Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=batc20 Critical Reviews in Analytical Chemistry ISSN: 1040-8347 (Print) 1547-6510 (Online) Journal homepage: https://www.tandfonline.com/loi/batc20 A Critical Review of Analytical Methods for Determination of Ceftriaxone Sodium Mariana Teixeira da Trindade & Hérida Regina Nunes Salgado To cite this article: Mariana Teixeira da Trindade & Hérida Regina Nunes Salgado (2018) A Critical Review of Analytical Methods for Determination of Ceftriaxone Sodium, Critical Reviews in Analytical Chemistry, 48:2, 95-101, DOI: 10.1080/10408347.2017.1398063 To link to this article: https://doi.org/10.1080/10408347.2017.1398063 Published online: 29 Jan 2018. Submit your article to this journal Article views: 95 Citing articles: 2 View citing articles https://www.tandfonline.com/action/journalInformation?journalCode=batc20 https://www.tandfonline.com/loi/batc20 https://www.tandfonline.com/action/showCitFormats?doi=10.1080/10408347.2017.1398063 https://doi.org/10.1080/10408347.2017.1398063 https://www.tandfonline.com/action/authorSubmission?journalCode=batc20&show=instructions https://www.tandfonline.com/action/authorSubmission?journalCode=batc20&show=instructions https://www.tandfonline.com/doi/citedby/10.1080/10408347.2017.1398063#tabModule https://www.tandfonline.com/doi/citedby/10.1080/10408347.2017.1398063#tabModule A Critical Review of Analytical Methods for Determination of Ceftriaxone Sodium Mariana Teixeira da Trindade and H�erida Regina Nunes Salgado Department of Pharmaceutics, School of Pharmaceutical Sciences, Universidade Estadual Paulista, Araraquara, SP, Brazil ABSTRACT Ceftriaxone sodium is a third-generation semi-synthetic antibiotic belonging to the class of cephalosporins. Is administered only by parenteral route and has the ability to cross the blood-brain barrier. It has bactericidal action; its main activity is related to the Gram-negative bacteria, being also able to act against Gram-negative bacilli resistant to the first- and second-generation cephalosporins. The present study presents a survey of the characteristics, properties and analytical methods used for the determination of ceftriaxone sodium, for the gathering of data searches were carried out in scientific articles in the world literature, as well as in the official compendia. It is necessary to create awareness about the importance of developing effective and reliable analytical methods for quality control and consequently for conducting pharmacokinetic, bioavailability, bioequivalence studies as well as for the therapeutic monitoring of this drug. Most of the methods found use high-performance liquid chromatography, but also methods that use absorption spectroscopy ultraviolet, infrared spectroscopy, spectrofluorimetry and microbiological methods have been presented. A discussion was presented highlighting the need to develop new ecological methods using less toxic solvents, rapid analysis and miniaturization of the samples. KEYWORDS Analytical methods; ceftriaxone sodium; quality control; review Introduction Natural antibiotics and their semi-synthetic derivatives com- prise the majority of antibiotics in clinical use; the class of b-lac- tams constitutes the first class of derivatives of natural products used in the therapeutic treatment of bacterial infections.[1] Since 1970, cephalosporins are among the most potent and widely used anti-infective agentes.[2] They are the second larg- est class of b-lactam antibiotics which have a broad spectrum of antibacterial activity, clinical efficacy and excellent safety profile, acting on the enzyme transpeptidase, which is unique in bact�eria which confers the action in impediment of synthesis of the wall bacterial.[1] Cephalosporins are classified into gener- ations according to general characteristics of antimicrobial activity. Currently, there are five generations of cephalosporins. They differ in relation to the action spectrum, stability to b-lac- tamase, pharmacokinetics, stability and collateral reactions.