amber nawab et al. int. res. j. pharm. 2016, 7 (1) · amber nawab et al. int. res. j. pharm. 2016,...

Amber Nawab et al. Int. Res. J. Pharm. 2016, 7 (1)

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INTERNATIONAL RESEARCH JOURNAL OF PHARMACY

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ISSN 2230 – 8407

Research Article DISSOLUTION PROFILE OF METRONIDAZOLE FILM COATED TABLET 400 MG (FLAGYL) IN THE PRESENCE OF DIFFERENT JUICES: AN IN VITRO STUDY Amber Nawab *, Sidra Ghayas, Samina Alam, Najaf Farooq

Faculty of Pharmacy. Jinnah University for Women. Karachi, Pakistan

*Corresponding Author Email: [email protected] Article Received on: 22/11/15 Revised on: 10/12/15 Approved for publication: 29/12/15 DOI: 10.7897/2230-8407.0719 ABSTRACT The aim of the investigational research is to learn the in vitro comparative dissolution details of metronidazole tablet by means of changeable dissolution medium (mango juice, water melon juice and gastric medium). The intention of proficient work is to obtain an improved understanding regarding the quick dissolution of metronidazole tablet in a relevant dissolution medium in order to conquer the quickest, rapid and reflective therapeutic effect of the metronidazole tablet. Outline of the dissolution of marketable formulation of metronidazole 400 mg film coated tablet accessible in Karachi (Pakistan) were used for estimation brand (flagyl) with different vehicle (mango juice, water melon juice, gastric medium pH 1.2). For achieving maximum and appropriate dissolution of metronidazole in any vehicle we used simulated gastric condition with different medias. In mango juice metronidazole 400mg tablet were dissolved reasonably higher in gastric medium as compare to water melon juice in gastric medium in 60 minutes. Tablet Dissolution is a standardized method for measuring the rate of drug release from a dosage form. The principle function of the dissolution test is the optimization of therapeutic effectiveness during product development and stability assessment, routine assessment of production quality to ensure uniformity between production lots. So the dissolution is the main criteria to be focused in a drug’s life matrix. Mango juice is well-known to promote the health of the digestive system Therefore; here it has been summarized from the practical approach that metronidazole 400 mg tablet release was increased in mango juice as compared to water melon juice. Key words: Metronidazole, investigational research, dissolution, mango juice and water melon juice. INTRODUCTION Metronidazole (MTZ, 1-[2-hydroxyethyl]-2-methyl-5-nitroimidazole)1 is an antiprotozoal, anti-parasitic agent, very effective in the treatment of amoebiasis, trichomoniasis, giardiasis and many other parasitic diseases. It occurs as pale‐yellow crystals that is slightly soluble in water and alcohol2. Metronidazole has a selective activity against anaerobic microorganisms, including bacteria and protozoa3. It is a systemic trichomonicide which has been used extensively since 1960, has recently been shown to be active against various anaerobic bacteria in vitro and in experimental infections 4. The gastrointestinal (GI) tract is the primary disease site for Clostridium difficile infection (CDI), which is the leading cause of hospital-acquired diarrhea in developed countries. The antibiotics metronida-zole and vancomycin are the current first-line treatments for mild and severe forms of CDI, respectively5. Bacteroides fragilis is the anaerobe most commonly isolated from human infections and has demonstrated significant resistance to many antimicrobial agents, metronidazole may prove to be very useful4. Metronidazole is the drug of choice for the treatment of various parasitic infections, pseudomembranous colitis, anaerobic infections, acne rosacea, Helicobacter pylori and Crohn's disease and has been used in clinical practice for many years3. It was not clinically tested until some years later. In laboratory tests, Metronidazole is effective against intestinal amoebiasis in rats and hepatic amoebiasis in hamsters and also active against Entamoeba histolytica in vitro. The initial clinical tests of metronidazole indicated that it was capable of curing invasive amoebic dysentery and amoebic liver abscess. Subsequent clinical tests have established metronidazole as the drug of choice in the treatment of all forms of amoebiasis in humans6.

