Investigation of the Interchangeability Between Cefuroxime Axetil Tablets Marketed in Palestine

Palestinian Medical and Pharmaceutical Journal (PMPJ). 2016; 1(1): 7-14

Investigation of the Interchangeability between Cefuroxime Axetil Tablets Marketed in Palestine. Is there A Quality Reason behind the Price? Naser Shraim*1, Abdel Naser Zaid1, Numan Malkieh2, Nidal Jaradat1, Sabreen Abdelhafez1, Osama Alqaryouti1, Ahlam Saleem1 1Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine. 2Jerusalem Pharmaceuticals Co. Ltd., Ramallah, Palestine *Corresponding author: [email protected] Received: (30/5/2016), Accepted: (1/9/2016)

ABSTRACT According to Food and Drug Administration (FDA), therapeutically equivalent antibiotics is expected to have equivalent clinical efficacy and safety when used under the conditions of their labeling. However, any defect in the quality of an antibiotic may negatively affect its efficacy and safety and accordingly are considered a substandard drug. Cefuroxime is a semi-synthetic, broad- spectrum cephalosporin antibiotic intended for oral administration. Any quality defect in this product may cause inefficacy and future bacterial resistance. The aim of this study was to evaluate the quality and cost price of all commercial Cefuroxime axetil tablet products available on the Palestin- ian market (One brand and two generic products). A survey on the price of all commercial tablet products was conducted. To assess quality, all products were examined visually for their general appearance. They were tested for weight uniformity, friability, disintegration, and dissolution profile, and assayed for Cefuroxime content. The original brand was more expensive than the two locally produced generic products. Based on our testing procedure, all Cefuroxime tablet products were equivalent to the brand product. Although, the two generic products released more than 85% of their Cefuroxime content within 15 minutes, while the brand released only 74.5%. These results demonstrate that generic Cefuroxime tablets produced by local manufacturers are often comparable in vitro to the brand product and have lower price. Accordingly, we encourage our physician to prescribe the local product since they may be interchangeable and have same safety and efficacy profile. Keywords: Cefuroxime Axetil, Tablet, Analysis, Interchangeability, Price.

