91 .Creative Commons Attribution 4.0 International License This work is licensed under a A Subject Review on Some Analytical Methods for Determination of Fosfomycin Drugs Abstract Medicines comprising fosfomycin are prescribed for urinary tract infections. These drugs are available for oral use as tromethamine and calcium, while fosfomycin-sodium and disodium are given for intravenous (IV) and intramuscular (IM). Many quantitative analytical methods have been reported to estimate Fosfomycin in blood, urine, plasma, serum, and pharmaceutical dosage formulations. Some techniques were spectrophotometric, mass spectrometry, gas chromatography, high-performance liquid chromatography, and electrochemical methods. Here we perform a rapid narrative review that discusses and comparison between them of various analytical methods for the determination of Fosfomycin- containing drugs. Keywords: Review, Fosfomycin, Drugs, Medicines. 1. Introduction Fosfomycin (Fig.1) is a broad-spectrum antibiotic that inhibits the phosphoenol pyruvate transferase enzyme involved in the synthesis of peptidoglycan (found in the cell wall of Gram- positive and negative bacteria)[1,2]. S. aureus, staphylococci, penicillin-resistant S. pneumonia, Enterococcus species, Escherichia coli (E. coli), Klebsiella pneumonia, Citrobacter, and N. meningitides are often referred to as meningococcus, in addition to Ibn Al-Haitham Journal for Pure and Applied Sciences http://jih.uobaghdad.edu.iq/index.php/j/index: Journal homepage Doi: 10.30526/35.3.2826 Article history: Received 13 March 2022, Accepted 3 April 2022, Published in July 2022. Ali Khalil Mahmood Department of Chemistry, College of Education for Pure Science / Ibn Al- Haitham, University of Baghdad, Iraq. ali.khalil.mahmood@gmail.com Khalid Waleed S. Al-Janabi Department of Chemistry, College of Education for Pure Science / Ibn Al- Haitham, University of Baghdad, Iraq. Khalid.Janabi@gmail.com Takleef Dheyab Sallal Ministry of Education, Baghdad, Iraq. sallaltakleef535@gmail.com https://creativecommons.org/licenses/by/4.0/ file:///F:/العدد%20الثاني%202022/:%20http:/jih.uobaghdad.edu.iq/index.php/j/index mailto:ali.khalil.mahmood@gmail.com mailto:Khalid.Janabi@gmail.com mailto:sallaltakleef535@gmail.com IHJPAS. 53 (3)2022 92 Enterobacteriaceae and carbapenemase strains[3,4]. This drug's intravenous (IV) is widely prescribed in combination with other antimicrobial agents; it has an excellent safety profile with long-term administration[5]. This naturally occurring antibiotic agent was discovered in 1969[6]. Figure 1. Chemical structure of Fosfomycin The first chemical synthesis (Figure 2) was described by (Christensen, B. G.) et al. in 1969, based on epoxidation of the cis-Propenylphosphonic acid since diverse synthesis (chemical synthesis) of this drug has been described. Currently, there are three stages[6]. Figure 2. The first chemical synthesis of Fosfomycin 2. Results and Discussion This literature review demonstrated various analytical methods for the quantitative determination of fosfomycin[7–32]. Many of these techniques were reported, as shown in (Table 1) below. Now Fosfomycin has been used to treat particularly urinary infections that occur from bacteria. Furthermore, fosfomycin differs from other antibiotics that are non-cross- resistance for Fosfomycin indicated in clinical application[33]. There was research to estimate fosfomycin in pharmaceutical preparations or biological fluids. HPLC