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An Alternative Methodology for Determination of Cephamycin C

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An Alternative Methodology for Determination of Cephamycin C aphy & S gr ep to a a ra t m i o o r n h T C e de Baptista Neto et al., J Chromat Separation Techniq 2012, 3:3 f c o h Chromatography l n a i DOI: 10.4172/2157-7064.1000130 q n u r e u s o J Separation Techniques ISSN: 2157-7064 Research Article OpenOpen Access Access An Alternative Methodology for Determination of Cephamycin C from Fermentation Broth Álvaro de Baptista Neto1, Liliane Maciel de Oliveira2, Carolina Bellão2, Alberto Colli Badino Jr2, Marlei Barboza2* and Carlos Osamu Hokka2 1Verdartis- Desenvolvimento Biotecnológico Ltda – ME, Brazil 2Departamento de Engenharia Química - Universidade Federal de São Carlos, Brazil Abstract Cephamycin C is a β-lactam antibiotic used as a raw material in several commercial antibiotics. The production and purification process of this antibiotic requires a fast, simple and accurate method to quantify it. In this paper, it was developed a high-performance liquid chromatography method to determine cephamycin C concentration, in order to offer an option for the traditional, but laborious, bioassay method normally employed. A method to obtain a calibration curve using the bioassay and cephalosporin C as standard was also proposed. The method showed more efficiency in determining cephamycin C than the bioassay, and it was simpler and faster to execute. Keywords: Cephamycin C; Bioassay method; Quantification; In a patent filled by Kamogashira et al. [10], the authors describe the Chromatography; Mass spectrometry determination of cephamycin C concentrations without derivatization of the antibiotic, using an acetic acid solution as the mobile phase Introduction and a Waters C-18 µ-bondapak column. The chromatogram and the cephamycin C peak obtained using this chromatographic method was Cephamycin C is a β-lactam antibiotic used as a raw material in not described in the patent. the production of several commercial antibiotics, such as cefoxitin, cefmetazole, temocillin and cefotetan [1]. It is normally produced Another method for determining cephamycin C without in submerged fermentation from cultures of Nocardia lactamdurans derivatization is reported by Leitão et al. [11]. The method involves and Streptomyces clavuligerus. There are a couple of reports in the the use of phosphate buffer as the mobile phase and a Waters C-18 literature dealing with cephamycin C production by these bacteria. µ-bondapak column. However, in the chromatogram obtained using Batch operations using immobilized cells of S. clavuligerus [2], this method, the cephamycin C’s peak was poorly resolved. solid state fermentation [3,4], and search for alternative carbon and In a specified literature about quantification of metabolites nitrogen sources have been reported [5,6]. Currently, cephamycin C produced by Streptomyces clavuligerus, Liras and Martín [12] describe concentrations are determined by laborious and time-consuming the use of a method for cephamycin C determination by HPLC without biological methods, which do not provide good results. Therefore, derivatization. The methodology proposed was able to separate some it is important to have a rapid and precise method to determine the intermediates in the metabolic pathway of cephamycin C, but the concentration of this antibiotic in the cephamycin C production and resolution of the chromatographic peaks obtained was low. Therefore, purification processes. determination of cephamycin C concentration by this methodology The importance of β-lactam antibiotics is reflected by the numerous did not provide high precision. reports in the literature about the analysis of these antibiotics by high- Although there are numerous methods that use HPLC for performance liquid chromatography (HPLC). Rogers et al. [7] describe cephamycin C determination, these analytical methods are difficult a method for the determination of several β-lactam antibiotics, to implement due to the lack of a commercial standard. Therefore, including cephalosporin C, penicillin N, and cephamycin C, using biological assays for the determination of this antibiotic, such as derivatization with o-phthaldialdehyde (OPA) and detecting the peaks that described by Liras and Martín [12], are still widely used. The with a fluorescence-measuring device. Based on their method, it was authors argue that penicillin N has no influence on the determination possible to design a highly sensitive method with high resolution to of cephamycin C concentration in fermentation broths from wild determine these antibiotics in fermentation broths. microorganisms. They describe the use of cephalosporin C as standard In another paper, Rogers et al. [8] describe the need for derivatization of β-lactam antibiotics to increase their