Research Article pubs.acs.org/journal/ascecg
Efficient Recovery of Penicillin G by a Hydrophobic Ionic Liquid Qingfen Liu,* Yingbo Li, Wangliang Li, Xiangfeng Liang, Chao Zhang, and Huizhou Liu** Key Laboratory of Green Process & Engineering, Institute of Process Engineering, Chinese Academy of Sciences, No. 1 BeiErJie, ZhongGuanCun, Haidian District, Beijing 100190, China ABSTRACT: Penicillin G is a widely used antibiotic, but the traditional volatile organic solvent extraction causes serious environmental problems. In this work, a hydrophobic ionic liquid ([Bmim]PF6) was developed as a new extraction agent for recovery of penicillin G from aqueous solutions. The extraction efficiency and the partition coefficient of penicillin G were used as the indexes to evaluate the IL extraction ability. Key factors affecting the effectiveness of recovery, such as the pH of the aqueous solution, the initial concentration of penicillin G, and the IL-to-aqueous solution volume ratio, were investigated to determine the optimal conditions. The results showed that the pH of the aqueous phase strongly influenced the success of the extraction. The optimal pH value, phase ratio, and penicillin concentration were 1.5−2.0, 1.5/1 to 2.0/ 1, and 3.00−5.00 × 104 units/mL, respectively, whereby the partition coefficient and extraction efficiency were more than 30 and 91%, respectively. The extraction mechanism was explored by analyzing the chemical bonds using spectrographic analysis. Preliminary results indicated that penicillin G can be effectively extracted from fermentation broth by [Bmim]PF6 with extraction efficiencies of >87%. In addition, a higher selectivity and a much lower extent of emulsification were achieved by [Bmim]PF6 compared to those of butyl acetate. It demonstrates that the IL-based extraction strategy developed in this work is promising and effective, and as a result, the development of an IL-based extraction process for the recovery of penicillin G is straightforwardly envisaged. KEYWORDS: Penicillin G, Ionic liquids, Liquid−liquid extraction, Partition coefficient, Mechanism
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INTRODUCTION Penicillin G is a widely used antibiotic and a starting material for the synthesis of β-lactam antibiotics.1,2 The production process of penicillin G involves fermentation, recovery, and purification. The recovery step is the most important step during the whole production process of penicillin G because it would significantly affect the subsequent purification steps.3 Liquid−liquid extraction by n-butyl acetate is the most used technology for the recovery of penicillin G in industry.4,5 However, this conventional liquid−liquid extraction process utilizes a molecular solvent that is flammable and volatile and has the potential for explosion hazard and severe emulsification. Recently, many new extraction technologies, including aqueous two-phase extraction,6,7 supported liquid membrane extraction,8 the microfiltration technique,9 and solvent sublation,10 have been developed for the recovery of penicillin G. Although these technologies have some advantages over the conventional process, their low separation efficiencies and high costs present a major hurdle in their practical application. Without doubt, innovative and green extraction processes are highly desired with regard to growing concerns about the safety and environmental impact of conventional liquid−liquid extraction processes. Ionic liquids (ILs) make up a class of organic salts with a melting point below 100 °C. Their negligible vapor pressure, © XXXX American Chemical Society
nonflammability, and easy modification make them very attractive as extraction media in various processes. Since Rogers and co-workers first reported the use of ILs to separate substituted benzene derivatives,11 ILs have attracted an increasing level of attention in the development of environmentally benign separation processes.12 An increasing number of reports demonstrate that ILs perform well in the separation and extraction of many compounds, such as rare earth compounds,13 organic acids,14 amino acids,15 biofuels,16 and antibiotics.17 Recently, various aqueous two-phase systems formed by hydrophilic ionic liquids and inorganic salts have been developed for the recovery of penicillin G.18−20 Despite these systems presenting high extraction efficiencies, the ionic liquids and inorganic salts are very difficult to separate and recycle, thus resulting in their costly extraction and difficulty in their industrial application. Alternatively, these problems might be overcome by the direct application of hydrophobic ILs because it can form a clear interface between the IL phase and Special Issue: Ionic Liquids at the Interface of Chemistry and Engineering Received: August 31, 2015 Revised: October 16, 2015
A
DOI: 10.1021/acssuschemeng.5b00975 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering
filtrate and [Bmim]PF6 were placed in a beaker and stirred magnetically at 10 °C for 5 min. The volume ratio of fermentation filtrate to [Bmim]PF6 was 1.5/1. The pH of fermentation filtrate was adjusted to 2. When the extraction was completed, the volumes of both phases were recorded. Extraction of penicillin G with butyl acetate was used as a comparison, and the extraction conditions were the same as those of [Bmim]PF6. Because the fermentation broth includes many other organic acids besides penicillin G, a contamination index (CI) was used to represent the selectivity of [Bmim]PF6. The definition and calculation formula are described in Analysis Methods.