INTRODUCTION Cefuroxime axetil is a second generation cephalosporin with a broad-spectrum antibac- terial activity intended for oral (PO) administration. It is (RS)-1-hydroxyethyl(6R,7R)- 7-[2-(2-glyoxylamido]-3-(hydroxymethyl)-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylate, 7-(Z)-(O-methyloxime), 1- acetate 3-carbamate (Fig. 1). Cefuroxime acts by interfering with the peptidoglycan synthesis of the bacterial cell wall resulting in inhibition of the final transpeptidation needed for the cross-links (1). It is effective against wide range of microbes including Figure (1): Chemical structure of cefuroxime Aerobic Gram-positive Microorganisms, axetil. Aerobic Gram-negative Microorganisms and Spirochetes (2) ”...... Investigation of the Interchangeability between“ ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ 8 Cefuroxime axetil has a good pharmaco- ucts. One of the most important problems kinetic behavior such that it is well absorbed that facing antibiotics is the growing re- from gastrointestinal (GI) tract and is rapidly sistance of microorganism due to the irra- hydrolyzed in the intestinal mucosa and tional use of these antibiotics or due to sub- blood to cefuroxime. Peak plasma concentra- standard quality of the produced dosage tion was reported to range between 2 to 3 forms containing antibiotics. Therefore, regu- hours after PO administration. With regards larly, investigations of the quality of medi- to its elimination manner, cefuroxime is ex- cines in the pharmaceutical market are cru- creted unchanged (about 95%) by glomerular cial. Such aspects may include the extent of filtration and renal tubular secretion with a availability of counterfeit pharmaceuticals in terminal elimination half-life of 1.5 hour (3). the local market and to what extent generics In addition, cefuroxime is widely distributed were comparable to the originator (branded) in the body fluids. It has the capacity to pass medicine. The quality of pharmaceutical through the placenta and is excreted with products might be assessed by visual exami- milk in lactating mother. Approximately, nation, quantitative and qualitative identifica- 33% of cefuroxime is bound to albumin (4). tion pharmacopoeial analysis. Ideally, analy- However, the pharmacokinetic data could be sis of pharmaceutical products starts during influenced by food administration. The extent manufacturing and continues after registra- of cefuroxime systemic absorption is en- tion and marketing. However, only few coun- hanced when taken with food as its absolute tries have regulatory authorities that analyze bioavailability rises to reach approximately pharmaceutical products before and after reg- 50%. istration (8). Nevertheless, Finn and co-workers The quality of oral tablets and other drug demonstrated that despite this alteration in dosage forms must be built in during differ- absorption, the clinical effects and antibacte- ent stages of production, testing, storage and rial activity were not affected by food intake distribution (9). However, the quality of end at the time of tablet administration (5). Likely product is not guaranteed. The essential qual- to other antibiotics, cefuroxime may interfere ities of good compressed tablet are character- with oral contraceptive efficacy because of ized by a number of specifications. These decreases estrogen re-absorption (6). Alt- include the appearance, size, shape, thick- hough the desired therapeutic effect that Ce- ness, weight, homogeneity, stability, hard- furoxime gives as antibiotic, it like other ness, dissolution time, and disintegration medicines causes some side effects such as time. All such qualities are designed to en- diarrhea , feeling or being sick, stomachache, sure a safe, therapeutically, effective oral headache, dizziness and penicillin allergic solid dosage form. Official QC tests for tab- patients have a 5% to 10% incidence to have lets or Compendial tests (i.e., pharmacopeial) a cross-hypersensitivity reaction to include; uniformity of content of the API cephalosporins (7). Cefuroxime axetil is (i.e., Uniformity of weight & Content uni- marketed in Palestine under three trade formity), disintegration test, dissolution test names (Zinnat®, Zinex® and Zinaxim®). and friability test. It is formulated either as an oral solid However, there are other tests that are dosage form such as film-coated tablets con- frequently applied to tablets for which there taining 250 or 500 mg of Cefuroxime or as are non-pharmacopoeial requirements but oral suspension containing 125, 250 mg of will form a part of manufacture's owner the same API. During the development of product specifications. These non- generic dosage forms, pharmaceutical scien- compendial tests include color, shape, tablet tists play an important role in the selection of thickness, tablet hardness and tablet volume. excipients and manufacturing process. In Accordingly, this study was conducted in fact, these two factors have huge impact on order to evaluate the quality of commercially the final quality and therapeutic outcomes of Cefuroxime axetil tablet products available the obtained products. Wrong selection of on the Palestinian market and to assess if these factors will result in substandard prod- there any justification for their market price.

Manufacturing Physical appear- Price Product Classification date (Expiration ance USD /10tablets period) Oblong biconvex March 2016 (3 A Local 10.5 caplet shape years) Oblong biconvex March 2016 (3 B Local 10.5 caplet shape years) C Oblong biconvex March 2016 (3 Imported (brand) 14 (reference) caplet shape years)

