Professional Documents
Culture Documents
Keywords
In Vitro Equivalence,
Cefuroxime Axetil,
Biowaiver,
Dissolution.
ABSTRACT
World Health Organization (WHO) recommends biowaivers for immediate-release solid oral
products employing dissolution testing as a surrogate for in vivo bioequivalence studies.
Cefuroxime is a semi-synthetic antibiotic belonging to the cephalosporin group. The drug is
poorly soluble in water. In the present investigation, the in vitro equivalence of tablets
containing cefuroxime axetil , for commercially available in Ras AlKhaimha, UAE under
biowaiver conditions and the innovator product, was conducted. The dissolution profiles of
cefuroxime axetil products were determined using the USP dissolution paddle method. Both
products are rapidly dissolving, but they do not meet the criteria for dissolution profile
similarity, f1 and f2. This may be attributed to the formulation variations between the two
products. Therefore, in vivo bioequivalence studies are required to ascertain therapeutic
equivalence. Assessment of different generic products available in the market is very
important to ensure that generic drugs being sold can be used interchangeably with the
branded products.
Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
www.iajpr.com
Page
Please cite this article in press as Omar Sarheed et al. In Vitro Equivalence Studies of Commercially Available Cefuroxime Axetil
Tablets Under Biowaiver Conditions. Indo American Journal of Pharm Research.2014:4(12).
5644
Corresponding author
Omar Sarheed
RAK Medical & Health Sciences University,
Ras Al Khaimah, UAE.
sarheed@rakmhsu.ac.ae
INTRODUCTION
Cefuroxime is an oral semi-synthetic antibiotic and the first commercially-available second-generation cephalosporin to be
widely used in therapy (1). Cefuroxime axetil is the acetoxyethyl ester prodrug of cefuroxime as shown in Figure 1. It has proven in
vitro antibacterial activity against several gram-positive and gram-negative organisms (2).
The World Health Organization (WHO) has promoted the use of generic drugs in order to make the cost of medicines
affordable especially for the developing countries (3). A generic drug is defined as pharmaceutical product,, that is manufactured
without a license from the innovator company and marketed after the expiry date of the patent. It is usually intended to be
interchangeable with an innovator product when they are pharmaceutically and therapeutically equivalent (4).
Bioequivalence (BE) studies are commonly used to assess therapeutic equivalence. They involved many methods such as
pharmacokinetics (PK) studies and pharmacodynamics (PD) studies. However, these studies are often costly and require human
volunteers. Alternatively, the Biopharmaceutics Classification System (BCS) can be used for biowaivers which is the absence clinical
bioequivalence testing in humans.
Cefuroxime axetil is class II drug according Biopharmaceutics Classification System (BCS) and has a poor aqueous
solubility. Cefuroxime is a weak acid with pKa of 2.5 (5).
The number of generic drug products registered in the United Arab Emirates is increasing day by day. Those products are
used interchangeably. So to ensure the quality of the products, equivalence studies are necessary to evaluate the quality of different
formulations available in the market. There are no reports on the in vitro equivalence for cefuroxime axetil in the United Arab
Emirates.
The aim of this work was to investigate if there are any differences between various commercially available cefuroxime
axetil tablets through the evaluation of in vitro dissolution profiles. Two brands of immediate-release solid dosage form cefuroxime
axetil tablets were obtained from pharmacies in Ras AlKhaimah, United Arab Emirates for this study. The selection based on survey.
www.iajpr.com
Page
5645
Dissolution Testing
In vitro dissolution was carried out via USP Apparatus 2,paddle type (Copley, UK) at a speed of 55 rpm in 900 mL of the
dissolution media USP mentioned in above and maintained at 37 0.5 C using a water bath fitted with a variable speed stirrer and
heater (Erweka DT 600, Frankfurt, Germany). The selection of paddle rotation speed is based on the dissolution method of cefuroxime
axetil in the United States Pharmacopoeia (6).
Samples of 5 mL were taken manually at 5, 10, 20, 30, 45 and 60 min and replaced with an equal volume of fresh medium to
maintain a constant dissolution volume. The samples were filtered with 0.8 micrometer syringe filter, and the absorbance was
measured at 278 nm using a UV spectrophotometer (Shimadzus UV-1800 spectrophotometer). Each profile is the average of six
individual tablets.
Data Analysis
Drug release data had been analyzed using model-independent approaches which was proposed by Moore and Flanner (7). It
is the simplest mathematical model to compare the dissolution profile using two factors, f1 and f2 and provides a single number to
describe the comparison of dissolution profile data. This approach is endorsed by the FDA and the European Agency for Evaluation of
Medicinal Products (EMEA) as criteria for assessment of similarity between two dissolution profiles.
Fit Factors
According the FDA (8), the difference factor (f1) calculates the percent (%) difference between the two curves at each time point
and is a measurement of the relative error between the two curves:
The compared dissolution curves are considered similar and bioequivalent, if f1 is between 0 and 15.
Whereas the similarity factor (f2) is defined as a logarithmic reciprocal square root transformation of the sum of squared error and
is a measurement of the similarity in the percent (%) dissolution between the two curves.
where Rt and Tt are the cumulative percentage dissolved at each of the selected n time points of the reference and test product
respectively and n is the number of time points. Values of 50 or above (50100) ensure similarity (difference 10%) of the curves.