aqueous phase. Cull et al. have shown that 1-methyl-3butylimidazolium hexafluorophosphate ([Bmim]PF6) can be successfully used in place of conventional solvents for the extraction of erythromycin A from an aqueous solution.17 Michiaki Matsumoto et al. used trioctylmethylammonium chloride (TOMAC), [Bmim]PF6, 1-methyl-3-hexylimidazolium hexafluorophosphate ([Hmim]PF6), and 1-methyl-3-octylimidazolium hexafluorophosphate ([Omim]PF6) as the extractant for extraction of penicillin G.21 They found that TOMAC showed the best extraction efficiency, but it was difficult to strip penicillin G from the TOMAC phase. Backward extraction of penicillin G from hydrophobic imidazolium-based ionic liquids has not been described. Moreover, it remains unclear how the experimental factors influence the partitioning of penicillin G between hydrophobic ILs and aqueous media despite its necessity for the development and optimization of the extraction process. More importantly, the knowledge of molecular level interactions behind the extraction lags greatly. In our preliminary experiments, three hydrophobic ionic liquids, i.e., [Bmim]PF6, [Hmim]PF6, and [Omim]PF6, had been evaluated for extraction of penicillin G, and [Bmim]PF6 showed the best extraction efficiency among the test ionic liquids in the pH range of 2−7, which was inconsistent with the report by Michiaki Matsumoto et al.21 The maximal extraction efficiency (91.5%) of [Bmim]PF6 was obtained at pH 2. Therefore, [Bmim]PF6 was chosen as the best candidate for the possibility of recovering penicillin G from aqueous solutions in this study. The effects of different experimental conditions, such as the pH values of aqueous solutions, initial concentrations, and volume ratios, were studied. The mechanism of the extraction process was explored. Finally, the application of [Bmim]PF6 to recover penicillin G from fermentation broth is investigated.
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partition coefficient: K =
C 2 IL C 2 aq
extraction efficiency (EE): EE =
(1)
C 2 ′ILV 2 IL C1aqV 1aq
backward extraction efficiency: BEE =
× 100%
C 3aqV 3aq C 2 ILV 2 IL
(2)
× 100%
(3)
where aq indicates the aqueous phase and IL the ionic liquid phase. C1 and V1 represent the penicillin G concentration and the volume of the aqueous solution before extraction, respectively. C2 and V2 represent the penicillin G concentration and the volume of the IL phase after extraction, respectively. C3 and V3 represent the penicillin G concentration and the volume of the aqueous phase after backward extraction, respectively. Analysis Methods. During the extraction of the model aqueous solution, the concentrations of penicillin G in the aqueous solution phase and butyl acetate phase were determined by polarimetry. The standard curve was supplied by North China Pharmaceutical Ltd. Co. The concentration of penicillin G in the IL [Bmim]PF6 phase was determined by polarimetry. The method was developed by our work team and has never been reported in the literature. The principle is that there are three chiral carbon atoms (*) in the penicillin G molecule, while there are no chiral carbon atoms in the ionic liquid [Bmim]PF6 (Figure 6); therefore, the polarimetry value of the [Bmim]PF6 phase depends on only the penicillin G concentration. The penicillin concentration (Y) and absorption value (X) exhibit a good linear relationship with a coefficient of 0.9999, and the standard curve was Y = 8.83 × 103 × X. During the extraction of fermentation broth, the total organic acids were determined as follows. A 5 mL sample of the extraction phase and 10 mL of ethanol (95%) were added to a flask. Then 2 drops of bromothymol blue as a indicator was added and the mixture titrated with 0.5 N NaOH. When the color of the solution changed from yellow to light green, the reaction was complete. The titration volume was marked as A. Penicillin G was determined by titration with 0.5 N NaOH. The volume of NaOH was recorded as B.