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. Normally available in 400-800 mg film coated tablet and show interaction with alcohol medication3. The use of metronidazole during pregnancy is associated with a higher risk of congenital malformations7. Indian Pharmacopoeia describes the non-aqueous titration method using Perchloric acid as titrant and malachite green as indicator for the assay of metronidazole. British Pharmacopoeia describes potentiometric and non-aqueous methods using perchloric acid as titrant. United States Pharmacopoeia describes HPLC and non-aqueous titration methods for the assay of metronidazole. Several methods have been reported for the determination of metronidazole including Spectrophotometry, Polarography6. Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro 8. The traditional medium to simulate gastric conditions in the fasted state has been simulated gastric fluid (SGF) of the USP. This medium contains hydrochloric acid and sodium chloride, as well as pepsin and water, and has a pH of 1.2.9The mango is considered as one of the most delicious and healthiest fruits. The “king of the fruits” has a yellow, reddish orange or green skin and a deep yellow pulpy interior. Mango juice is well-known to promote the health of the


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digestive system by settling an upset stomach. If you are suffering from constipation, consume this marvelous juice in combination with grapefruit and pineapple juices10. Metronidazole release was increasing in presence of mango juice was observed2. The red watermelon has lycopene in high quantities. Lycopene is an antioxidant and helps to prevent many diseases Watermelon juice is essential as a preventive against bone loss. A watermelon diet is an excellent source of energy because it contains Vitamin B.It can offer more nutrients per calorie as it mainly made of water and contains very few calories.Watermelon seeds are rich sources of protein and micro and macro-nutrients like calcium, iron, potassium, zinc and phosphorus11.To conclude, orange, mousambi, mango, pomegranate, apple, chikku and watermelon juices had no erosive effect on the human enamel, with the presence of highest amount of trace elements like fluoride and phosphorous which are considered as strongly cariostatic. Watermelon juice, the pH was 4.24 and the juice did not show any erosive effect due to the baseline surface micro hardness or iodide permeability of enamel12. MATERIAL AND METHOD Standard Material of Metronidazole has been provided by Jinnah university for women, Karachi. All reagents used for dissolution studies were of analytical grade such as hydrochloric acid (Merck, Germany); potassium chloride (Merck, Germany)3. Equipment An Automated six-basket tablet dissolution tester Galvano Scientific, Standard electrical balance for weighing, Double beam Shimadzu UV-visible spectrometer (UV mini-1700, Shimadzu Corporation, Kyoto, Japan with 1 cm quartz cells). HANNA HI 2211 pH meter (Romania)3. Samples compilation Metronidazole(Flagyl) 400 mg tablet is usually an available marketed brand. The sample was appropriately checked for their manufacturing batch number, license number, manufacturing date and expiring dates before collecting. The labeled active ingredients contents of metronidazole were 400 mg and are packaged in strip or blister packing3. Standard Solutions 0.101 gm of standard metronidazole including 40 ml of 0.1 HCl solutions was transferred to the volumetric flask and added up to 100 ml. Then, dilute 2.2 ml in 50 volumetric flasks. Dissolution Study Dissolution study by in vitro was performed by using British Pharmacopoeia dissolution test type I apparatus at 37±0.5°C with a degree of agitation 100 Rpm/minutes and 900 ml of dissolution medium per vessel was used. The dissolution experiment was conducted in the dissolution apparatus of Galvano scientific. 400 mg of metronidazole contained 700 ml of 0.1 N HCl and 200 ml of vehicles (mango juice, water melon juice and gastric medium) Dissolution medium Preparation of juice Fruit juices are popular worldwide with children of all ages as they are sweet and perceived to be healthful. Mango juice First slice the mango and then place it in a bowl or plate with a fork to avoid mess. 500 g mango fresh fruit was taken to which 200 ml of water and 4 g of sugar were added and mixed well, mangoes were prepared in a mixer used for the study12. After preparation of mango juice take 200 ml of mango juice solution and 700 ml of 0.1 N HCl solution mix well before placing in dissolution basket. Take tablets Flagyl 400 mg, weigh and placed

