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Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 37
Dissolution Profile of Expired Metronidazole Tablet
Nazik Hamad
Faculty of pharmacy, Benghazi University,
Nazik.hamad@uob.edu.ly
Rasha saleh Hussein Fenesha
Faculty of pharmacy, Benghazi University,
rashasaleh8888@yahoo.com
Abstract:
In recent years the growing interest in drug stability problem has been observed. However, the
studies that reported about the stability of drugs past their expiration dates were limited. If analysis
of tablet stability is considered, the most important ones are content determination and dissolution
test. The objective of the current study was to examine the Percent of drug release for both expired
and valid Metronidazole tablets through dissolution test. According to IP the valid drug has
acceptable dissolution rate and excepted good bioavailability. In contrast, the expired
Metronidazole tablet listed 71% percent of drug release as the highest rate at 30 min. This study
suggested that the expired tablet is not equivalent or similar to valid tablet and recommended to
use the valid one to give the therapeutic effect.
Keywords: Metronidazole, Expired, Dissolution, Drug Release
Introduction
Background
Metronidazole (MTZ) is one of the mainstay drugs for the treatment of anaerobic bacterial
infections, protozoal infections, and microaerophilic bacterial infections. It is cytotoxic to
facultative anaerobic microorganism. This activity will highlight the mechanism of action, adverse
event profile, and other key factors pertinent to members of the inter professional team in the care
of patients being treated with this medication. [5]
Metronidazole indication
FDA-approved MTZ for the treatment of a broad range of infections such as intestinal amebiases,
liver amebiasis, bacterial septicemia, bone and joint infections, central nervous system (CNS)
infections (meningitis and brain abscess), endocarditis, gynecologic infections (endometritis, tubo-
ovarian abscess, bacterial vaginosis), intra-abdominal infections, lower respiratory tract infections,
skin structure infections, and surgical prophylaxis surgeries. [7]
Mechanism of action
Metronidazole diffuses into the organism, inhibits protein synthesis by interacting with DNA and
causing a loss of helical DNA structure and strand breakage. Therefore, it causes cell death in
susceptible organisms. [1]
, ,
Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 38
Metronidazole pharmacokinetic
Metronidazole is rapidly absorbed from the small intestine on through oral administration
including distribution in all tissues and fluids. In liver metabolism through oxidation and
conjugation process with glucuronic acid. It eliminates with urine concluding 7-8 hours of half-
life period. [6]
Solubility of metronidazole
Metronidazole’s solubility in water was reported as 10 mg/mL at 20◦C and 10.5 mg/mL at 25◦C.
Another source reported a solubility of 64.8 mg/mL at room temperature and pH 1.2, decreasing
to around 10 mg/mL at pH values between 2.5 and 8.0(Wu Y, Fassini,2005).
Chemically, metronidazole is [2-(2-methyl-5-nitro-1H-imidazol1-yl) ethanol] with molecular
weight of 171.15 g/mol and classified according to BCS as Class I drug i.e., highly soluble and
highly permeable [2]
Figure 1. Metronidazole chemical structure
Stability of Valid and expired metronidazole tablet:
In recent years the growing interest in drug stability problem has been observed. However, the
studies that reported about the stability of drugs past their expiration dates were limited. If analysis
of tablet stability is considered, the most important ones are content determination and dissolution
test. [11]
Research on the release of medicinal substances is accompanied by a broad range of information
concerning the analyzed preparation, i.e. numerous physical and chemical properties of the dosage
form, the methods of production. Finally, the changes in dissolution profile might be the result of
ageing of the product. [4]
Aim of study:
The objective of the current study was to examine the Percent of drug release for both expired and
valid Metronidazole tablets through dissolution test.
, ,
Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 39
Materials and Methods
Apparatus
Metronidazole tablets (250 mg) were kindly provided by Abozriba pharmacy (Benghazi, Libya).
The other chemicals and reagents were used of analytical grade.