EXPERIMENTAL SECTION
Materials. Penicillin G potassium (99.5%) and fermentation broth of penicillin G were kindly supplied by the North China Pharmaceutical Group Co. Ltd. The fermentation broth has been filtered to remove the mycelia and other particles prior to use. H2SO4, KHCO3, and butyl acetate (AR grade) were purchased from Beijing Chemical Reagents Co. Ltd. Ionic liquids [Bmim]PF6, [Hmim]PF6, and [Omim]PF6 were purchased from Shanghai Chemical Reagents Co. Ltd. with mass fraction purities of >99%. Extraction and Backward Extraction Procedures. The penicillin G aqueous solution is prepared by dissolving a known mass of potassium salt of penicillin G in deionized water. Then the concentration of penicillin G was tested with the method of polarimetry. Certain volumes of a penicillin solution and [Bmim]PF6 were added to a beaker and stirred magnetically at 10 °C for 5 min to sufficiently reach equilibrium; the pH was adjusted with 10% (w/v) H2SO4. After the two phases were separated, the volumes of both phases and the pH value were recorded. The pH values were measured using a Mettler Toledo MP225 instrument. The concentration of penicillin in each phase was determined by polarimetry. Then the partition coefficient and extraction yield were calculated. The [Bmim]PF6 phase loaded with penicillin G was used for backard extraction. The KHCO3 solution [1.9% (w/v)] was added to the [Bmim]PF6 phase until the pH increased to a certain level. Back extraction was conducted at 10 °C, and the mixture was stirred magnetically for 15 min to reach equilibrium. Then the two phases were separated, and the volumes of both phases and the pH value were recorded. The concentration of penicillin G in each phase was determined by the polarimeter. The backward extraction yield was calculated. The application of [Bmim]PF6 to extract penicillin G from fermentation filtrate was conducted as follows. The fermentation
CI =
A−B B
(4)
After extraction, the IL phase was measured using a Fourier transform infrared (FT-IR) spectrometer (Nicolet 380, Thermo Fisher Scientific). The spectra were recorded at room temperature. [Bmim]PF6 has the properties of a surfactant and thus can form microemulsions. The droplet size distributions of [Bmim]PF6 microemulsions were determined by dynamic light scattering (DLS) using a 90 Plus particle size analyzer (Brookhaven Instruments Ltd. Co.). The test was conducted at 25 °C, and the sample was scanned three times at 50−50000 nm. The microstructure of the [Bmim]PF6 phase was studied with freeze-fracture transmission electron microscopy (FF-TEM). The frozen samples were fractured and replicated in a BAF 400 freezefracture apparatus (Bal-Tec, Balzer, Liechtenstein) at −140 °C. Pt/C was deposited at an angle of 45°. The microstructure of the sample was observed by TEM (JEM100 CX, JEOL). B
DOI: 10.1021/acssuschemeng.5b00975 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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RESULTS AND DISCUSSION Influence of Various Parameters on the Extraction Process. The extraction process can be affected by various
Figure 3. Effect of the initial concentration of penicillin G on the partition coefficient and extraction efficiency (pH 2.0, T = 10 °C, W/ O = 2.0/1).
Table 1. Backward Extraction Efficiencies (EE) at an Aqueous Solution-to-[Bmim]PF6 Volume Ratio of 1/2
Figure 1. Effect of pH on the partition coefficient and extraction efficiency (T = 10 °C, extraction phase ratio W/O of 1.5/1, initial penicillin concentration of 3.13 × 104 units/mL).
