Hebei Zhongrun Pharmaceutical Co.

Shijiazhuang, China

Hebei Zhongrun Pharmaceutical Co.

Shijiazhuang, China
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Zhu K.,Hebei Zhongrun Pharmaceutical Co. | Wang Y.-Y.,Hebei Zhongrun Pharmaceutical Co. | Ding H.-P.,Hebei Zhongrun Pharmaceutical Co. | Yan G.-D.,Hebei Zhongrun Pharmaceutical Co. | Wang F.,Hebei Zhongrun Pharmaceutical Co.
Chinese Journal of Antibiotics | Year: 2011

Objective To study the process optimization and stability of amoxicillin by enzymatic synthesis. Methods The amoxicillin was synthesized with the use of p-hydroxyphenylglycine methyl ester as a side chain and the substrate 6-APA in penicillin acylase catalyzed; temperature, pH, side chain and substrate feed ratio, investment conditions, such as the amount of enzyme was optimized; chemical and enzymatic amoxicillin was taken six months accelerated test, comparing content changes, examining the stability of products. Results The molar yield of amoxicillin was 84.3% after process optimization; after six months accelerated test, the content of enzymatic amoxicillin dropped by an average 0.78% less than the chemical method. Conclusion Enzymatic amoxicillin process was simple, methods of green environmental protection, product stability was better than chemical method.


Zhang J.F.,Hebei University of Science and Technology | Liu X.,Hebei University of Science and Technology | Hou L.M.,Hebei University of Science and Technology | Liu Q.,Hebei Zhongrun Pharmaceutical Co.
Applied Mechanics and Materials | Year: 2014

7-amino-cephalsporanic acid (7-ACA) is the key intermediate of cephalosporin, which has a strong sensitization and explosion hazard. So it seriously affects the worker's health in the workshop, the environment safety out of the workshop and work safety. The drying workshop of 7-ACA at a pharmaceutical enterprise in Shijiazhuang is investigated and the production process is analyzed, the key places of dust leakage and the causes of dust generation are identified. Combined with the pollution and safety risk in drying workshop, the targeted control measures are taken from the process technology, ventilation system and dust collecting device, which effectively removed the adverse effects from 7-ACA leaking. The study provides a reference for the dust control in similar enterprises. © (2014) Trans Tech Publications, Switzerland.


Yu H.,China Institute of Technology | Chen L.,Tianjin University | Geng H.,China Institute of Technology | Zhao Z.,Hebei Zhongrun Pharmaceutical Co.
Huagong Xuebao/CIESC Journal | Year: 2010

Coal granular activated carbon with particle size distribution from 0.27 mm to 1.70 mm was used as adsorbent in a fixed-bed to separate deacetyl cephalosporin C(DCPC) from the waste drainage. The adsorbed DCPC on the carbon was eluted with 8%(vol)ethanol aqueous solution, and the obtained eluate contained DCPC in a yield of 60%~65% with a purity higher than 85%. After being further condensed through nanofilter membrane, the eluate was allowed to pass through anion-exchange resin Amberlite IRA67 on which DCPC was adsorbed. Desorption with 0.5 mol·L-1 sodium acetate buffer solution (pH6.3), DCPC was obtained as sodium salt solution in a yield of 90%~95% with 96% purity and the concentration was higher than 30 g·L-1. DCPC sodium salt was isolated by crystallization through adding acetone to the eluate. The adsorption capacity of the used coal granular activated carbon could be restored by saturation with alkali solution containing isopropanol and then neutralization with acidic solution. © All Rights Reserved. © All Rights Reserved.