Study of Metronidazole dissolution was carried out on electronic balance (Kern 870), pH meter,
Desicator, dissolution apparatus (ERWEKA DT600) and UV -Vis Spectrophotometer (analytik
jena) available in Research Lab of Benghazi University, school of pharmacy.
Preparation of dissolution medium (buffer solution pH 6.8):
Dissolve 28.20gm of disodiumhydrogen phosphate and 11.45gm of potassium dihydrogen
phosphate in sufficient water to produce 1oo ml
Standard curve preparation:
50 mg of reference metronidazole is dissolved in 0.1 N HCl to make volume 100 ml. From above
solution 1, 2, 3, 4, 5,6 ml is taken respectively and each of them was made 100 ml with 0.1N HCl.
All gradual concentrations of solution were conducted for plotting standard curve at 277 nm. The
corresponding regression data, indicated reasonable linear relationship R2 = 0.9749. The
calibration curve was shown in (Figure 2)
Figure 2. Metronidazole calibration curve
Dissolution test:
Dissolution test was conducted according to International Pharmacopeia. Dissolution rates of
metronidazole tablets were determined in 500 mL of buffer solution (pH6.8) at 37 ± 0.5 °C using
an Erweka dissolution apparatus at a rotational speed of 75rpm. Samples (5 mL) were removed at
10,15,20 ,30-min intervals over 30 min and replaced immediately with an equal volume of buffer
solution to maintain sink conditions. The amount of metronidazole that dissolved over 30 min was
determined by measuring absorbance at 277 nm using a UV–vis spectrophotometer.
y = 0.0956x - 0.0382
0
0.1
0.2
0.3
0.4
0.5
0.6
01234567
Absorbance
concentration
Metronidazole calibration curve
, ,
Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 40
Using the y =mx + c equation derived from the standard curve of Metronidazole, concentrations
of sample at different above-mentioned times were calculated. From these data Cumulative amount
release and then % Drug release were calculated using the following equation:
% Drug release= (cumulative amount release(mg))/(strenght in (mg)) x100
Result:
Sample 1:
Metronidazole(250mg) tablet Sanofi- aventis
B. No: EG008
Mfg.date:10\2018
Exp.date:09\2021
Table (1): Absorbance of drug sample 1.
Table (2): Percent of drug release sample 1.
Percent
of drug
release
Conc(mg). \500ml
Conc(Mg). \500ml
Cumulative
conc.5ml\Mg
Conc. \5ml
Dilution
factor
Conc. Mg
Abs.
Time
24
60
60,000
600
600
120
12
1.05
10
50
125
125.000
1250
650
130
13
1,13
15
86
215
215000
2150
900
180
18
1,59
20
134
335
335000
3350
1200
240
24
2,07
30
Sample 2:
Metronidazole(250mg) Medopharm industrial
B. No: 5MF77
Mfg.date:06\2015
Exp.date:05\2018
Absorbance
at
Absorbance
at
Absorbance
at
Absorbance
at
Wt. of
tab.
No.
of
tab.
30 min
20 min
15 min
10 min
Time
1.984
0.3538g
1
2.273
0.3548g
2
2.069
0.3586g
3
1.943
0.3420g
4
, ,
Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 41
Table (3): Absorbance of drug sample 2.
Average of
absorbance
Absorbance
at
Absorbance
at
Absorbance
at
Absorbance
at
Wt. of
tab.
No. of
tab.
30 min
20 min
15 min
10 min
Time
0.603
0.358g
1
0.758
0.357g
2
0.722
0.356g
3
0.494
0.362g
4
Table (4): Percent of drug release sample 2.
Percent
of drug
release
Conc.
(mg)\5ml
Conc.(Mg).
\500ml
Cumulative
concentration
Conc.
(Mg)\5ml
Dilution
factor
Conc.
(Mg)
Abs.
