
Troge Medical. GMBH
PANPHARMA
Chemical Industries
Development
S.D.I
Laborate Pharmaceutical
Harbin Pharmaceutical
Group Co., LTD
Sishui Pharmaceutical
Co., LTD
PANPHARMA
global pharma
neopharma
Elsaad Pharma
22
Ciprofloxacin 500 mg
23
24
Ciprofloxacin 500 mg
Ciprofloxacin 500 mg
13
14
15
16
Antibiotic
Concentrati
on (mg/ml)
10
10
10
10
Diameter of Inhibition Zone (mm)
PA
SP
SA
BS
EC KP
8
----------
15
9
12
11
27
12
22
24
30
26
30
28
30
22
24
23
29
22
26
25
10
10
10
----------
9
9
10
8
25
25
31
26
26
26
22
25
29
22
22
10
----
10
22
26
22
22
10
10
10
5
---8
---8
15
13
16
27
22
18
---27
25
29
26
32
25
16
25
23
22
30
27
30
Micro Labs Limited
5
8
27
25
32
22
29
Troge Medical. GMBH
5
----
15
20
25
20
12
Sishui Pharmaceutical
Co., LTD
Barakat Pharmaceutical
Industries
Micro Labs Limited
S.D.I
ZMC
Medical Bahry Company
Unique Pharmaceutical
Labs
Shijiazhuang Taihang
Medicines Co., LTD
Ajanta pharma limited
Sofarimex Lda
5
----
11
20
26
23
10
5
----
11
15
30
26
15
10
10
10
5
5
---------30
29
26
26
19
40
30
20
22
25
40
40
39
39
39
40
40
27
24
22
40
40
18
25
20
40
40
5
30
30
40
40
40
40
5
5
29
27
30
30
40
35
40
36
40
34
40
35
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Tetracycline 250 mg
Tetracycline 250 mg
Tetracycline 250 mg
Chloramphenicol 250
mg
Chloramphenicol 1 g.
Chloramphenicol 1 g.
25
26
27
28
29
30
S.D.I
Ajanta pharma limited
Troge Medical. GMBH
ZMC
5
5
5
5
10
10
10
18
22
30
18
29
14
27
---35
25
27
20
35
29
24
11
23
23
27
8
39
ZMC
5
20
27
27
27
17
Shifa Pharmaceutical
5
20
11
23
16
14
Industries
PA, Pseudomonas aeruginosa; SP, Streptococcus pyogenes; SA, Staphylococcus aureus; BS,
Bacillus subtilis; EC, Escherichia coli; KP, Klebsiella pneumoniae.
28
11
Table 3. Bacterial species that grew in picking and patching method.
1
2
3
4
5
Antibiotic
Generic Name
Ampicillin 500
mg
Cefalexin 500 mg
Ciprofloxacin
500 mg
Tetracycline
250 mg
Concentratio
n(µg/ml)
100
Troge Medical. GMBH
100
20
ZMC
Sofarimex Lda
20
Troge Medical. GMBH
Chloramphenicol
1 g.
50
Shifa Pharmaceutical
Industries
Industry
Type(s) of Bacterial Species That
Grew
Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes
Pseudomonas aeruginosa;
Streptococcus pyogenes;
Staphylococcus aureus; Escherichia
coli.
Streptococcus pyogenes;
Staphylococcus aureus; Escherichia
coli; Klebsiella pneumoniae.
35
S.D.I
Troge Medical
30
PANPHARMA
Inhibition Zone(mm)
No.
Chemical Industries
Development
25
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
20
15
10
5
0
PA
SP
SA
BS
Bacterial Species
433
EC
KP
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2010 : )18( ‫ المجلد‬/ )2(
Figure 1. Effect of Ampicillins on the applied bacterial species.