KHCO3 (%)
pH
backward EE (%)
2.06 4.09
6.1 6.1
95.5 95.1
partition coefficient was obtained at pH 2.0. Therefore, the optimized pH for the extraction of penicillin G from an aqueous solution is confirmed to be approximately 1.5−2.0. It is well-known that penicillin G is a weak monocarboxylic acid, and its pKa is equal to 2.75. Depending on the pH of the solution, penicillin G can be present in the form of an ion or a molecule because of the ionization and/or protonation of its characteristic functional carboxyl. When the pH is >3, penicillin G exists in its ionic form, which is ready to dissolve in water, and thus does not favor distribution in hydrophobic [Bmin]PF6. This also suggests that penicillin G exists as a molecular form in the [Bmin]PF6 phase. Aqueous Solution-to-[Bmim]PF6 (W/O) Ratio. The volume ratio is an important parameter for the extraction process. Therefore, its effect was thoroughly investigated. Aqueous solution-to-[Bmin]PF6 volume ratios of 1/1, 1.5/1, 2/ 1, 2.5/1, and 3/1 were used. The extractions were performed at 10 °C for 5 min. Figure 2 shows the results. The partition coefficient increased from 21.7 to 29.8 as the volume ratio changed from 1/1 to 3/1. This is different from that determined with the traditional molecular solvent n-butyl acetate. When using n-butyl acetate for the extraction of penicillin G, penicillin G forms a hydrogen bond with n-butyl acetate at a constant molar ratio and is not affected by the phase ratio at a given pH and temperature. However, when using [Bmim]PF6, penicillin G enters into the IL phase and weakens the interaction between [Bmim]PF6, thus increasing the chance of penicillin G entering the [Bmim]PF6 phase. As a result, the penicillin G concentration in the IL phase increased, so the partition coefficient increased. As for the EE, it decreased from 93 to 89% as the volume ratio changed from 1/1 to 3/1. This is relevant to the solubility of penicillin G in [Bmim]PF6. Although a higher EE was achieved at a volume ratio of W/O 1/1, it needed more [Bmim]PF6 and thus increases the production cost. Therefore, a phase ratio between 1.5/1 and 2.0/1 was selected in the following experiment given that they
Figure 2. Effect of the phase ratio (W/O) on the partition coefficient and extraction efficiency (T = 10 °C, pH 2.0, initial penicillin concentration in aqueous solution of 5.12 × 104 units/mL).
parameters. As penicillin G is relatively unstable under highertemperature conditions, the succeeding experiments were performed at 10 °C. The extraction time was set for 5 min because it was sufficient for the extraction equilibrium based on preliminary results. Then, the effects of pH of the aqueous solution, aqueous solution-to-[Bmim]PF6 (W/O) ratio, and initial concentration were systematically investigated in this work. pH of the Aqueous Solution. Figure 1 includes plots of the partition coefficient and extraction efficiency of penicillin G versus the pH of the aqueous solution. It could be seen that the partition coefficient and extraction efficiency showed a strong dependence on acidity. When the pH of the aqueous solution was in the range of 1.5−3, the EE was more than 85%. With the increase in pH from 3 to 5.0, EE dramatically decreased and reached a value of 5) was unfavorable for extraction, which indicated a higher pH of the aqueous solution might extract penicillin G from the IL phase. KHCO3 was chosen as the backward extraction agent because it is a weak base and would alleviate the degradation of penicillin G. Thus, the backward extraction was conducted with two concentrations of KHCO3, i.e., 2.06 and 4.09% (m/v). As shown in Table 1, the pH of two aqueous solutions was adjusted to 6.1, and the EE of penicillin G was >95%, indicating the easy stripping of penicillin G from the IL phase and easy recycling of the IL. Mechanism of the Extraction Process. [Bmim]PF6 has the properties of a surfactant and can form microemulsions. The morphology of [Bmim]PF6 before and after extraction was studied by dynamic light scattering and freeze-fracture transmission electron microscopy. It could be seen from Figure
offered an EE of >90%, which is considerable in industrial application. Initial Concentration. The initial concentrations of penicillin G ranging from 2.0−6.1 × 104 units/mL (i.e., 2.0 × 104, 3.2 × 104, 4.1 × 104, 5.1 × 104, and 6.1 × 104 units/mL) were investigated. The extractions were performed under the following conditions: extraction temperature of 10 °C and an aqueous solution-to-[Bmim]PF6 volume ratio of 2.0/1. The results are shown in Figure 3. It could be seen that the partition coefficient of penicillin G increased as the initial concentration increased over the whole tested range. This is different from that determined with the traditional molecular solvent n-butyl acetate. In the n-butyl acetate system, penicillin G forms a hydrogen bond with n-butyl acetate at a constant molar ratio and is not affected by the initial concentration at a given pH and temperature, so the partition coefficient is constant. The EE of penicillin G also increased at an elevated initial concentration of penicillin G in the whole tested range. The increased extent of EE was slight. When the initial concentration exceeded 4.1 × 104 units/mL, >90% of EE was obtained. Higher EEs of 92.7 and 92.9% were achieved at initial D
DOI: 10.1021/acssuschemeng.5b00975 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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Figure 6. Possible interaction between penicillin G and [Bmim]PF6. Hydrogen bonding between penicillin G and [Bmim]PF6 (A, B, D, and E) and π−π stacking between penicillin G and [Bmim]PF6 (C).