strength or hardness (N) using a hardness Methods and instrumentations tester (Erweka TB24, Germany). For the pur- All methods used to determine the quali- pose of determination of the volume of each ty of the tablet products were conducted ac- product, the displacement method was used. cording to the United State Pharmacopeia A 25-mL calibrated graduated cylinder in 0.1 (10). All tests were performed within product mL divisions was employed using a silicon expiry dates. Before starting the study, the oil as a soaking solvent. Five tablets of each Palestinian Medicines Index (PMI) and the of the tested product were immersed and the Israeli Medical Index (MEDIC, 2013 edition) observed change in oil level was obtained, were consulted to determine the brands afterwards, the average volume was calculat- which are currently available on the Palestin- ed. ian market. Uniformity of dosage unites was Tablet disintegration time was also as- assessed according to the following proce- sessed, the test accomplished by introducing dure: a set of 10 tablets was chosen randomly 6 tablets into the tubes of the rack assembly and weighed individually using high sensitiv- of a disintegration tester (Erweka ZT 320, ity analytical balance (Erweka, Germany). Germany). The assembly was suspended in The weight variation was assessed by weigh- 1000 mL simulated gastric fluid (SGF) pH ing 20 tablets individually for all of the tested 1.2 maintained at 37◦C and the apparatus was products. The average weight and the stand- operated for a specified time until no frag- ard deviation were determined and the per- ments of un-dissolved tablets observed on the centage deviation from the mean of each tab- sieve of the apparatus. The device was set for let was calculated. The USP acceptance crite- raising and lowering in the basket in the im- ria for weight variation test is “Not more than mersion fluid at constant frequency rate be- two of the individual weights deviates from tween 29 and 32 cycles per minute. Drug re- the average weight by more than 5% and lease studies were performed according to the none deviates by more than 10%. Hardness USP apparatus II paddle method using a dis- test was performed on 10 tablets by simulta- solution apparatus (Erewka, Heusenstamm, neously measuring the thickness (mm), Germany). The paddles were rotated at 55 length (mm), width (mm) and crunching Palestinian Medical and Pharmaceutical Journal (PMPJ). 2016; 1(1): 7-14 ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ ”...... Investigation of the Interchangeability between“ ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ 10 rpm and the temperature was kept at 37 ± 0.5 of 1.5 ml/min. Percentage content of the re- ◦C. Dissolution vessels were filled with 900 lated substances calculated from the areas of mL of SGF. All SGF was prepared using the peaks in the chromatogram by the nor- 0.07 N hydrochloric acid. Samples were malization procedure. withdrawn at 15 and 45 minutes, filtered, RESULTS diluted as appropriate and measured at 278 nm using Ultra violet (UV) Spectrophotome- Only three different commercial prod- ter (Shimadzu UV 1700). ucts of Ceferuxime tablets (500 mg/tablet) are available on the Palestinian pharmaceuti- All chromatographic experiments were cal market (two locals and one brand). They performed using a High performance liquid were classified into brand and locally pro- chromatography (HPLC) system (Dionex - duced products and they were analysed for UltiMate 3000 LC System, USA) consisting price to public. The results showed that both of a pump, auto-sampler injector and a UV local products had same cost price and was detector. All LC parts were controlled by approximately 33% less expensive than the Chromeleon® version 6.80 (Dionex). Separa- original brand (Table 1). This may raise a tions were done on a reversed phase column question about the quality of these products using the LC method described earlier in ac- and if the can be interchangeable or not. cordance to the USP procedures (10); the method provided a quantitative determination In fact, according to FDA, products of the content of Cefuroxime axetil as API in evaluated as therapeutically equivalent can the tested medicines. However, a brief de- be expected to have equivalent clinical effi- scription for standard preparation was shown cacy and safety when used under the condi- here; “Transfer about 30 mg of Cefuroxime tions of their labeling. However, these prod- axetil to a 25 mL volumetric flask, dissolve ucts may differ in the following characteris- in methanol, dilute with Methanol to volume, tics: shape, scoring configuration, release and mix. Promptly transfer 10.0 mL of this mechanisms, packaging, excipients (includ- solution to a 50 mL volumetric flask and then ing colors, flavors, and preservatives), expi- dilute with 0.2 M MAP to volume, and mix”. ration date/time, and, sometimes may have The area under the peak (AUP) from the different labels. Therefore, if these products chromatogram was obtained for this standard are substituted, there is a potential for patient solution and then was used to determine the confusion due to differences in color or shape content of Cefuroxime in the tablets. of tablets. Moreover, inability to provide a given dose using a partial tablet if the proper Related substances examined in accord- scoring configuration is not available, or de- ance to British Pharmacopeia (BP) (11) in creased patient acceptance of certain prod- which the LC method used as described un- ucts because of flavor or taste. There may der assay. The method was performed by also be better stability of one product over preparing test solution to dissolve tablet sub- another under adverse storage conditions, or stance equivalent to 10 mg of cefuroxime allergic reactions in rare cases due to a color- axetil in to the mobile phase and dilute to 50 ing or a preservative ingredient, as well as ml with the mobile phase. Reference solution differences in cost to the patient (12). (1) prepared by diluting 1 ml of test solution to 100 ml with the mobile phase, for refer- Accordingly, visual quality was used to ence solution (2) heat 5 ml of test solution at examine and to evaluate the organoleptic 60° for 1 h to generate the ∆3-isomers and properties due to the impact of these proper- for reference solution (3) expose 5 ml of test ties on patient compliance. The appearance solution to ultraviolet light at 254 nm for 24 of tablets of the selected brands was elegant h to generate E-isomers. Reference solution and their color, size, texture were consistent (4) prepared by dissolving 10 mg of cefurox- with no sign of defects in all tested tablets. In ime axetil in the mobile phase and dilute to fact, no one of the tested commercial prod- 50 ml with the mobile phase. Inject 20 µl ucts had one of the above advantages on the each of reference solutions (1-4) and chroma- other. tograms recorded at 278 nm with a flow rate