35
S.D.I
Laborate Pharmaceutical
Harbin Pharmaceutical
Group
Sishui Pharmaceutical
Company
25
PANPHARMA
global pharma
20
neopharma
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
15
10
5
0
KP
EC
BS
SA
SP
PA
Bacterial Species
Figure 2. Effect of Amoxicillins on the applied bacterial species
35
Elsaad Pharma
30
Micro Labs Limited
25
Inhibition Zone(mm)
Inhibition Zone(mm)
30
20
15
10
5
434
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
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Figure 3. Effect of Amoxicillins+Clavulanic Acid on the applied bacterial species
35
Troge Medical
Sishui Pharmaceut ical Company
Barakat Pharmaceut ical Indust ries
inhibition Zone(mm)
30
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
25
20
15
10
5
0
PA
SP
SA
BS
EC
KP
Bacterial Species
Figure 4. Effect of Ampicillins+Cloxacillins on the applied bacterial species
45
Micro Labs Limited
S.D.I
40
ZMC
hibition Zone(mm)
35
30
25
20
435
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
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Figure 5. Effect of Cephalexins on the applied bacterial species
45
Medical Bahry Company
Unique Pharmaceutical Labs
40
Shijiazhuang Taihang Medicines
Ajanta pharma limited
35
Sofarimex Lda
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
Inhibition Zone(mm)
30
25
20
15
10
5
0
PA
SP
SA
BS
EC
KP
Bacterial Species
Figure 6. Effect of Ciprofloxacins on the applied bacterial species
35
S.D.I
Ajanta pharma limited
Troge M edical
30
hibition Zone(mm)
25
20
15
436
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
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Figure 7. Effect of Tetracyclines on the applied bacterial species
45
ZMC(Capsules)
ZMC(Vials)
40
Shifa Pharmaceutical Industries
Inhibition Zone(mm)
35
PA, Pseudomonas aeruginosa
SP, Streptococcus pyogenes
SA, Staphylococcus aureus
BS, Bacillus subtilis
EC, Escherichia coli
KP, Klebsiella pneumoniae
30
25
20
15
10
5
0
PA
SP
SA
BS
EC
KP
Bacterial Species
Figure 8. Effect of Chloramphenicols on the applied bacterial species
Discussion
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Results showed a considerable variations between products manufactured
from different pharmaceutical industries for the same type of antibiotic in their
antibacterial activities toward certain bacterial species. This work agreed with results
of Abdul-Sadda, 2008 who made a comparative study tested many antibiotics from
different sources to determine their activities against some bacterial species, the study
revealed a wide differences in inhibition zones for the origins of the same antibiotic
against the same type of bacteria in vitro. Another research of (White & Hancock,
2007) recorded the differences between five origins of Tetracycline, they reported a
high variations among these five origins. Adham et al., 2006 mentioned a clear
variation between different antibiotic origins against isolate of Staphylococcus aureus.
Producing pharmaceuticals is a complex process that requires a reliable, high
quality supply of raw materials, technical expertise and a stable supply of electricity,
gas and other utilities, plus sufficient human resource capacity with Ph.D-level
scientists and expertise in pharmaceutical process and regulation. Pharmaceutical
plants are capital intensive and take many years to develop and tend to be located in
countries with good infrastructure, reliable utilities and access to technical
expertise(Kaplan and Laing, 2005). There is many reasons may effect the efficacy of
antibacterial effect of antibiotic from different pharmaceutical industries,
unfortunately, large multinational companies spend more time and financial resources
on the generation and dissemination of medical information than they do on
researching and developing new treatments(Dukes, 2002). The problem is accentuated
by large pharmaceutical companies insisting that they need financial incentives before
they can re-start their antibacterial drug development programmes(Projan, 2003). The
problem is different with the many off-patent, older antibiotics that have legally been
available in cheap, generic versions. They are widely available, but often of dubious
quality. Counterfeit medicines are another global problem, which can reach enormous
proportions in Third World countries with negligible or no regulation(Kapp, 2002).
The counterfeiting of pharmaceuticals has been detected since about 1990 and,
recently, the problem has escalated, the World Health Organization(WHO) has
defined counterfeit drug as those which are “deliberately mislabeled with respect to
identity and/or source. Counterfeiting can apply to both branded and generic products
with counterfeit products including drugs with the correct ingredients or with the
wrong ingredients; without active ingredients, with insufficient active ingredients or
with fake packaging.”(Deisingh, 2005).
Impurities in pharmaceuticals are the unwanted chemicals that remain with the
active pharmaceutical ingredients(APIs), or develop during formulation, or upon
aging of both API and formulated APIs to medicines. The presence of these unwanted
chemicals even in small amounts may influence the efficacy and safety of the
pharmaceutical products(Roy, 2002). Impurities can also be formed by degradation of
the end product during manufacturing of bulk drugs. However, degradation products
resulting from storage or formulation to different dosage forms or aging are common
impurities in the medicines. The degradation of Penicillins and Cephalosporins is a
well-known example of degradation products. The presence of a β-lactam ring as well
as that of an a-amino group in the C6/C7 side chain plays a critical role in their
degradation(Krimpen et al., 1987).
References
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2010 : )18( ‫ المجلد‬/ )2(
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