detection sensitivity. In the case of penicillins, the authors describe the use of a solution containing *Corresponding author: Marlei Barboza, Programa de Pós-Graduação em imidazole and mercury chloride (pre-column derivatization), and Engenharia Química, Universidade, Federal de São Carlos, Via Washington Luís, ultraviolet determination. The authors also describe another method km 235, SP-310, CP 676 CEP 13565-905, São Carlos, SP, Brazil, Tel: + 55 16 using post-column derivatization and reaction of the antibiotic with 33518264; Fax + 55 16 33518266; E-mail: [email protected] OPA, for the analysis of cephalosporins and penicillins. Both methods Received May 07, 2012; Accepted July 11, 2012; Published July 15, 2012 yield high-resolution chromatograms and can be used to determine Citation: de Baptista Neto Á, de Oliveira LM, Bellão C, Badino AC Jr, Barboza β-lactam compounds in fermentation broths. M, et al. (2012) An Alternative Methodology for Determination of Cephamycin C from Fermentation Broth. J Chromat Separation Techniq 3:130. doi: 10.4172/2157- Holzhauer-Rieger et al. [9] describe an on-line method for the 7064.1000130 determination of cephalosporin C, penicillin N and other antibiotics Copyright: © 2012 de Baptista Neto Á, et al. This is an open-access article during the culturing of Cephalosporium acremonium. The method does distributed under the terms of the Creative Commons Attribution License, which not require derivatization and cephalosporin C is determined with permits unrestricted use, distribution, and reproduction in any medium, provided high precision at high-resolution peaks. the original author and source are credited. J Chromat Separation Techniq ISSN:2157-7064 JCGST, an open access journal Volume 3 • Issue 3 • 1000130 Citation: de Baptista Neto Á, de Oliveira LM, Bellão C, Badino AC Jr, Barboza M, et al. (2012) An Alternative Methodology for Determination of Cephamycin C from Fermentation Broth. J Chromat Separation Techniq 3:130. doi: 10.4172/2157-7064.1000130 Page 2 of 5 and the difficulties caused by the absence of cephamycin C as standard. defined in terms of units of cephalosporin C (UCephC), where 1 UCephC corresponds to the amount of cephamycin C required to produce an As can be seen, cephamycin C determination by a biological method inhibition halo equal to that produced by 1 mg of cephalosporin C. is limited not only due to the lack of precision of the measurements, but also because they are laborious and time-consuming, which greatly Determination of cephamycin C concentrations in TB samples was hampers their production and purification processes. performed in quintuplicate in order to ensure low error values, while that of the RB was performed in triplicate. Batista Neto et al. [13] described a methodology for purification of cephamycin C from fermentation of Streptomyces clavuligerus. Qualitative tests were also carried out. Plates were prepared in The authors used membrane filtration processes - microfiltration and the same way as in quantitative method. The difference in qualitative ultrafiltration - followed by chromatographic steps with nonspecific method is that only undiluted samples, without dilution, were applied and anionic resins. The results obtained showed the efficiency of the in the plates. These assays were used only to check the presence of purification methodology proposed. antibacterial activity of samples and collected fractions. Inhibition zones formed in agar indicated the presence of a compound with In this context, this paper proposes a new HPLC method for antibacterial activity. cephamycin C determination in fermentation broths without the use of a standard. UV spectrum and high-resolution mass spectroscopy HPLC analysis were used to indentify cephamycin C in an isolated chromatogram peak. To quantify cephamycin C concentration, experimental data Chromatographic analyses were carried out in a Waters HPLC obtained by bioassay were correlated with the peaks areas from the UV system (Waters, USA) equipped with two pumps, temperature control, chromatogram for cephamycin C. automatic injector and 996 PDA detector. The first chromatographic condition was based on the method described by Kamogashira et al. Materials and Methods [10]. The mobile phase used was a 0.01M solution of acetic acid, and the temperature of the column was maintained at 28°C. Peaks were Materials detected at a wavelength of 254 nm. UV scan spectra were also obtained HPLC grade water and acetic acid were used in HPLC runs and for the peaks supposed to be cephamycin C. Four methodologies in LC-MS analysis. Water was prepared using a Milli-Q system at a were tested. The differences between them, described below, were the resistivity of 18 MΩ.cm (Millipore, USA). Acetic acid was purchased stationary phase and the flow rate of mobile phase. from Mallinckrodt (USA). The resins
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