[2–5] Ceftriaxone sodium is a third-generation semi-synthetic cephalosporin, derived from a fermentation product, for paren- teral use, being this group of extreme importance because they are able to overcome the blood-brain barrier, since previous generations do not have this capacity.[1,6,7] It acts on Gram-positive and Gram-negative bacteria, the activity against Gram-positive is noticeably smaller in relation to the first-generation cephalosporins. Its major activity is related to Gram-negative bacteria, and it is also capable of act- ing against Gram-negative bacilli resistant to the first- and sec- ond-generation cephalosporins.[2,7,8,9] Ceftriaxone is presented in the form of single-ingredient prep- arations in the USA, United Kingdom, Japan and Canada as RocephinTM; in Brazil as RocefinTM, CeftriaxTM, CelltriaxonTM, KeftronTM, TriaxinTM, AmplospecTM, CeftrionaTM, TriaxtonTM; in China as AnsailongTM, CefinTM, DezhiTM, Likang KesongTM, LivzonphinTM, LocekinTM, OframaxTM, RocephinTM, XianqinTM; in Germany as CefotrixTM, RocephinTM; in Italy as AxobatTM, BixonTM, CefragTM, DavixonTM, DaytrixTM, Dei- ximTM, DiaxoneTM, EftryTM, EraxitronTM, FidatoTM, FriengTM, KocefanTM, MonoxarTM, NilsonTM, PanatrixTM, PantoxonTM, RagexTM, RocefinTM, SetrioxTM, SirtapTM, ValeximeTM.[10–12] It is indicated for cases of septicemia, meningitis, dissemi- nated Lyme borreliosis (early and late stages of the disease) (Lyme disease), intra-abdominal infections (peritonitis, gastro- intestinal and biliary tract infections), bone, joint, soft tissue, skin and wound infections, infections in immunocompromised patients, kidney and urinary tract infections; infections of the respiratory tract, particularly pneumonia andotolaryngological infections, genital infections, including gonorrhea, periopera- tive prophylaxis of infections.[10,11,13] The development of effective and reliable analytical methods is extremely important for quality control of marketed drugs, being this a multidisciplinary task. The need to demonstrate such efficacy and trust is increasingly recognized and demanded. Therefore, the validation process of the analysis is fundamental to guarantee the analytical quality, providing reli- ability in the obtained results.[3,4,14,15] CONTACT Prof H�erida Regina Nunes Salgado salgadoh@fcfar.unesp.br School of Pharmaceutical Sciences, Universidade Estadual Paulista, Araraquara, SP, Brazil. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/batc. © 2018 Taylor & Francis Group, LLC CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY 2018, VOL. 48, NO. 2, 95–101 https://doi.org/10.1080/10408347.2017.1398063 https://crossmark.crossref.org/dialog/?doi=10.1080/10408347.2017.1398063&domain=pdf&date_stamp=2018-02-14 mailto:salgadoh@fcfar.unesp.br http://www.tandfonline.com/batc https://doi.org/10.1080/10408347.2017.1398063 Due to the importance of this information, the present study presents a review of the characteristics of ceftriaxone sodium, its properties and the analytical methods used for its identifica- tion and quantification. Ceftriaxone sodium Structural modification Ceftriaxone sodium was synthesized through the precursor 7-amino-cephalosporanic acid (7-ACA). Synthesis occurred by the addition of an acyl molecule at the 7-amino position and the dis- placement of the acetoxy group by thio-substituent heterocyclic at the 3-methyl position. Then, the substitution of the R-alkyl group was determined by the addition of 6-hydroxy-2-methyl-5-oxythia- diazine-3-thiol, the RO-alkyl group was substituted by 2- (2- amino-4-thiazolyl) -2-amino- [(Z) -methoxylamino] acetyl com- pleting the synthesis of ceftriaxone sodium. The model for the syn- thesis of ceftriaxone sodium is shown in Figure 1.