Time
(min)
6.8
17
17000
170
170
34
3.4
0.3
10
20.2
50.5
50500
505
335
67
6.7
0.6
15
41
102.5
102500
1025
520
104
10.4
0.9
20
71
177.5
177500
1775
750
150
15
1.3
30
Figure 3: percent of metronidazole release
24
50
86
134
6.8 20.2 41
71
0
50
100
150
1 2 3 4
percentage
Time(10-15-20-30 min)
Percent of drug release
M1 M2
, ,
Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 42
Discussion
According to IP the acceptable percent of metronidazole release was more than 85% [ 8]. In this
study the vitro dissolution experiment subsequently completed with two different expiration date
metronidazole tablets, that have the same strength, the release rate of valid drug was recorded
through 30 minutes as 24,50,86,134 respectively (table 1). The highest percentage 134% was listed
after 30 min (table 2). According to IP this drug has acceptable dissolution rate and excepted good
bioavailability. Our results were compatible with many previous studies.
In contrast, the expired Metronidazole tablet listed 71% percent of drug release as the highest rate
at 30 min (table3 and 4).
This percent is less than lower limit of drug release and reflect poor bioavailability. Although many
researches explained that drugs stored under optimal conditions, retain 90% of their potency for at
least five years after the labeled expiration date, and sometimes longer [3,9,10]. This study showed
deterioration in percent of released drug after one year from expiration date. Hence these results
may be coming from many factors, such as inappropriate storing conditions.
Conclusion
In conclusion, Dissolution test was applied on both valid and expired metronidazole tablet. This
work found that the expired tablet exhibited less than the acceptable limit (71% percent of drug
release as the highest rate at 30 min) and was failed. whereas the valid one appeared in the
acceptable range and showed more than 85% drug release within 30 minutes. This study suggested
that the expired tablet is not equivalent or similar to valid tablet and recommended to use the valid
one to give the therapeutic effect.
References
1.Edwards DI. Nitroimidazole drugs--action and resistance mechanisms. I. Mechanisms of action.
J Antimicrob Chemother. 1993 Jan;31(1):9-20. [PubMed]
2.Fatima et al., IJPSR, 2017; Vol. 8(7): 3133-3137. E-ISSN: 0975-8232; P-ISSN Löfmark S,
Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic
infections. Clin Infect Dis. 2010 Jan 01;50 Suppl 1:S16-23. [PubMed]
3.Gray, Vivian A., and Thomas W. Rosanske. "Dissolution." Specification of Drug Substances
and Products. Elsevier, 2020. 481-503.
4.Kurczewska, Urszula. 2009."Stability studies of expired tablets of metoprolol tartrate and
propranolol hydrochloride part2.dissolution study."*Acta Poloniae Pharmaceutica ñ Drug
Research, 66 No. 6 pp. 703ñ707, 200911
5. Löfmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of
anaerobic infections. Clin Infect Dis. 2010 Jan 01;50 Suppl 1:S16-23. [PubMed]
6.Nagadurga, Divvela Hema. "Bioavailability and Bioequivalence Studies." Pharmaceutical
Formulation Design-Recent Practices. IntechOpen, 2019.
7. Nawab, Amber, and Samina Alam. "Dissolution profile of Metronidazole tablet in diverse fatty
dissolution mediums." Journal of Applied Pharmacy 12 (2020): 19-26.
, ,
Social SciencesConference on Medical, Applied, and International Libyan
th
6
(Formally known: Libyan Conference on Medical and Pharmaceutical Sciences)
Alq J Med App Sci. vol5, supp1, 2022 43
8.Pharmacopeia, U. S. "and National Formulary 29 (2011) US Pharmacopeial Convention."
Rockville, MD (34): 4403-4404.
9.Qureshi, Saeed A. "Development and validation of drug dissolution methods-A rational and
systematic approach." American Pharmaceutical Review 10.3 (2007): 41
10.Wu Y, Fassini R. 2005. Stability of metronidazole, tetracycline HCl and famotidine alone and
in combination. Int J Pharm 290:1–13
1.Zhang, Audrey D., et al. "Assessment of clinical trials supporting US Food and Drug
Administration approval of novel therapeutic agents, 1995-2017." JAMA network open 3.4
(2020): e203284-e203284.