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Objective To establish a high performance size esclusion chromatography (HPSEC) method for the determination of high molecular weight impurities of cefotiam hydrochloride for injection.Methods A TSK G2000 SWXL column(7.8 mm × 30 cm,5μm) was used,the mobile phase consisting of phosphate budder solution [0.1 mol·L-1 disodium hyrogen phosphate-0.1 mol·L-1 sodium dihydrogen phosphate (61:39)],the flow rate was 0.7 mL· min-1,the detection wavelength was 254 nm,the column temperature was 30 ℃,the injection volume was 20 μL,and the concentration of polymers was quantified by external standard method.Results For HPSEC method,the calibration curves were linear in the range of 5.0-25.0 μg·mL-1 for cefotiam,and the LOD and LOQ was 0.1 μg·mL-1 and 0.246 μg· mL-1,the RSD for replicate for injections of reference solution was 0.50％,the sample solution was not stable in room temperature.Conclusion The method has high separation efficiency and good specificity,which provides reference for the further study of the polymer of cefotiam hydrochloride for injection.
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Objective:To interpret the main revision about the test method for bacteriostat effect in Chinese Pharmacopoeia(2015 edition). Methods:The main difference of the bacteriostat effect test method in Chinese Pharmacopoeia(2015 edition) and (2010 edi-tion) was compared. Results:The bacteriostat effect test method in the 2015 edition was revised at a comparatively large scale in the positioning of bacteriostat effect test, product classification, assessment criteria and so on. Conclusion: The bacteriostat effect test method in Chinese Pharmacopoeia (2015 edition) gradually improves the check standards in line with the international standards.
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Objective:To interpret the main revision of the microbiological examination for nonsterile products:tests for specified microorganisms in Chinese Pharmacopoeia (2015 edition). Methods:The microbiological examination for nonsterile products:tests for specified microorganisms in Chinese Pharmacopoeia (2015 edition) was compared with the relevant content in the 2010 edition, and then the differences were investigated. Results:Microbiological examination for nonsterile products:tests for specified microorganisms in Chinese Pharmacopoeia (2015 edition) had been revised at a comparatively large scale in the inspection items, test method, micro-bial culture system, the quality control concept and so on. Conclusion:Microbial inspection system in Chinese Pharmacopoeia (2015 edition) is gradually improved to become a high standard check system in line with the international standards.
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Furbenicillin is a broad-spectrum semisynthetic penicillin with strong antibacterial activity against Gram-negative bacteria. Furbenicillin sodium is determined by volumetric method in current criteria. However, the criteria does not contain an assay of related substances of furbenicillin sodium. In this study, we established a method for detection and analysis of furbenicillin sodium and its related substances by HPLC. The analysis was performed with a C18 column under a gradient elution, the detection wavelength was 225 nm, and the column temperature was 35 degrees C. The reliability and accuracy of established method was validated in this study. Pure samples of furbenicillin sodium and its related substances were prepared. The structures, biological activities, and chromatographic retention behaviors of furbenicillin sodium and its related substances were identified using NMR, CLSI agar dilution method, and HPLC. All results in the current study provide ample evidence that this method is able to determine the reasonable limits in the quality-control protocol for furbenicillin sodium.
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The molecular descriptors of impurities with known structure in cefdinir were calculated, selected and associated with the chromatographic retention behavior to establish a model. This quantitative structure retention relationships (QSRR) model for the related substances of cefdinir was established under specific chromatographic condition and verified by other impurities. 12 molecular descriptors were used to establish the QSRR model, F_AFRBWF, Blbn_J, SsCH3, SssCH2, SsNH2, SssNH, SssS, SHdCH2, EEM_AFc, EEM_AFpl, EEM_XFpl and Pi_MaxQ. The relativity between true values and predictions in QSRR of cefdinir is R2 = 0.9836 (n = 18), ΔRRT is no more than 0.154, as 10.17% in RRT. The results indicate that the QSRR model for the related substances of cefdinir can be used to evaluate the analysis methods for related substances and predict the chromatographic behavior of new impurities, which will provide a new way for the evaluation of the effectiveness for drug quality control.