[16] Structural forms Ceftriaxone sodium is present in disodium hemieptahydrate form, its molecular structure is observed in Figure 2.[17–22] Action mechanism Ceftriaxone sodium has a bactericidal action, through the inhi- bition of cell wall synthesis. It is highly stable in the most b-lac- tamases, shows greater activity against Gram-negative bacteria and is also capable of acting against Gram-negative bacilli resis- tant to the first- and second-generation cephalosporins, it is effective against the enterobacteria Haemophilus influenzae and Streptococcus pneumoniae, as well as Citrobacter, Serratia mar- cescens and Providencia. It has synergistic action with the aminoglycosides.[8,23,24] Pharmacokinetics Ceftriaxone sodium is administered parenteral route and is not absorbed by the oral route. The daily dose of 1 g is satisfactory for most serious infections, it is recommended to administer 4 g once daily in the treatment of meningitis. It has a half-life between 6 and 9 hours and may be prolonged in neonates. This cephalosporin can be injected every 24 hours at a dose of 15– 50 mg/kg/day, it has satisfactory penetration of body fluids and tissues, it reaches sufficient levels in the cerebrospinal fluid to inhibit most pathogens except Pseudomonas, it is more active against pneumococci resistant to penicillin. About 85 to 95% is bound to plasma proteins. Crosses the placenta and low con- centrations have been detected in breast milk; ceftriaxone is excreted unchanged in the urine (40 to 65%), the remainder is excreted in the biliary tract and there is no need for dose adjust- ment in renal insufficiency.[10,23,24,25] Physicochemical properties Ceftriaxone sodium is a semi-synthetic antibiotic derived from a fermentation product chemically designated asdisodium (6R,7R)-7-[[(2Z)-(2-aminothiazol-4-yl)(methoxyimino)acetyl] amino]-3-[[(2-methyl-6-oxido-5-oxo-2,5-dihydro-1,2,4-tria- zin-3-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 3.5 hydrate.[17] It has the molecular formula C18H16N8Na2O7S3, 3 1/2H2O, with molecular weight of 661.60 g/mol and for the anhydrous form (C18H18N8O7S3) 598.56 g/mol.[22] Ceftriaxone sodium is in the form of a crystalline powder, almost white or yellowish, slightly hygroscopic, very soluble in water, poorly soluble in methanol, very sparingly soluble in eth- anol. It has at least 905 mg (potency) and not more than 935 mg/mg calculated on the anhydrous basis.[17–19] It shows melting point > 155�C, logP ¡1.7 with pka 3.19 (acid) and 4.17 (alkaline).[26] Analytical methods for determining the ceftriaxone sodium The analytical methods for ceftriaxone evaluation were researched in the literature through scientific articles, as well as in official compendium (Portuguese Pharmacopoeia, 2005; SP, 2007; JP, 2011; BP, 2013; EP, 2013; USP, 2016). The sites used during a survey were: http://www.sciencedirect.com/, http:// www.scopus.com/ and http://www.ncbi.nlm.nih.gov/pubmed/. Key words were used: ceftriaxone sodium, analytical methods and green chemistry. The research was carried out from July to September 2017. Quantitation of the ceftriaxone sodium is of the utmost importance for conducting pharmacokinetic studies of bio- availability and bioequivalence therefore for the therapeutic Figure 1. Synthesis of ceftriaxone sodium. Figure 2. Chemical structure of ceftriaxone disodium hemieptahydrate (CAS 104376-79-6).