the imidazole ring, respectively. Via comparison of plots b and c, the strong adsorption peaks in these two plots were almost inconsistent, while new peaks at 1775, 1680, 1619, and 1509 cm−1 appeared in plot c, which corresponds to the carbonyl at the lactam, the carbonyl at the carboxyl group, the carbonyl at the amide, and the CC group at the benzene ring of penicillin G, respectively. This result suggested penicillin G entered into the [Bmim]PF6 phase. Via comparison of plots c and a, except for the carbonyl at the lactam (1775 cm−1), the carbonyl at the carboxyl group and the carbonyl at the amide of penicillin G were all shifted to high wave sites, indicating that these groups formed a hydrogen bond with [Bmim]PF6 (Figure 6A,B). The CC group at the benzene ring of penicillin G was shifted to a higher wave site, too, which suggested the benzene ring of penicillin G interacted with the imidazole ring of [Bmim]PF6 via π−π stacking (Figure 6C). Figure 5B shows that the ν-OH and ν-NH stretching vibration in penicillin G was between wavenumbers 3300 and 3400 cm−1. This vibration peak disappeared after extraction in the IL layer, which suggested the existence of two hydrogen bonds, i.e., N−H···F and O−H···F (Figure 6D,E), between [Bmim]PF6 and penicillin G. As a result, these weak interactions drive penicillin G into [Bmin]PF6. Extraction of Penicillin G from Fermentation Broth. The fermentation broth provided by the pharmaceutical company contains not only penicillin G but also other proteins, polysaccharides, organic acids, etc. The extractions were performed under the following conditions: extraction temperature of 10 °C, pH 2, and an aqueous solution-to-[Bmim]PF6
Figure 5. FT-IR spectra of [Bmim]PF6 before and after extraction of penicillin. (A) Wavenumbers between 1000 and 2000 and (B) wavenumbers between 2700 and 4000 (liquid, BaF2; solid, KBr): (a) pure penicillin powder, (b) pure [Bmim]PF6, and (c) pH 2.0, 3.00 × 104 units/mL penicillin G in [Bmim]PF6.
4A that there are aggregates formed by [Bmim]PF6 before and after extraction. The diameter of aggregates before extraction centralized at 358 nm, while that after extraction centralized at 200 nm with a wide distribution range. This suggested that the morphology of aggregates before extraction was a uniform sphere, while after extraction, they were changed because of the interaction of penicillin G and [Bmim]PF6. This is confirmed by freeze-fracture transmission electron microscopy (Figure 4B). The [Bmim]PF6 could extract penicillin G from the aqueous solution because the intermolecular forces between the [Bmim]PF6 and penicillin G are stronger than those between water and penicillin G. To further explore the extraction mechanism, the chemical bonds between penicillin G and [Bmim]PF6 were analyzed via FT-IR studies. The FT-IR spectra of [Bmim]PF6, penicillin G, and the IL layer are shown in Figure 5. As shown in Figure 5A, plot a is the IR spectrum of pure penicillin G, in which four peaks at 1775, 1667, 1610, and 1490 cm−1 showed the carbonyl at the lactam, the carbonyl at the carboxyl group, the carbonyl at the amide, and the CC group at the benzene ring, respectively. Plot b is the IR spectrum of pure [Bmim]PF6, in which peaks at 1169, 1465, and 1574 cm−1 showed the C−H, C−C, and C−N groups at E
DOI: 10.1021/acssuschemeng.5b00975 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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be seen that the EE of penicillin G using either [Bmim]PF6 or n-butyl acetate in different batches is almost unchanged, indicating the good reusability of [Bmim]PF6. The average EEs with [Bmim]PF6 and n-butyl acetate were 88 and 93% in single-stage extraction (Table 2), respectively. Although the EE with [Bmim]PF6 is lower than that with n-butyl acetate, this could be overcome by multiple-stage extraction. Moreover, the contamination index shown in Figure 7B is much lower than that with n-butyl acetate, suggesting that [Bmim]PF6 has a relatively higher selectivity for penicillin G. More importantly, the emulsification during penicillin G extraction was mainly caused by proteins contained in the fermentation broth, which remains a problem in the penicillin G industry. When using nbutyl acetate as the extractant under acidic conditions, the protein was denatured and acted as an emulsifier, which resulted in severe emulsification during the extraction process (Figure 7C, right side). However, this phenomenon is greatly alleviated by using [Bmim]PF6 as the extractant, because [Bmim]PF6, as a kind of quaternary ammonium salt, could act as demulsifier and enhance the extent of aggregation of the protein in the interface between [Bmim]PF6 and fermentation broth, which thus enhances the EE and the quality of penicillin G. Therefore, [Bmim]PF6 is a promising extractant for recovery of penicillin G from fermentation broth.