in the baskets with 900 ml of mango juice plus 0.1 N HCl medium was placed in each vessel and the apparatus was assembled. The operation in the mango juice medium was carried out for 60 minutes. After 60 minutes, sample solution was withdrawn and filtered. The released drug was assayed by using UV spectrophotometer at 278 nm3. Watermelon juice First slice the watermelon and then place it in a bowl or plate with a fork to avoid mess. 500 g of water melon fresh fruit was taken to which 200 ml of water12. Then, it was placed in the juicer. As the watermelon itself is sweet, adding sugar is not really necessary. The difference between seedless watermelons and watermelons with seeds lies not in their tastes but only in that seedless watermelons contain white edible seeds11. After preparation of watermelon juice take 200 ml of water melon solution and 700 ml of 0.1 N HCl solution mix well before placing it in dissolution basket. Take tablets Flagyl 400 mg formulation, weigh and placed in the baskets with 900 ml of watermelon juice plus 0.1 N HCl medium was placed in each vessel and the apparatus was assembled. The operation in the watermelon juice medium was carried out for 60 minutes. After 60 minutes, sample solution was withdrawn and filtered. The released drug was assayed by using UV spectrophotometer at 278nm. Gastric medium (0.1 N HCl) Preparation of simulated gastric medium (0.1 N HCl; pH 1.2): for 0.1N HCl, 8.5 ml of Hydrochloric acid (36.5% w/v) was diluted with sufficient water to produce 1000 ml. Take tablets Flagyl 400 mg formulation were weighed and placed in the baskets with 900 ml of 0.1N HCl was placed in each vessel and the apparatus was assembled. The operation in the gastric medium was carried out for 60 minutes. After 60 minutes, sample solution was withdrawn and filtered. The released drug was assayed by using UV spectrophotometer at 278 nm3. Procedure of dissolution method (B.P): Medium 0.1 N hydrochloric acid : 900 ml Apparatus 1 : 100 rpm Time 60 minutes Procedure Determine the amount of C6H9N303 dissolved from UV absorbance at wavelength of maximum absorbance at about 278 nm of filtered portions of solution under test, suitability diluted with 0.1 N HCl, in comparison with a standard solution having a known concentration of USP Metronidazole RS in the same medium. Tolerance Not less than 85 % (Q) of the labeled amount of C6H9N303 is dissolved in 60 minutes13. OUTCOMES AND DISCUSSION The drug rate of release is controlled by increase or decrease in the drug solubility and concentration of drug in matrix system. Also dissolution depends on the surrounding medium3. Food intake exerts a complex influence on the bioavailability of drugs. It may interfere not only with tablet disintegration, drug dissolution and drug transit through the gastrointestinal tract, but may also affect the metabolic transformation of drugs in the gastrointestinal wall and in the liver. Different food components can have different effects, and food may interact in opposite ways, even with drugs that are chemically related. Therefore, the net effect of food on drug bioavailability can be predicted only by direct clinical studies of the drug in question food and its components and contaminants may have both short and long term effects on both the absorptive and biotransformation processes influencing systemic availability of drugs15. In vitro dissolution study of this experiment subsequently completed in two different phases, the release rate of


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brand found relatively higher in gastric medium containing mango juice and after 60 minutes the Metronidazole release was increased in presence of mango juice is observed as compared to the water melon juice. The mean results of Metronidazole releasing rate of 60 minutes were MGF-01 (99.17%)MGF-02 (99.40%)MGF-03 (99.232%)MGF-04 (98.94%)MGF-05 (99.00%)MGF-06 (99.34%) in the gastric dissolution medium. Also in water melon juice medium samples were MWJ-01(97.60%), MWJ-02(97.72%), MWJ-03(97.72%), MWJ-04(97.31%), MWJ-05(97.25%), MWJ-06(97.48%) and in mango juice medium samples were MMJ-01(113.36%), MMJ-02(113.42%), MMJ-03(113.60%), MMJ-04(113.77%), MMJ-05(113.89%), and MMJ-06 (114.00%) (Table:7), All the requirements of metronidazole brand 400 mg tablet were fulfilled according to BP (in vitro dissolution specification within 60 minutes in acidic media), British pharmacopeia specifies that the results of dissolution of metronidazole tablets should not be less than 85% in 60 minutes. Metronidazole 400 mg tablet were fulfilling the specification in presence of water melon juice, mango juice and gastric fluid. After 1 hour, it is observed that Metronidazole 400 mg tablet released more

than 90% of drug in presence of water melon juice, mango juice and gastric fluid. Statistical analysis is conducted by using the test of one-way analysis of variance to investigate that is there any difference between the means of the three mediums in order to evaluate the difference between the dissolution of three mediums at mean levels. The results evaluate that p value is less than 0.05 which indicates that there is a significant mean difference between all of the three groups, further Post Hoc Turkeys test is applied to observe the differences between the means of the three medium in comparison, taking into account two groups separately one by one, the table 9 shows the significant mean difference of dissolution between gastric juice and mango juice, between gastric juice and water melon juice, and also between the mango juice and watermelon juice. Thus the hypothesis is rejected that dissolution in all three mediums i.e. gastric, mango and water melon juice is same because p values are less than 0.05 and there is significant difference between their means. It has been observed that mango juice was producing faster dissolution release of metronidazole as compared to the gastric and water melon juice in in vitro dissolution medium.