Cao Y.-X.,Tianjin University | Qiao B.,Tianjin University | Lu H.,Hebei Zhongrun Pharmaceutical Co. | Lu H.,Shijiazhuang Pharmaceutical Group Co. | And 3 more authors.
Applied Microbiology and Biotechnology | Year: 2011

The disparity of secondary metabolites in Penicillium chrysogenum between two scales of penicillin G fermentation (50 L as pilot process and 150,000 L as industrial one) was investigated by ion-pair reversed-phase liquid chromatography tandemed with hybrid quadrupole time-of-flight mass spectrometry. In industrial process, the pools of intracellular L-α-aminoadipyl-L- cysteinyl-D-valine (LLD-ACV) and isopenicillin N (IPN) were remarkably less than that in the pilot one, which indicated that the productivity of penicillin G might be higher in the large scale of fermentation. This conclusion was supported by the higher intracellular penicillin G concentration as well as its higher yield per unit biomass in industrial cultivation. The different changing tendencies of IPN, 6-aminopenicillanic acid and 6-oxopiperide-2-carboxylic acid between two processes also suggested the same conclusion. The higher content of intracellular LLD-ACV in pilot process lead to a similarly higher concentration of bis-δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine, which had an inhibitory effect on ACV synthetase and also subdued the activity of IPN synthetase. The interconversion of secondary metabolites and the influence they put on enzymes would intensify the discrepancy between two fermentations more largely. These findings provided new insight into the changes and regulation of secondary metabolites in P. chrysogenum under different fermentation sizes. © 2011 Springer-Verlag.


Qiao B.,Tianjin University | Lu H.,Tianjin University | Lu H.,Hebei Zhongrun Pharmaceutical Co. | Lu H.,Shijiazhuang Pharmaceutical Group Co. | And 4 more authors.
Engineering in Life Sciences | Year: 2013

Optimizing industrial-scale fermentation for Penicillium chrysogenum is of significance for increasing commercial production of antibiotics. Lipidomics could be a valuable tool for the investigation in the behaviors of P. chrysogenum in realistic industrial environments. In this work, the phospholipid (PL) profiles of an industrial strain of P. chrysogenum were compared in different scale processes. PL was performed on LC/ESI/MSn system. It was found that industrial P. chrysogenum cells absorbed significant amounts of exogenous saturated and (poly) unsaturated fatty acids (PUFAs) from feedstock and incorporated them into their cell membranes during two fermentations. Results showed that the PL species that contain the PUFAs, that is, linolenic acid and hexadecadienoic acid, were quite variable between pilot and industrial scales of fermentations. Higher levels of PUFA-containing PLs in rapid- and linear-growth stages during industrial fermentation implied the occurrence of dramatic variations in cell membrane fluidity during these periods. It was speculated that this behavior was due to impacts of multiple physical and chemical factors present in the fermentation environment during this large-scale fed-batch process. The identified PUFA-containing PLs could be used as valuable biomarkers for optimizing industrial-scale fermentation for P. chrysogenum. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Zhang J.,Hebei Zhongrun Pharmaceutical Co. | Zhang J.,Hebei Normal University | Wang J.-F.,Hebei Normal University | Zhang J.-J.,Hebei Normal University
Wuli Huaxue Xuebao/ Acta Physico - Chimica Sinica | Year: 2012

Three rare earth complexes of [Ln(5-Cl-2MOBA) 3phen] 2 (Ln=Nd(1), Eu(2), Ho(3); 5-Cl- 2MOBA: 5-chloro-2-methoxybenzoate; phen: 1,10-phenanthroline) were synthesized and characterized by elemental analysis, thermogravimetry-differential thermogravimetry-differential scanning calorimetry (TG-DTG-DSC), infrared (IR) spectra, ultraviolet (UV) spectra, and molar conductance techniques. The fluorescence spectra showed that complex (2) emitted a characteristic fluorescence of the Eu 3+ ions. The thermal properties are discussed by thermogravimetry - differential scanning calorimetry / Fourier transform infrared (TG-DSC/FTIR) techniques. And the three-dimensional IR accumulation spectra for the three complexes were also analyzed. © Editorial office of Acta Physico-Chimica Sinica.