Page
5646
Statistical Analysis
Results are expressed as mean S.D. for replicate samples. The statistically significant difference among the groups was
determined by one-way analysis of variance (ANOVA) using statistical software (Version 17; Minitab Inc., Coventry, UK). Statistical
significance was considered at a level of p < 0.05.
www.iajpr.com
Evaluated Product
1, 2
1, 2
1, 2
1
1
1
1
1
1
1
2
2
2
2
Medium
pH 6.8
Reference Product
% dissolved % dissolved
( ) 20 min
( ) 30 min
85.5
87.8
Test Product
% dissolved % dissolved
( ) 20 min
( ) 30 min
88.7
91.3
pH 6.8
Test Product
% dissolved
( )
66.4
85.8
93.3
93.8
93.2
93.6
61.0
79.4
90.0
92.3
91.2
91.0
60.9
76.1
88.7
91.3
90.0
89.6
RSD
(%)
6.8
10.0
7.9
8.2
9.3
6.8
6.2
4.1
3.2
4.2
3.4
3.0
8.3
7.0
5.0
4.0
4.1
4.3
Dissolution at pH 1.2
Dissolution profile at pH 1.2, 4.5 and 6.8 is shown in Figures 2-4.
Figure 2 shows the comparative dissolution profile of the reference and the test products at pH 1.2. Both the reference and the
test products were rapidly dissolved as shown in Table 3.However the products are not similar (f2 = 44 and f1 = 16).Based on fit factors
method as they are not fulfilling the FDA criteria which requires the f1 values up to 15 and f2 values greater than 50 to ensure
equivalence of the dissolution curves. This dissimilarity might be attributed to the amount of SLS present in the products. The
difference in the types of excipients used in the formation may play role in the dissimilarity between the two products. However, such
difference between the reference and the test products may not necessarily lead to in vivo bioinequivalence especially for class II drugs
such cefuroxime axetil where the drug permeability is high (11,12).
www.iajpr.com
5647
pH 4.5
Time (min)
5
10
20
30
45
60
5
10
20
30
45
60
5
10
20
30
45
60
RSD
(%)
2.7
6.1
7.0
7.0
6.6
8.5
3.0
2.6
3.1
3.7
3.4
4.2
5.8
3.2
2.6
3.6
3.3
4.2
Page
Medium
pH 1.2
Reference Product
% dissolved
( )
48.0
65.9
81.8
86.5
87.8
88.4
55.3
72.0
86.0
89.7
90.8
90.5
51.1
69.3
85.5
87.8
89.3
87.6
The dissolution method validity is confirmed by the calculation of the relative standard deviation for all time points fulfilling
all requirements (20% for first time point, 10% for other time points).
Page
5648
www.iajpr.com
www.iajpr.com
Page
REFERENCES
1. Dellamonica P., Cefuroxime axetil, International J Antimicrobial Agents, 1994; 4:1:23-36.
2. Scott LJ., Ormrod D., Goa KL., Cefuroxime axetil: an updated review of its use in the management of bacterial infections, Drugs,
2001:61:10:1455-500.
3. WHO, author. World Health Organization medicines strategy; countries at the core 20042007. 2004. p. 68.
http://libdoc.who.int/hq/2004/WHO. (2 Nov.2014).
4. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Proposal to waive in vivo bioequivalence
requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms; WHO Technical Report
Series,
No.
937,
Annex
7;
World
Health
Organization:
Geneva,
Switzerland,
2006.
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf. (2 Nov.2014).
5. Nau R, Srgel F, Eiffert H., Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central
nervous system infections, Clin Microbiol Rev, 2010: 23:4:858-83.
6. United States Pharmacopeia and National Formulary USP 29NF 24; The United States Pharmacopeial Convention, Inc.:
Rockville, MD, 2006.
7. Moore JW, Flanner HH., Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles, Pharm. Tech.,
1996: 20: 6: 64-74.
8. FDA Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. U.S. Department of Health and
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), U.S. Government Printing
Office: Washington, DC, 1997.
9. WHO Expert Committee on Specifications for Pharmaceutical Preparations. WHO Technical Report Series, No. 937, Annex 8.
Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral
dosage forms; World Health Organization: Geneva, Switzerland, 2006.
10. Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, Conner DP, Shah VP, Lesko LJ, Chen ML, Lee VH, Hussain AS.,
Biopharmaceutics classification system: the scientific basis for biowaiver extensions, Pharm Res., 2002:19: 7:921-5.
5649
ACKNOWLEDGMENT
The authors express their gratitude to the Vice Chancellor of RAK Medical & Health Sciences University and the Dean of
RAK College of Pharmaceutical Sciences for the encouragement and facilities provided. The authors also would like to thank Mr.
Mohammad Quamrul Islam, Mohammed Bassam Shehada, Mohammed Sariah Haroosh Mossa and Noor Anwar Al Halabi for their
assistance.
11. Shohin IE., Kulinich JI., Ramenskaya GV., Vasilenko GF., Evaluation of in vitro equivalence for drugs containing BCS class II
compound ketoprofen, Dissolution Technologies, 2002: 17: 1: 26-29.
12. Prajapati S., Gamit A., Patel A., Solanki J., Kyada C, Dissolution technology in pharmaceutical science, Indo American Journal
of Pharmaceutical Research, 2013:3:4:3535-3564.
Page
5650
54878478451141151
www.iajpr.com