methods were used utilizing different mobile phases of several solvents with different degrees of dilution having diverse columns. The first method used to determine the above drug in urine in 1970 was Thin-layer paper and gas-liquid chromatography with linearity ranging from (1-5)µg [7]. Also, it was found that the minimum linearity range for determining fosfomycin was (0.01-0.4) µg.mL-1 in chicken muscle, liver, and kidney using HPLC-MS/MS [23]. The highest linearity was over (50-5000) µg.mL-1 for determining fosfomycin in urine using capillary gas chromatography[14] with varying detection limits. It was also noted that the spectrophotometric methods were not widely used for assaying the above drug. Mostly, the simple chemical structure of the drug led to not being able to react with different reagents to estimate it in the visible region of the spectrum. It was observed that there were three methods IHJPAS. 53 (3)2022 93 for the spectrophotometric determination of fosfomycin; the first method was at the visible region, λmax = 605 nm, with a specific absorptivity of 4.59 x 104 L. mol-1.cm-1 and linearity = (0 - 28 x 10- 6)M [15]. However, it has been estimated within the ultraviolet region at λmax = 254 nm, with specific absorptivity equal to (4.59 x 104 L.mol1-.cm-1 and its linearity = (30- 70) μg.mL-1. In addition Flow Injection Spectrophotometric method used for determination of it in urine at visible region, λmax = 960 nm, Linearity = (3x10-6- 6x10-4) mol.L-1, T = 90°C, r = 0.9969, LOD= 1x10-6, RSD =1.2%, flow- rate = 0.2 mL.min-1. The drug is currently widely used to treat urinary tract infections with only one dose in the form of oral granules. Table 1.Some analytical methods for the determination of Fosfomycin Methods sample Results Years Ref. No. Thin-layer, paper and gas-liquid chromatography Urine Linearity= (1-5)µg, RF =(0.16-0.86), preparative PC crude (30-5o)%, TL plates loaded up to 150 µgof drug in (2-5) µL 1970 7 Specific ion monitoring method Blood and urine Linearity= (0.5-10) and (0.25-50) µg.mL- 1for microbiological and Sim methods respectively, Total Re. 25-28.1 1981 8 Gas chromatography Biological and bacterial culture medium apillary column OV 17-01, LOD = 1µ.mL- 1, assay of 100 microliters. 1987 9 anion-exchange chromatography Plasma λ max = 272 nm, leanirity(5-100)µg.mL-1, mobile phase, is 0.4 mM of phthalate- buffer (pH =8.5), r= 0.999, RSD =(0.6-5.3) 1993 10 capillary zone electrophoresis Serum Linearity(10-100) µg. mL-1, Re.=(0.5- 18)%, RSD ˂ 2%, buffer mobile phase (200 mM sodium borate + 10 mM phenylphosphonic acid) 1993 11 High performance liquid Chromatography Plasma Linearity = (10-80µg.mL-1), IC-Pak, column (4.6x50) mm, pH =8.5, mobile phase acetonitrile: borategluconate v/v (12∶88), r=0.999. 1993 12 Capillary electrophoresis Serum and cerebrospinal fluid Linearity = (2.5-200) µg/mL-1, LOD = (1.0- 2.5 µg. mL-1) in serum and aqueous fluids respectively, r= 0.999, SD = 94.5%. 1994 13 Capillary gas chromatography Urine Linearity=(50-5000)µg.mL-1, LOD equal 10 µg. mL-1 , CV = 0.006, r = 0.999 1996 14 spectrophotometric method pharmaceutical manufacture λ max = 605 nm, E= 4.59x104 L. mol-1.cm- 1, Linearity = (0-28x10-6 )M. 1999 15 Gas chromatography Plasma Commercial Complexes of Drug(CCd) : a levorotatory, Ca (-) salt, a racemic, Ca (+/-) salt, and (THAM) salt. 1999 16 Gas chromatography Chicken plasma Linearity=(1-150)µg.mL-1, column: HP-5 capillary, detector: flame ionisation (FID)LOD and LOQ = (1 and 2.1) μg mL−1 respectively, Re. 109%. R2 =0.997, CV= (2.8 and 5.1). 