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CONCLUSION It was found that hydrophobic [Bmim]PF6 could be used successfully as an extraction medium for the extraction of penicillin G from fermentation broth. The effects of different extraction conditions, such as pH, initial concentrations, and aqueous solution-to-[Bmim]PF6 volume ratios, were investigated. The pH had a significant influence on the extraction process. Optimal extraction conditions were obtained. When the pH value was 1.5−2.0, the phase ratio was 1.5/1 to 2.0/1, and the initial penicillin concentration was 3.00−5.00 × 104 units/mL, a penicillin G EE of >91% and a partition coefficient of >30 were obtained as comparatively good results. [Bmim]PF6 was easily recycled by backward extraction agent KHCO3, and the backward extraction EE of penicillin G was >95%. The FT-IR spectrum of the [Bmim]PF6 phase after extraction suggested the formation of hydrogen bonds and π−π stacking between [Bmim]PF6 and penicillin G. Moreover, it is quite possible to apply [Bmim]PF6 to recover penicillin G from fermentation broth because of the comparatively high singlestage EE. This method is environmentally friendly compared with the traditional method because it can avoid the use of volatile organic solvents, thus avoiding the potential explosion hazard, severe emulsification, and environmental impact.
Figure 7. Extraction of penicillin G from fermentation broth by [Bmim]PF6 and n-butyl acetate. (A) Extraction efficiency with [Bmim]PF6 and n-butyl acetate in different batches. (B) Contamination index of penicillin G with [Bmim]PF6 and n-butyl acetate in different batches. (C) Digital photographs of emulsification of extractions by [Bmim]PF6 and n-butyl acetate.
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AUTHOR INFORMATION
Corresponding Authors
*Telephone: +86-10-82545010. Fax: +86-10-82545010. E-mail: qfl
[email protected]. **Telephone: +86-10-62554264. Fax: +86-10-62554264. Email:
[email protected].
volume ratio of 1.5/1. The extraction with n-butyl acetate is used for comparison. The results are shown in Figure 7A. It can
Table 2. Comparison of Extraction Effectiveness of Penicillin G with [Bmim]PF6 and Butyl Acetate extractant
evaporation pollution
explosion
pH
temp (°C)
EE (%)
partition coefficient
[Bmim]PF6 butyl acetate
no yes
no yes
1.5−2.5 1.8−2.0
10 10
88.0 93.0
31.5 47
F
DOI: 10.1021/acssuschemeng.5b00975 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering Notes
in ionic liquids aqueous solution. Ind. Eng. Chem. Res. 2007, 46, 6303− 6312. (21) Matsumoto, M.; Ohtani, T.; Kondo, K. Comparison of solvent extraction and supported liquid membrane permeation using an ionic liquid for concentrating penicillin G. J. Membr. Sci. 2007, 289, 92−96.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge financial support from the National Science Fund of China (21136009 and 21506221) and NCPC Pharmaceutical Co. Ltd. for their supply of the penicillin G standard sample and fermentation broth.
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REFERENCES
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