He J.,Hebei Normal University | Xu R.,Hebei Normal University | Chen X.,Hebei Normal University | Jia K.,Hebei Normal University | And 2 more authors.
Acta Biochimica et Biophysica Sinica | Year: 2010

To reduce the immunogenicity of recombinant staphylokinase, structure-based mutagenesis of Glu80 residue in wild-type staphylokinase (wt-Sak) was rationally designed and carried out by a modified QuikChange site-directed mutagenesis. Sak mutants, including Sak(E80A) and Sak(E80S), were successfully expressed in E. coli DH5α as a soluble cytoplasmic proteins and accounted for more than 40 of the total cellular proteins. The expressed proteins were purified by a three-step chromatographic purification process. SDS-PAGE and HPLC analyses results indicated that the purified proteins were almost completely homogeneous and the purities of Sak mutants exceeded 97. Analysis of fibrinolytic activity revealed that substitution of E80 residue with serine and alanine resulted in slightly increased specific activities of Sak mutants. Investigation of the immunogenicity of Sak mutants showed that the amount of specific anti-Sak IgG antibodies elicited by Sak(E80A) and Sak(E80S) in BALB/c mice decreased ∼35 and 27, respectively compared with wt-Sak. The abilities of Sak mutants to stimulate proliferation of T cells from BALB/c mice and to bind mouse anti-Sak polyclonal serum were significantly lower than those of wt-Sak. These results suggested that substitution of Glu80 residue by alanine and serine successfully eliminated part of T- and B-cell epitope of Sak molecule. Our findings suggested that simultaneous elimination of T- and B-cell epitopes was a useful method to reduce the immunogenicity of wt-Sak molecule and provided a strategy for engineering safe Sak-based fibrinolytics for the clinical treatment of acute myocardial infarction.


Cao Y.-X.,Tianjin University | Lu H.,Hebei Zhongrun Pharmaceutical Co. | Qiao B.,Tianjin University | Chen Y.,Hebei Zhongrun Pharmaceutical Co. | Yuan Y.-J.,Tianjin University
Journal of Industrial Microbiology and Biotechnology | Year: 2013

Cephalosporin C (CPC) is the precursor of a class of antibiotics that were more effective than traditional penicillins. CPC production is performed mainly through fermentation by Acremonium chrysogenum, whose secondary metabolism was sensitive to the environmental changes. In the present work, secondary metabolites were measured by ion-pair reversed-phase liquid chromatography tandemed with hybrid quadrupole time-of-flight mass spectrometry, and the disparity of them from two scales of CPC fermentations (pilot and industrial) and also two different post-treatment processes (oxalic acid and formaldehyde added and control) were investigated. When fermentation size was enlarged from pilot scale (50 l) to industrial scale (156,000 l), the remarkable disparities of concentrations and changing trends of the secondary metabolites in A. chrysogenum were observed, which indicated that the productivity of CPC biosynthesis was higher in the large scale of fermentation. Three environmental factors were measured, and the potential reasons that might cause the differences were analyzed. In the post-treatment process after industrial fermentation, the changes of these secondary metabolites in the tank where oxalic acid and formaldehyde were added were much less than the control tank where none was added. This indicated that the quality of the final product was more stable after the oxalic acid and formaldehyde were added in the post-treatment process. These findings provided new insight into industrial CPC production. © 2012 Society for Industrial Microbiology and Biotechnology.


Cheng J.-S.,Tianjin University | Zhao Y.,Tianjin University | Qiao B.,Tianjin University | Lu H.,Tianjin University | And 5 more authors.
Applied Biochemistry and Biotechnology | Year: 2016