[17] 96 M. T. DA TRINDADE AND H. R. N. SALGADO http://www.sciencedirect.com/ http://www.scopus.com/ http://www.scopus.com/ http://www.ncbi.nlm.nih.gov/pubmed/ Table 1. Chromatographic analytical methods described in the literature for the determination of ceftriaxone sodium. Method Conditions Detection system Matrices Reference HPLC-UV Column C18 (250 mm £ 4.6 mm; 5 mm). Mobile phase: dissolve 2 g of tetradecyl ammonium bromide and 2 g of tetraheptyl ammonium bromide in a mixture of 440 mL of water, 55 mL phosphate buffer pH 7, 5.0 mL citrate buffer pH 5 and 500 mL of acetonitrile; flow rate 1.5 mL/min; injection volume 20 mL. 254 nm Standard [17–22] HPLC-UV Column hypersil gold C18 (100 mm £ 4.6 mm; 10 mm); at ambient temperature. Mobile phase: methanol: 0.025 M monopotassium phosphate adjusted to pH 7.5 using triethylamine (16:84, v/v); flow rate 1 mL/min; injection volume 10 mL. 254 nm Standard and pharmaceutical form [29] HPLC-UV Column ODS hypersil C18 (250 mm £ 4.6 mm; 5 mm). Mobile phase: 50 mM ammonium phosphate buffer and methanol (90:10% v/v) adjusted to pH 7.0 with triethylamine; flow rate 1 mL/min; injection volume 20 mL. 230 nm Parenteral formulation [36] HPLC-UV Column waters£ Terra RP-18 (250 mm £ 4.6 mm; 5 mm). Mobile phase: 0.1 M triethylammonium acetate and acetonitrile (60:40 v/ v); flow rate 1 mL/min; injection volume 20 mL. 240 nm Standard and pharmaceutical form [25] HPLC-UV Column shimpack GLC-ODS (150 mm £ 6 mm; 5 mm); at ambient temperature. Mobile phase: acetonitrile and 0.1 M ammonium acetate solution (10:90 v/v), pH 7.5 using ammonium solution; for alkaline degradation was used phosphate buffer (pH 10) with heating; flow rate 1.5 mL/min; injection volume 50 mL. 270 nm Powder for injectable solutions and their degradation products [43] HPLC-UV Analytical column Spherisorb ODS C18 (250 mm £ 4.6 mm; 10 mm). Mobile phase: monopotassiumphosphate buffer pH 2.5 and methanol (70:30 v/v); flow rate 1 mL/min; injection volume 10 mL. 254 nm Standard [40] HPLC-UV Column sphere-Image 80–5 ODS 2 (250 mm), at 30�C. Mobile phase: acetonitrile and aqueous 0.1 M citrate buffer with 5 mM ammonium perchlorate and 2 mM tetrabutylammoniumhydrogen sulfate (11:89 v/v). 265 nm Plasma and bone [27] HPLC-UV Column waters£ bridge C18 BEH (50 mm £ 3 mm; 2.5 mm), at 40�C. Mobile phase: 100 mM o-phosphoricacid and/or sodium dihydrogen-phosphate with NaOH pH 2.55 and acetonitrile (100:12 v/v). 260 nm Plasma [28] HPLC-UV Column C18 (250 mm £ 4.6 mm; 5 mm); at ambient temperature. Mobile phase: acetonitrile, methanol and triethylamine (TEA) buffer (pH 7) (1:1:2 v/v), flow rate 0.6 mL/min, injection volume 20 mL. 240 nm Biological sample [30] HPLC-UV Column Kromasil C18 (250 mm £ 4.6 mm; 5 mm). Mobile phase: 1.5 mM potassium dihydrogen phosphate (adjust the pH to 4.5 with phosphoric acid) with 0.0125% triethylamine – methanol (70:30, v/v); flow rate 1 mL/min; injection volume 20 mL. 247 nm Human urine [31] HPLC-UV Column C18 (30 mm £ 4.6 mm; 2.5 mm) at ambient temperature. Mobile phase: acetonitrile and 50 mM phosphate buffer at pH 2.4 (8:92 v/v); flow rate 1 mL/min; injection volume 25 mL. 260 nm Human plasma [32] HPLC-UV Column Atlantis T3 (150 mm £ 4.6 mm; 5mm) Mobile phase: 10 mM phosphoric acid solution, adjusted to pH 2 with hydrochloric acid, and acetonitrile (gradient elution). 230 nm Human plasma [33] HPLC-UV Column C18 Atlantis (150 mm £ 4.6 mm; 3 mm), at 35�C. Mobile phase: 50 mM monopotassium phosphate and acetonitrile (gradient elution); flow rate 1 mL/min. 274 nm Bone [34] HPLC-UV Column C18 (30 mm £ 4.6 mm; 2.5 mm), at ambient temperature. Mobile phase: acetonitrile and 50 mM phosphate buffer at pH 2.4 (8:92 v/v). 260 nm Human plasma [37] HPLC-UV Column inertsil ODS-3 (250 mm £ 4.6 mm; 5 mm); at ambient temperature. Mobile phase: methanol and 10 mM dipotassium phosphate buffer at pH 6.7 (21:79, v/v); flow rate 1.1 mL/min; injection volume 20 mL. 270 nm Rat plasma and intervertebral disc [38] HPLC-UV Column £ Terra C18 (250 mm £ 4.6 mm; 5 mm) at 32�C. Mobile phase: 40 mM phosphate buffer (pH 3.2) and methanol (gradient mode); flow rate 0.85 mL/ min; injection volume 20 mL. ND Plasma and amniotic fluid [39] HPLC-UV Column Nova-Pak C18 (100 mm £ 8 mm; 4 mm). Mobile phase: 10 Mm of dibasicpotassium phosphate and 10 mM cetyltrimethyl ammonium bromide (pH 6.5) with acetonitrile (73:27 v:v). 