Average Estimated Tablet Thickness Length Width Product weight ± (mg) Volume hardness (mm) (mm) (mm) RSD% (cc) mean ± SD A 937.4 ± 2.56 6.77 ± 0.08 19.11 ± 0.02 9.14 ± 0.06 0.95 16.10 ± 3.50 B 1247.3 ± 0.82 8.14 ± 0.02 20.31 ± 0.22 9.78 ± 0.08 0.95 19.18 ± 0.85 C 912.2 ± 1.32 5.78 ± 1.3 19.63 ± 0.01 8.31 ± 0.03 0.87 23.51 ± 1.20 was determined at 2 time points particularly, Tablet hardness, tablet thickness and 15 and 45 minutes according to the USP length results of the different tested products monograph. The test was performed using were also assessed and our findings were re- dissolution apparatus II as described earlier. ported in Table 2. The size of the tablet was The result showed that all products passed estimated to assess swallowing problems this test in the first stage of dissolution test- which represents a persistent challenge espe- ing. The USP acceptance criteria of tablets cially in elderly individuals and patients who labeled to contain the equivalent of 500 mg have dysfagia or have experienced an oe- cefuroxime state that “Tolerances: not less sophageal ulceration after tablet or capsule than 50% (Q) of the labeled amount is dis- swallowing. The time required for complete solved in 15 minutes and not less than 70% disintegration of all tablets containing Ce- (Q) is dissolved in 45 minutes”. Where, Q, is furoxime (500 mg) was tested according to the amount of dissolved active ingredient the pharmacopeial guidelines. The results specified in the individual monograph, ex- demonstrated that time for disintegration of pressed as a percentage of the labeled con- both formulations A and C was about 1 mi- tents. The percentages of drug release in all nute. However, the time needed to disinte- examined units were more than 55 and 75% grate product B was about 2 minutes. The at 15 and 45 minutes respectively (Table 3). percentage of dissolved CA in each product Table (3): Dissolution and disintegration time results of all Cefuroxime axetil tablets on the Pales- tine market.

Dissolution Disintegration time Product Average % of dissolved CA USP Limit (NMT 15 min) 15 min. 45 min. A 1 74.5 ± 5.5 91.8 ± 4.6 B 2 88.0 ± 3.1 100. 1 ± 1.5 C 1 93.15 ± 1.6 96.18 ± 2.2 specifies a range of 90 -110% of the stated The amount of Cefuroxime in each tablet amount of Cefuroxime tablets. Accordingly of the examined pharmaceuticals was determined using the HPLC method. The estimat- all of the tested tablets were complies with ed percentages per labels, from the assay, the USP specifications. In addition, the ob- together with their relevant statistical analy- tained results pertaining related substances sis, are shown in Table 4. The USP 2014 were summarized in Table 4.