Table 1: Product detail, Flagyl 400 mg tablet (metronidazole)

S.NO Product detail 1 Company name Sanofi Aventis Pakistan limited 2 Generic name Metronidazole B.P 3 Mfg date 05- 2015 4 Exp.date 05-2019 5 Batch # WD290 6 Appearance Yellow coloured round biconvex shaped film coated tablet with 122 AV embossed on one side 7 Registration # 000827 8 Packaging 10 tablets in one blister PVC / printed aluminum foil with one side

Table 2: Parameters of dissolution test of metronidazole tablets (B.P)

Parameters Specification Dissolution medium

Mango juice Water melon juice Gastric medium

Volume of medium 900 ml(700:200 ,0.1 NHCl :Vehicles) Revolution per speed 100

Time Wavelength measurement

60 minutes 278 nm

Table 3: Observations from experiment: Standard absorbance values of metronidazole by UV spectrophotometer 14

STANDARD CODE # ABSORBANCE Metronidazole MZST-00 1.719

Table 4: Samples absorbance values of metronidazole by UV spectrophotometer 14

SN# MEDIUM MANGO JUICE CODE #

ABSORBANCE 0F SAMPLES

1 MMJ-01 1.949 2 MMJ-02 1.950 3 MMJ-03 1.953 4 MMJ-04 1.956 5 MMJ-05 1.958 6 MMJ-06 1.960 00 MZST-00 1.719

Table 5

SN# MEDIUM WATER MELLON JUICE CODE #

ABSORBANCE 0F SAMPLES

1 MWJ-01 1.678 2 MWJ-02 1.679 3 MWJ-03 1.680 4 MWJ-04 1.673 5 MWJ-05 1.672 6 MWJ-06 1.676 00 MZST-00 1.719


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Table 06 SN# MEDIUM GASTRIC FLUID

CODE # ABSORBANCE 0F SAMPLES

1 MGF-01 1.705 2 MGF-02 1.709 3 MGF-03 1.706 4 MGF-04 1.701 5 MGF-05 1.702 6 MGF-06 1.708 00 MZST-00 1.719

TABLE 7

MEDIUM CODE# ABSORBANCE % DISSOLVED AVERAGE OF % OFFICIAL LIMIT REMARKS Metronidazole

(Standard) MZST 1.719 100 ---- ------ -------

Mango Juice

MMJ-01 MMJ-02 MMJ-03 MMJ-04 MMJ-05 MMJ-06

1.949 1.950 1.953 1.956 1.958 1.960

113.36 113.42 113.600 113.77 113.89 114.00

113.67%

NLT 85 %

Pass

Water Melon juice

MWJ-01 MWJ-2 MWJ-03 MWJ-04 MWJ-05 MWJ-06

1.678 1.679 1.680 1.673 1.672 1.676

97.604 97.72 97.72 97.313 97.25 97.48

97.51%

NLT 85 %

Pass

Gastric fluid

MGF-01 MGF-02 MGF-03 MGF-04 MGF-05 MGF-06

1.705 1.709 1.706 1.701 1.702 1.708

99.17 99.407 99.232 98.94 99.00 99.34

99.18%

NLT 85 %

Pass

Table 8: ANOVA Dissolved

Sum of Squares df Mean Square F Sig. Between Groups 947.800 2 473.900 10084.748 .000 Within Groups .705 15 .047

Total 948.505 17

Table 9: Multiple Comparisons Dependent Variable: dissolved Tukey HSD

Dissolution mediums

Mean Difference (I-J)

Standard Error Sig. 95% Confidence Interval Lower Bound Upper Bound

Gastric juice Mango juice -14.49183* .12516 .000 -14.8169 -14.1667 Water melon juice 1.66700* .12516 .000 1.3419 1.9921

Mango juice Gastric juice 14.49183* .12516 .000 14.1667 14.8169 Water melon juice 16.15883* .12516 .000 15.8337 16.4839

Water melon juice Gastric juice -1.66700* .12516 .000 -1.9921 -1.3419 Mango juice -16.15883* .12516 .000 -16.4839 -15.8337

Figure 1: Molecular structure of metronidazole18


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Figure 2: Comparison of metronidazole % dissolution in different medium