274 nm Plasma [41] HPLC-UV Column C18 Hypersyl (200 mm £ 2.1 mm; 5 mm); at ambient temperature. Mobile phase: for the analysis of the drug in the aqueous system, methanol-acetonitrile-phosphate buffer, pH 7.4 (20:20:60, v/v/v); for the plasma and cerebrospinal fluid, (30:40:30, v/v/v); flow rate 0.5 mL/min. 270 nm Aqueous and rabbit biological samples [42] HPLC-UV Column supelcosil LC-18 (150 mm £ 4.6 mm; 3 mm); at ambient temperature. Two analytical mobile phases were used: mobile phase I: methanol –acetonitrile – 0.01 M phosphate buffer (pH 7.0) (20:15:65) and 5 mM tetrabutyl ammonium hydrogensulfate; mobile phase II: acetonitrile was omitted and 30% of methanol was used; flow rate 1 mL/min; injection volume 20 mL. 267 nm Serum concentrations [44] (Continued on next page ) CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY 97 monitoring of the substance. In the analyzed literature, there is a predominance of determination by high-performance liquid chromatography (HPLC), but there are also determinations using ultra-performance liquid chromatography (UPLC), absorption spectroscopy ultravioleta (UV), infrared spectros- copy (IV), spectrofluorimetry and microbiological methods. Table 1. (Continued ) Method Conditions Detection system Matrices Reference HPLC-UV Column p-Bondapak C18. Mobile phase: 56% 0.07 M sodiumacetateand 44% acetonitrile, pH ofthesolutionwasadjustedto 5.7 with acetic cid; flow rate 1 mL/min. 270 nm Plasma and urine [45] HPLC-UV Column hypersil ODS (250 mm £ 4.6 mm; 5 mm), at 50�C. Mobile phase: acetonitrile: water: pH7: pH5 (39–55–5.5–0.5); flow rate 1.5 mL/min; injection volume 20 mL. 254 nm Residues on stainless steel surface of pharmaceutical manufacturing equipments [35] HPLC-MS Column cosmosil packed HILIC (150 mm £ 2.0 mm) at 30�C. Mobile phase: acetonitrile and 10 mMol/L ammonium acetate (7:3), flow rate 0.5 mL/min; injection volume 10 mL. Electrospray ionization (ESI) operated in negative mode Powder for injectable solutions [46] HPLC-MS Column 1: DevelosilPhA (150 mm£ 0.5 mm; 5 mm) 2: Develosil PhA (30 mm £ 0.5 mm; 10 mm). Mobile phase: 1: deionized water, methanol, acetic acid, glycerol pH 3.0 (59:40:0.5:0.5 v/v) 2: deionized water, methanol, acetic acid, diethanolamine pH 3.0 (57:40:2.5:0.5 v/v). Operated in positive and negative mode Human serum [47] UPLC-UV Column Acquity UPLC BEH C18 (100 mm £ 2.1 mm; 1.7 mm). Mobile phase: Solution A containing potassium dihydrogenphosphate buffer (pH adjusted to 6.5 § 0.2 with o-phosphoric acid), citric acid buffer (pH adjusted to 5.0 § 0.2 with NaOH solution) and acetonitrile and solution B containing tetradecyl ammonium bromide, tetraheptyl ammonium bromide and acetonitrile. Solution A: Solution B 65:35 (v/v); flow rate 0.3 mL/min. 230 nm Powder for injectable solutions [50] UPLC-UV Column purospher star C18 (100 mm£ 2.1 mm; 2 mm). Mobile phase: 0.05 M sodium dihydrogen o-phosphate dihydrate: acetonitrile (86:14 v/v) adjusted to pH 4.5 with 0.1 M o-phosphoric or 0.1 M sodium hydroxide; flow rate 0.4 mL/min. 254 nm Powder for injectable solutions [51] UPLC-UV Column acquity UPLC BEH C18 (50 mm £ 2.1 mm, 1.7 mm). Mobile phase: acetonitrile and 10 mM oxalic acid (gradient elution); flow rate of 0.35 mL/min; injection volume 5 mL. 380 nm (0–0.58 min), 268 nm (0.58–1.01 min), 229 nm (1.01–1.12 min) and 268 nm (1.12–6.00 min) Residues in milk [52] UPLC-MS/MS Column AcquityUplcBehC18 (50 mm £ 2.1 mm; 1.7 mm) at 35�C. Mobile phase: 0.1% formic acid in ultra-pure water and 0.1% formic acid in acetonitrile (gradient mode); flow rate 0.4 mL/min. Positive electrospray ionization (ESI) using multiple reaction monitoring (MRM) Waste water [48] UPLC-MS/MS ColumnC18 Wwaters acquity T3 (50 mm £ 2.1 mm; 1.7 mm). Mobile phase: 0.1% formic acid in water and 0.1% formic acid in acetonitrile (gradient mode); flow rate 0.4 mL/min; injection volume 5 mL. Positive electrospray ionization (ESI) using multiple reaction monitoring (MRM) Blood [49] HPLC-UV: High-performance