Palestinian Medical and Pharmaceutical Journal (PMPJ). 2016; 1(1): 7-14 ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ ”...... Investigation of the Interchangeability between“ ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ 12 Our findings suggest that all of the tested shows a representative chromatogram of re- products met the pharmacopoeial specifica- lated substances test under the chromato- tions regarding related substances. Figure 2 graphic conditions explained earlier. Table (4): Assay and related substances results of the tested products with their statistical parameters.

Average Assay Related substances (%) Product (%) ± SD (n = E 1 enantio- E 2 enantio- Other impuri- ∆3-isomer 10) mer mer ties Pharmacopeial 90-110% NMT 2.0% Sum NMT 1.5% NMT 1.0% limit A 98.51±0.52 0.9 0.2 0.1 0.49 B 98.57±0.44 0.9 0.1 0.1 0.16 C 97.38±0.91 1.3 0.0 0.0 0.1

Figure (2): obtained chromatogram for related substances test. DISCUSSION pharmacopeial and non-pharmacopeial Palestine relies under the Israel occupa- standards in order to identify if these prod- tion and this impact negatively on many as- ucts could be interchangeable. pect of Palestinian occupation, especially the Quality control tests and specifications economic side. In fact, Palestine is consid- for some of the experimental part of the cur- ered a low income country. However, many rent study are given in pharmacopoeia. The patients try to not save many when the issue most important for these are; weight uni- is related to medication. According to local formity, the drug release in terms of tablet community pharmacists and physicians, pa- disintegration and drug dissolution, re- tients usually prefer imported drugs since sistance of tablets to fracture in terms of fria- they believe that these products have superior bility and hardness testing of the product. therapeutic effect and safety than the locally Previous studies have shown alarming seri- produced products. Many of these patients ous levels of substandard medicines in some can pay a higher price for brand products Arab and developing countries (8, 13-15). despite the poor economic circumstances of Indeed, the major aim of the research project many of them. Many of care providers also was to investigate if the local medicines are have this belief and sometimes encourage comparable with the imported products and patients to buy the brand products. The ob- hence, their interchangeability may be grant- jective of this study was to survey Cefurox- ed. The Palestinian Ministry of Health ime tablet products available on the Palestin- (MOH) and the Department of Drug Control ian pharmaceutical market according to their and Registration (DDCR) are the regulatory price and to assess their quality according to authorities that grant marketing authorization for branded and generic drug products. Ac- cording to the current regulation (16), a

ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ Palestinian Medical and Pharmaceutical Journal (PMPJ). 2016; 1(1): 7-14 13 ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ .Naser Shraim, et al product has to satisfy the compendial re- of side effects. However, today regulatory quirements for safety, purity and quality ac- agencies like the FDA and the EMEA allow cording to either the USP or the British the replacement (waiver) of in vivo Pharmacopeia (BP). Additionally, a bioe- bioequivelence studies by in vitro dissolution quivalence study is required to show that the testing especially for class 2 drugs (highly generic is bioequivalent to the brand name soluble, highly permeable. Accordingly the drug according to the USA Food and Drug in vitro dissolution test is used to predict the Administration (FDA) and the European in vivo absorption of the drug product, by Medicines Agency (EMEA) (17, 18). The means of in vivo/in vitro correlations Palestinian regulatory authorities recognize (IVIVC). The dissolution of the drug from and accept properly conducted studies per- oral solid dosage forms is essential for drug formed in vitro to support in vivo data (19). bioavailability, especially for slightly water The result showed low price (one third less) soluble drugs such Cefuroxime. For this rea- of Cefuroxime local product comparable the son, dissolution studies can give an idea of original brand. In fact the cost of original the amount of drug available for absorption brand exceeds the local products about 4 after oral administration (19, 20). Drugs with USD for each box of course therapy. This poor dissolution profiles will not be suffi- large price represents a negative impact on ciently available in the body system to pro- the economical situation of both patients and duce the desired therapeutic response (21). Palestinian MOH. A visual QC examination The dissolution profiles of all tested brands was carried on all Cefuroxime tablet selected were performed in Simulated gastric Fluid in this study for the purpose of evaluating (SGF) and they were found to be comparable. their organoliptic properties (i.e., shape, size, More precisely the average release of ce- color, texture and presence of black spots). In furoxime in SGF from the local was greater fact, these parameters play a very important than 85% after 15 minutes while the brand role in patient’s acceptance or compliance released about 74.5 % of its content after toward any dosage form. With regard to tab- same time and both local showed almost bet- let strength, all the tested products passed the ter drug release after 45 minutes than the friability test demonstrating that these prod- original bran which may encourage us to ucts do not lose Cefuroxime during the trans- conclude that the quality of these two local portation or handling process. However, high products are of high standard. tablet strength should not compromise disin- CONCLUSION tegration in the stomach. The obtained results indicated that all of Besides, the tablet size may be associat- the examined products were in accordance ed with swallowing problems. In fact, the with the pharmacopeial specifications. The drug induced oesophageal ulceration is a se- local products showed little significant dif- rious problem and is due to a delay in the ferences compared to the original brand. passage of the tablet or capsule because of However, the price of the brand is higher their sticking in the oesophagus. Indeed, sev- than the locally produced generics. Our find- eral recommendations were proposed to ings signify that generic Cefuroxime tablets avoid this problem. Among these recommen- produced by local manufacturers are often dations; the use of a low size tablets or cap- comparable in vitro to the innovator product sules, taking appropriate body posture and (even have better drug release) and have drink at least 100 mL of water or other ap- lower costs. According to the above men- propriate carrier. tioned findings, the local pharmaceutical Concerning dissolution, this test is used products containing cefuroxime axetil as a tool in order to ensure products quality showed comparable in vitro testing with the and batch to batch variability. It is also used originator. Hence, we should take in our con- as an alternative tool for the assessment of in sideration that the national pharmaceutical vivo bioequivalence. In vivo bioequivlence industry need care-providers and inhabitants studies are conducted in healthy volunteers. to be confident in their products, since they These studies are costly, time consuming and showed high quality standard with about 33% involve subjecting healthy volunteers to risks save on the cost of each product. Palestinian Medical and Pharmaceutical Journal (PMPJ). 2016; 1(1): 7-14 ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ ”...... Investigation of the Interchangeability between“ ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ 14 ACKNOWLEDGEMENTS 12) FDA. Orange Book: Approved Drug The authors would like to acknowledge Products with Therapeutic Equivalence Birzeit Pharmaceutical Company (BPC) for Evaluations. 2015; Available from: their assistance. http://www.fda.gov/Drugs/DevelopmentAp CONFLICT OF INTERESTS provalProcess/ucm079068.htm. The authors report no conflicts of inter- 13) Shakoor O, Taylor RB, Behrens RH. est in this manuscript. Assessment of the incidence of substandard drugs in developing countries. Tropical REFERENCES medicine & international health : TM & 1) Neu HC. The new beta-lactamase-stable IH. 1997; 2(9): 839-45. Epub 1997/10/07. cephalosporins. Annals of Internal 14) Taylor RB, Shakoor O, Behrens RH, Medicine. 1982; 97(3): 408-19. Everard M, Low AS, Wangboonskul J, et 2) Ballantyne FN. Comparative efficacy of al. Pharmacopoeial quality of drugs cefadroxil and cefaclor in the treatment of supplied by Nigerian pharmacies. Lancet. skin and soft-tissue infections. Clinical 2001;357(9272): 1933-6. 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