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Abstract
The present thesis is concerned with spectrophotometric and HPLC Ilalysis of cefepime in its pure form, dosage form and biological fluids. Also, it concerned with the clinical application of the developed HPLC method in goat. The thesis comprises 4 main parts:
It is an introductory part which includes general introduction about cephalosporins and the studied drug which is cefepime. The introduction shows the structure, chemical and physical properties, stability and medicinal importance of cefepime.
The introduction also includes a literature reVIew of the official and reported analytical methods used for the determination of cefepime.
It also comprises the scope of research.
Part 11: Spectrophotometric analysis of cefepime.
This part includes a preliminary spectroscopic investigation of the complexation behaviour of cefepime with different metal salts and selecting the most proper metal ion to be used as a complexing agent. Also, this part comprises a spectrophotometric determination of cefepime depending on the complexation of cefepime with Hg2(N03)2 in acid medium (pH 3.5) and measuring the absorbance intensity of the solution at 263 nm.
All reaction variables affecting the reaction conditions such as; the type, pH and ionic strength of the buffer solution, Hg2(N03)2 concentration, order of addition, reaction time, diluting solvent and stability time have been studied to optimize the conditions.
The molar ratio of the formed complex was determined by Yoe and Jones method and was found to be 1:2 ratio for cefepime:Hg(I) and the different probabilities of the formed complexes were suggested.
Also the effect of the interferences from the co-formulated compound which L-arginine and the main degradation product, NMP were investigated.
A validation study of the proposed method was carried out according to the SP XXXI (2008) and ICH- validation guidelines. Beer’s law was obeyed in the ncentration range of 3.65 - 40 Jlg mr!. The detection limit was 1.20 Jlg mr! while the quantitation limit was 3.65 Jlg mr!.
The developed method can be successfully applied for the analysis of eefepime in its pure form and its commercial vial. The results obtained were validated by comparison with those obtained from the official method by means oft• and F- tests at 95 % confidence limit. No significant difference was found indicating good accuracy and precision of the proposed method.
Part Ill: HPLC analysis of cefepime via its Hg(l)-complex.
This part contains an HPLC method for the determination of cefepime through its Hg(l) complex. Precolumn derivatization technique was adopted.
All reaction variables affecting the reaction conditions such as; % of organic modifier, cation type, pH and ionic strength of the buffer solution, flow rate, Hg2(N03)2 concentration and type of IS have been studied to optimize the
A validation study of the proposed method was carried out according to the USP XXXI (2008) and ICH- validation guidelines. Beer’s law was obeyed in the concentration range of 1.32-20 Jlg mr). The detection limit was 0.43 Jlg mr) while the quantitation limit was 1.32 Jlg mr).
The method was successfully applied for the analysis of cefepime in its pure form and its commercial vial. Results were compared with those obtained from the official method. The t- and F - values were calculated and compared with the theoretical values, indicating high accuracy and good precision of the proposed procedures. The assay results obtained by the proposed procedure were
unaffected by the presence of L-arginine as shown by the excellent recoveries obtained when analysing cefepime in presence of L-arginine in the vial.
The specificity of the method was checked by studying the interference from other drugs that could be co-administered or from other j3-lactams. It was found that the drugs tested either had retention times different from cefepime and
cefuroxime Na (IS) or were not detected. So the method was considered specific.
The high sensitivity attained by the proposed HPLC method allowed detennination of cefepime in biological fluids. The proposed method was applied for determination of cefepime in spiked goat plasma and milk.
Different extraction techniques for plasma and milk were investigated and 2 different extraction techniques were validated and employed for plasma and milk, based on the different physical and chemical properties of each biological fluid.
Excellent recoveries were obtained at 3 concentration levels (3 replicates of each concentration) in both plasma and milk with no significant interference from endogenous compounds.
The developed method has been proofed to be a stability indicating assay and could be used for determination of cefepime in presence of its degradation products.
Part IV: Pharmacokinetic study of cefepime in goat plasma & milk.
This part comprises a clinical application of the developed HPLC method for determination of the pharmacokinetics of cefepime in goat plasma and milk after a single i.m. dose of 50 mg/kg body weight. The administered dose was followed by a 12-h collection period to characterize the single-dose phannacokinetics of cefepime.
Based on the measured concentrations of cefepime in goats’ plasma and milk, individual concentration-time profiles following single i.m. injection of 50 mg cefepime/kg body weight were constructed.
Both cefepime plasma and milk concentration versus time data after i.m. inistration were best fitted to a one-compartment model with first-order absorption and elimination.
Pharmacokinetics of cefepime given by i.m. injection in goat was close to those in man. The terminal half lives are similar (human: 2.2 h; goat: 1.80 h), as in the case for clearance values (human: 1.86 ml min-1 per kg; goat: 1.91 ml min-1
from the results and considering other studied animal species (rabbit, dog, monkey, micro-pig, horse, foal, dog and calves), goat is an adequate species and a reliable model for the study of pharmacokinetics of cefepime.
The thesis lies in 134 pages and contains 29 figures, 19 tables, 5 equations and 128 references listed as they are mentioned in the text.