The intracellular proteomes of the Penicillium chrysogenum throughout pilot and industrial processes were investigated by using 2-DE combined with MALDI-TOF-TOF MS, respectively. We detected a total of 223 spots corresponding to 154 proteins and 231 spots corresponding to 157 proteins throughout pilot and industrial processes, respectively. The levels of glyceraldehyde-3-phosphate dehydrogenase increased (5.1- and 2.5-fold) under the pilot process, while its levels were no significant changes under the industrial process at 140 and 170 h when compared with that at 2 h. The levels of isocitrate lyase and fumarate hydratase were increased significantly under the industrial process, while their levels had no obvious changes after 20 h of fermentation throughout the pilot process. These results indicate that there were remarkable differences in carbohydrate metabolism (including glycolysis, gluconeogenesis, pentose phosphate pathway, and tricarboxylic acid cycle) of P. chrysogenum during the pilot and industrial fermentations, which likely result in alterations of the primary metabolism and penicillin biosynthesis. Moreover, the differences in the levels of proteins involved in amino acid metabolisms (including valine, cysteine, and α-aminoadipic acid biosynthesis) indicated that the pilot and industrial processes influenced the supplies of penicillin precursors. Compared with that at 2 h, the maximum levels of superoxide (6.9-fold, at 32 h) and catalase (9-fold, at 80 h) during the industrial process and the maximum levels of superoxide (1.2-fold, at 20 h) and catalase (7.7-fold at 128 h) during the pilot process revealed the significant difference in cell redox homeostasis and stress responses during scale-up fermentation. Particularly, 10 spots corresponding to isopenicillin N synthetase and 4 spots corresponding to isopenicillin N (IPN) acyltransferase in pilot and industrial processes were identified, respectively. The levels of IPN acyltransferase (spots 197 and 198) and CoA ligase at 80 h during the industrial process were around 2-fold of that during the pilot process, indicating that the industrial process with a higher penicillin production per cell might provide available environments to induce over-expression of IPN acyltransferase and accelerate penicillin formation. These results provide new insights into the globally potential responses of P. chrysogenum to variations of environments in different fermentation scales so as to consequently regulate the penicillin production. © 2016 Springer Science+Business Media New York


PubMed | Hebei Zhongrun Pharmaceutical Co. and Tianjin University
Type: Journal Article | Journal: Applied biochemistry and biotechnology | Year: 2016

The intracellular proteomes of the Penicillium chrysogenum throughout pilot and industrial processes were investigated by using 2-DE combined with MALDI-TOF-TOF MS, respectively. We detected a total of 223 spots corresponding to 154 proteins and 231 spots corresponding to 157 proteins throughout pilot and industrial processes, respectively. The levels of glyceraldehyde-3-phosphate dehydrogenase increased (5.1- and 2.5-fold) under the pilot process, while its levels were no significant changes under the industrial process at 140 and 170h when compared with that at 2h. The levels of isocitrate lyase and fumarate hydratase were increased significantly under the industrial process, while their levels had no obvious changes after 20h of fermentation throughout the pilot process. These results indicate that there were remarkable differences in carbohydrate metabolism (including glycolysis, gluconeogenesis, pentose phosphate pathway, and tricarboxylic acid cycle) of P. chrysogenum during the pilot and industrial fermentations, which likely result in alterations of the primary metabolism and penicillin biosynthesis. Moreover, the differences in the levels of proteins involved in amino acid metabolisms (including valine, cysteine, and -aminoadipic acid biosynthesis) indicated that the pilot and industrial processes influenced the supplies of penicillin precursors. Compared with that at 2h, the maximum levels of superoxide (6.9-fold, at 32h) and catalase (9-fold, at 80h) during the industrial process and the maximum levels of superoxide (1.2-fold, at 20h) and catalase (7.7-fold at 128h) during the pilot process revealed the significant difference in cell redox homeostasis and stress responses during scale-up fermentation. Particularly, 10 spots corresponding to isopenicillin N synthetase and 4 spots corresponding to isopenicillin N (IPN) acyltransferase in pilot and industrial processes were identified, respectively. The levels of IPN acyltransferase (spots 197 and 198) and CoA ligase at 80h during the industrial process were around 2-fold of that during the pilot process, indicating that the industrial process with a higher penicillin production per cell might provide available environments to induce over-expression of IPN acyltransferase and accelerate penicillin formation. These results provide new insights into the globally potential responses of P. chrysogenum to variations of environments in different fermentation scales so as to consequently regulate the penicillin production.

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