liquid chromatography with detection by ultraviolet; HPLC-MS: High-performance liquid chromatography coupled with mass spectrometry detection; UPLC-MS/MS: Ultra-performance liquid chromatography coupled with sequential mass spectrometry; HPLC-MS/MS: High-performance liquid chromatography coupled with sequential mass spectrometry and UPLC-UV: Ultra-performance liquid chromatography with detection by ultraviolet; ND: not declared. Table 2. Spectrometric analytical methods described in the literature for the determination of ceftriaxone sodium. Method Conditions Detection system Matrices Reference Absorption spectroscopy VIS Dilution in water until the concentration of 2-8 mg mL¡1 with 4-chloro-7- nitrobenzo-2-oxa-1,3-diazole. 390 nm Powder for injectable solutions [53] Absorption spectroscopy VIS Dilution of 250 mg of sample in water, after filtration was diluted with distilled water and made up to 100 mL. Using variamine blue for determination. 556 nm Commercial productcs [54] Absorption spectroscopy VIS Dilutions of the drug with methanol and acetonitrile, using chloranilic acid for determination. 520 nm Pharmaceutical formulation [55] Absorption spectroscopy VIS Metallic chromium (VI) reagent isoxidized directly by potassium dichromate in the presence of the drug in acid medium forming a ternary complex. 520 nm Commercial formulation [6] Absorption spectroscopy UV Volumes of 100–300 mL of ceftriaxona solutions (1 mg/mL) were mixed with 50 mL of the alkali-induced degradation product (1 mg/mL) and diluted to 10 mL with acetonitrile-water (10:90 v/v). 265–320 nm Powder for injectable solutions and their degradation products [43] Absorption spectroscopy UV A portion of powder equivalent to 100 mg of the drug was weighed and transferred into 100 mL volumetric flask, the drug was dissolved by adding 70 mL of distilled water and sonicated for 15 min. The volume was completed with distilled water and filtered. 241 nm Powder for injection dosage forms [56] Spectrofluorimetry Dilution with water until 20 mg/mL reacting with o-phthalaldehyde. 386 and 324 nm Pharmaceutical formulations and plasma [57] Infrared It was linear over the concentration range of 0.4–1.2 mg with correlation coefficient of 0.9983 and limits of detection and quantification of 0.016 and 0.049 mg 1800 and 1700 cm¡1 Powder for injectable solutions [59] 98 M. T. DA TRINDADE AND H. R. N. SALGADO Tables 1–3 present the chromatographic, spectrometric and microbiological analytical methods, respectively, described in the literature for the determination of ceftriaxone sodium in pharmaceutical formulations, standards and various biological matrices. Figure 3 shows graphically the percentage of different meth- ods used for the analysis of ceftriaxone sodium, the HPLC tech- nique was the most used in the found methods, being a fast, precise and specific technique but uses organic solvents (aceto- nitrile, methanol, for example), being toxic waste generators. Many methods use buffer solutions that are non-toxic to the environment and the operator, but can shorten the life of the equipment and accessories, for example, the chromatographic columns, impacting the cost of the analysis.[60–61] It is necessary to develop methods that use solvents with low toxicity (ethanol and water, for example), as well as to use them in low concentrations. The commitment to using reduced sam- ples through miniaturization, decreasing process steps and pre- treatment of samples, are alternatives that directly influence the amount of reagents used, time of analysis, number of materials required and cost involved. On the other hand, work on the recovery of these toxic solvents should be done, as these materi- als cannot be disposed of directly into the environment.[62–65] The equipment used should also be considered important, the proposal is to use those that require less solvent, which have less analysis time, generating lower energy consumption and as a consequence lower expenses for the company and lower final product prices.