Figure 3: Comparison of metronidazole absorbance in different medium

Figure 4: Comparative mean of absorbance

Figure 5: Comparative mean of dissolved metronidazole


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CONCLUSION Fraction of a dose of drug that is absorbed from its site of administration and reaches, in an unchanged form in to systemic circulation is a bioavailability When the drug is administered orally the bioavailability depends on physicochemical properties of the drug and its excipients that determine its dissolution in the intestinal lumen and its absorption across the intestinal wall, decomposition of the drug in the lumen, pH and perfusion of the small intestine, surface and time available for absorption, competing reactions in the lumen (for example of the drug with food) .In the pharmaceutical industry, drug dissolution testing is routinely used to provide critical in vitro drug release information for both quality control purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such as tablets, and drug development, i.e., to predict in vivo drug release profiles16. In vitro drug dissolution data generated from dissolution testing experiments can be related to in vivo pharmacokinetic data by means of in vitro-in vivo correlations (IVIVC). A well-established predictive IVIVC model can be very helpful for drug formulation design and post-approval manufacturing changes17. Analytical data from drug dissolution testing are sufficient in many cases to establish safety and efficacy of a drug product without in vivo tests, following minor formulation and manufacturing changes .Thus, the dissolution testing which is conducted in dissolution apparatus must be able to provide accurate and reproducible results.The brand Metronidazole film coated tablet 400 mg available in Pakistan revealed the satisfactory results in the presence of different juices (mango juice and water melon juice )and also met the official pharmacopeia limits. The mean is not same in all mediums thus, metronidazole 400 mg tablet were dissolved higher in mango juice with gastric medium as compared to water melon juice in gastric medium in 60 minutes. Therefore, mango juice gives faster beneficial effect of metronidazole 400 mg tablet and has started the rapid reaction as compared to water melon juice3. ACKNOWLEDGEMENTS We are obliged to the Pharmaceutical Research Technology Lab, Jinnah university for women Karachi Pakistan and Miss Saima Alam (Bio Engineer) from NED university and Technology for providing facilities and technical support3. REFERENCES 1 A Bendesky, D Menendez, Patricia Ostrosky-Wegman, Is metronidazole

carcinogenic? Mutation Research/Reviews in Mutation Research, 2002,511(2), Pages 133–144

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3 Asif, F. , Sultana, T. , Sohel, M. D. , Sumon, M. H. U. , Kawsar, M. H. , & Islam, M. A., In vitro dissolution pattern of metronidazole film coated tablet in presence of fruit juice. American Journal of Pharmacological Sciences, 2014, 2(2):32-36.

4 FP Tally, VL Sutter, SM Finegold, Metronidazole Versus Anaerobes—In Vitro Data and Initial Clinical Observations, Calif Med. 1972; 117(6): 22–26.

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7 Tomas Caro-Paton, Alfonso Carvajal , Isaac Martin de Diego, Luis H. Martin-Arias, Ana Alvarez Requejo and Elvira Rodríguez Pinilla, Is metronidazole teratogenic : a meta analysis, British journal of clinical pharmacology,1997, 44(2) :179–182, http://onlinelibrary.wiley.com /doi/10.1046/j.1365-2125.1997.00660.x/abstract

8 Jennifer B. Dressman, Gordon L. Amidon, Christos Reppas, Vinod P., Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms, Shah spring ,link Pharmaceutical Research , The American Association of Pharmaceutical Scientists ,1998, 15(1):11-22

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10 StylCraze, worlds best website for women health health beauty and wellness, Top 10 Best Benefits Of Mango Juice, http://www.stylecraze.com/articles/best-benefits-of-mango-juice/ (cited: 2015 Sep 30)

11 Best juicer reviews and rating juicer select.com, Watermelon juice the many health benefits of juicing watermelon http://www.juicerselect.com/watermelon-juice.html (cited: 2015 Oct 19)

12 Nirmala S, Subba Reddy V., A comparative study of pH modulation and trace elements of various fruit juices on enamel erosion: An in vitro study, J Indian Soc Pedod Prev Dent 2011;29:205-15.

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16 Bai, G., Wang, Y., Armenante, P. M., Velocity profiles and shear strain rate variability in the USP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds, International Journal of Pharmaceutics, 2011, 403 (1-2): 1-14.

17 Kortejarvi H, Malkki J, Marvola M, Urtti A, Yliperttula M, Pajunen P., "Level A In Vitro-In Vivo Correlation (IVIVC) Model with Bayesian Approach to Formulation Series". J Pharm Sci.2006, 95 (7):1595-1605.

18 M. Praveen Kumar, B. Mohammed Ishaq, J. Ravi Kumar Reddy, R. Pradeep Kumar, A. Badrinath, C. Madhusudana chetty, Formulation and evaluation of colon specific matrix and coated tablet of metronidazole, Int. Res. J. Pharm. 2011;2(9):194-199.

Cite this article as: Amber Nawab, Sidra Ghayas, Samina Alam, Najaf Farooq. Dissolution profile of metronidazole film coated tablet 400 mg (flagyl) in the presence of different juices: An In vitro study. Int. Res. J. Pharm. 2016;7(1):52-57 http://dx.doi.org/10.7897/2230-8407.0719

Source of support: Nil, Conflict of interest: None Declared

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