2001 17 Flow Injection Spectrophotometric Urine λ max = 960 nm, Linearity = (3x10-6- 6x10- 4) mol.L-1, T = 90°C, r = 0.9969, LOD= 1x10-6, RSD=1.2%, flow- rate = 0.2 mL.min-1. 2002 18 Capillary electrophoresis analysis Biological fluids λ max = 254 nm, Linearity = (3.5 or 6.8- 1000)mg./mL, LOD= (0.62-2), LOQ= (2.0-6.8) µg.mL-1, RSD=( 3.2-5.6), R˃ 0.9994. 2004 19 IHJPAS. 53 (3)2022 94 capillary zone electrophoresis Pus λ max = 254 nm, Linearity =(20 -7800) mg/mL/, LOD = 4.5 LOQ = 15, RSD = ( 2.4-8.2)%,, Re.= (75.4-90.0)%, R= 0.9956. 2005 20 liquid chromatographic/tandem mass spectrometric Plasma Column, ultimate XB-CN, Linearity = (0.1-12) mg .mL-1, LOD ˂ 0.02 µg.mL-1, RSD = (2.4-8.2)%, Er. = (1- 4.2)%, R˂10.6%. 2007 21 High performance liquid chromatography/tandem mass spectrometry Chicken serum Linearity(0.1-50)mg.mL-1, column (150x4.6) mm, mobile phase, (20:80)% acetonitrile : water, Re. (95 to 108)%, Er.= (-7-7.8)%, CV. ˂ 10%, Sd =(0.001-0.006). 2011 22 High performance liquid Chromatography Chicken Muscle, Liver and Kidney Con. Rang (0.1-0.28)µg.g-1, CV.=(0.23- 15.1)%, Re. = (81106%, 92-102% 99- 107% for muscle, liver and kidney respectively, Er. = (0.3-3.76)%, LOQ=0.1 µg.mL-1. 2011 23 liquid chromatography– tandem mass spectrometry Plasma Linearity =(50 -1200) ng.mL-1, column ACE, 150 mm × 4.0 mm, mobile phase acetonitrile: water (30:70)%, RSD =(2.2- 6.7)%, r2 ˃ 0.999, LOQ = 50ng.mL-1, 2014 24 High performance liquid Chromatography Urine, Plasma Linearity =(1 -2000), and (0.1-10) µg/mL, Re. = (68, 72%), precision (4.7%, 3.1%), accuracy (1.7% and 1.2%) for plasma and urine respectively. 2014 25 High performance liquid Chromatography Plasma Linearity = (5.000–2000) µg.mL-1, column, (2.1 x 50 mm), 5.0 μm, accuracy = ( 0.1- 3.9) %, precision =(2-8.2)%, Re. = 83.6%, limits of agreement (-2.6-30.6%). RSD =(2.2-6.7)%, R2 = 0.9998, LOQ = 0.75µg.mL-1. 2015 26 liquid chromatography– tandem mass spectrometry Plasma Linearity = (15-150) and (100-750) µg/ml, column HILIC (150 × 2.1) mm x 5 m, with the precision =(4.0-6.4)% and (2.0– 11.0)%, accuracy = (-1.1- 11.5) % and (0.6–7.8)%, R = 0.9976 and 0.9969. 2015 27 High performance liquid Chromatography Urine, Plasma Linearity =(0.75–375) µg.mL-1, column HILIC, column 1.7μm, (2.1×100)mm, ,accuracy = ( 2.1- 3.2) %, precision =( 1.5% -1.7)%, Re. = (99-103)%, RSD =(2.2-6.7)%, R2 = 0.9998, LOQ = 0.75µg.mL-1. 2017 28 High performance liquid Chromatography Urine, aqueous fluids, plasma Column, PS C18, Linearity: (12.5- 800μg/mL), (62.5-4000μg/mL), (1- 160μg/mL) for plasma, urine and aqueous fluid respectively, LOQ= plasma (≤ 6.5%, ≤ 8%), urine, (≤ 5.80, ≤ 6.30) %, and aqueous fluid (≤ 10.6, ≤12) %. 2017 29 High performance liquid Chromatography Lysogeny broth (antimicrobial resistance) Linearity = (1-1000)μg.mL-1, column Kinetex (2.1 × 50) mm, 2.6 μm, (pH 4.76), precision <15%, accuracy ( ±85 and 115% ). 2018 30 Liquid Chromatography Electrospray Ionization Mass Spectrometry Plasma and Dialysate Linearity = (25.0 – 700) μg. mL-1, precision, (1.1-1.2%), accuracy (5.9% to 0.9%) respectively, Recovery ≥87%, Matrix effects (2.2- 4.3)%, R2=0.999. 2021 31 spectrophotometric method pharmaceutical manufacture λ max = 254 nm, E= 4.59x104 L. mol- 1.cm-1, Linearity = (30-70 ) μg.mL-1, recovery was (98.75-101.00 )%, RSD = 0.41%. 2021 32 IHJPAS. 53 (3)2022 95 3. 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