[66–70] The questions tend to focus on the relationship between the new validated methods and their practical uses by chemical and pharmaceutical industries. In discussing the relevant issue, we have to consider how methods can be adopted to routine analy- sis. This is clearly not an exhaustive list, but it will be very useful for researchers to revise the key concepts and demonstrate the ability of these innovative techniques. The development of these methods should be encouraged more and more, due to their advantages and economic, environmental and social benefits. In this way, universities become reference research centers in the area, helping to achieve this goal.[3,4,15,71–74] Conclusion Ceftriaxone sodium is a third-generation antibiotic belonging to a class of cephalosporins, it has a bactericidal action and it shows greater activity against Gram-negative bacteria. The use of this drug contributes to the development of stud- ies that need to carry out their analytical and bioanalytical quantification. The drug has characteristics, properties and analytical methods well defined. However, it is necessary to encourage and raise awareness for the need to develop and vali- date innovative analytical methods using green chemistry. Conflict of interest The authors declare no conflicts of interest. Acknowledgments The authors acknowledge to CAPES and CNPq (Bras�ılia, Brazil). Funding Conselho Nacional de Desenvolvimento Cient�ıfico e Tecnol�ogico (304824/ 2013-5). ORCID Mariana Teixeira da Trindade http://orcid.org/0000-0003-0745-0277 H�erida Regina Nunes Salgado http://orcid.org/0000-0002-0385-340X References [1] Guimaraes, D. O.; Momesso, L. S.; Pupo, M. T. Antibiotics Thera- peutic Importance and Prospects for the Discovery and Development of New Agents. New Chem. 2010, 33, 667–679. Table 3. Microbiological analytical methods described in the literature for the determination of ceftriaxone sodium. Method Conditions Incubation time (hour) Matrices Reference Microbiological- diffusion in agar Plate cylinder method, 3 £ 3 using Staphylococcus aureus ATCC 6538P. 18 Standard [7] Microbiological- diffusion in agar Samples containing concentrations of 4.0 mg/mL, using phosphate buffer pH 6.0 as diluent; plates containing 21 mL of medium for antibiotic assay as base layer and 4 mL of the same medium inoculated with Bacillus subtilis (ATCC 6633) in a proportion of 0.5%; and incubation at 37 § 1�C for 18 hours. 18 Commercial productcs [9] Microbiological- diffusion in agar Six plates were used for each assay with Bacillus subtilis ATCC 9371 IAL 1027 as test microorganism. The plates were incubated at 35�C aerobically for 18 hours. The diameter of the growth inhibition zone (mm) was carefully measured with a digital caliper. 18 Powder for Injectable Solution [58] Figure 3. Percentage of various analytical methods used in the ceftriaxone sodium analysis. 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CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY 101 https://doi.org/10.5923/j.pc.20170703.01 http://seer.ufrgs.br/index.php/dar/article/view/73755/43166 http://seer.ufrgs.br/index.php/dar/article/view/73755/43166 https://doi.org/10.1155/2017/7530242 https://doi.org/10.4172/2380-9477.1000118 https://doi.org/10.4172/2380-9477.1000118 https://doi.org/10.5740/jaoacint.17-0102 https://doi.org/10.2174/1573412913666161213103657 https://doi.org/10.2174/1573412913666161213103657 https://doi.org/10.17628/ecb.2017.6.238-245 https://doi.org/10.1556/1006.2017.30.4.8 Abstract Introduction Ceftriaxone sodium Structural modification Structural forms Action mechanism Pharmacokinetics Physicochemical properties Analytical methods for determining the ceftriaxone sodium Conclusion Conflict of interest Acknowledgments Funding References