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Objective:To investigate the content rationality of antimicrobial agent thimerosal in chloramphenicol eye drops. Meth-ods:Chloramphenicol eye drops with thimerosal at different concentrations were prepared, and the antimicrobial activity was studied. Results:When the test solution contained 0. 02 mg·ml-1 thimerosal, the antimicrobial activity could achieve the requirement in the pharmacopoeia. Conclusion:Thimerosal at different concentrations in the commercial chloramphenicol eye drops all can reach the anti-microbial effect. However, the thimerosal concentration in some eye drops is unreasonably high, which should be reduced.
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Reversed-phase liquid chromatography coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to characterize impurities in cefpodoxime proxetil, an ester-modified prodrug. Based on the mechanisms by which cephalosporins are degraded, stress tests were designed and performed. The bulk material and capsule were eluted through a C18 column with formic acid-methanol-water as the mobile phase. In total, 15 impurities were characterized in commercial samples, including 7 known impurities and 8 new impurities. The structures of these unknown compounds were deduced via comparison with the fragmentation patterns of cefpodoxime proxetil. Data from this systematic study will help improve the safety and quality of cefpodoxime proxetil.
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Reference materials containing mixed degradation products of amoxicillin and ampicillin were developed after optimization of preparation processes. The target impurities were obtained by controlled stress testing, and each major component was identified with HPLC-MS and compared with single traceable reference standard each. The developed reference materials were applied to system suitability test for verifying HPLC system performed in accordance with set forth in China Pharmacopeia and identification of major impurities in samples based on retention and spectra information, which have advantages over the methods put forth in foreign pharmacopoeias. The development and application of the reference materials offer an effective way for rapid identification of impurities in chromatograms, and provide references for analyzing source of impurities and evaluation of drug quality.
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The near infrared ( NIR ) spectra of 76 batches of the amoxicillin capsules from different manufacturers and their corresponding content powder without capsules cell were used to find some quantitative indicators to evaluate whether the piecewise direct standardization ( PDS ) algorithm succeeded in NIR quantitative model updating. 54 batches were used to construct the NIR quantitative model for capsule preparation. All the NIR spectra of amoxicillin capsules were divided into five classes by cluster analysis, and each class can be regarded as a homology sample set. The average spectrum for each homology sample set was calculated. Ten to Fifteen spectra were selected from each homology sample set as the corresponding master spectra of the PDS algorithm to correct all the NIR spectra of the amoxicillin content powder respectively. Then the corrected spectra were predicted by the constructed NIR quantitative model for amoxicillin capsules. The prediction error for each corrected powder spectrum, and the correlation coefficient between each corrected powder spectrum and the average spectrum of the corresponding homolog sample set which the PDS master spectra came from, were calculated. Finally, the relationship between the prediction error and its corresponding correlation coefficient were studied. It was found that the correction results correlated closely with the selected master spectra set in PDS algorithm. The bigger the correlation coefficient ( r) , the better the correction results. In general, when r is less than 99%, it can be judged that the PDS correction is failed. At this condition, the prediction error is often more than 5%. Therefore, the correlation coefficient between the corrected spectrum and its corresponding average spectrum of the homology sample set can be used as an indicator to evaluate the efficiency of the PDS correction.
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Re-evaluation of bioequivalence of generic drugs is one of the key research focus currently. As a means to ensure consistency of the therapeutic effectiveness of drug products, clinical bioequivalence has been widely accepted as a gold standard test. In vitro dissolution testing based on the theory of the BCS is the best alternative to in vivo bioequivalence study. In this article, the conventional dissolution method and flow-through cell method were used to investigate the dissolution profiles of domestic amoxicillin capsules in different dissolution media, and the absorption behavior of the drugs with different release rates (t85% = 15-180 min) in the gastrointestinal tract was predicted by Gastro Plus. The flow-through cell method was thought better to reflect the release characteristics in vivo, and amoxicillin capsules with regard to the release rates up to 45 min (t85% = 45 min) were having a satisfied bioequivalence with the oral solution according to the C(max) and AUC. Although two different dissolution profiles of domestic amoxicillin capsules were found by flow-through cell methods, prediction results revealed that domestic capsules were probably bioequivalent to each other.
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Powder X-ray diffraction (PXRD) technology combined with cluster analysis method was used to classify 75 batches of crystalline ceftriaxone sodium into subtypes, the crystalline characteristics of each subtype were measured with scanning electron microscope (SEM). By comparing some parameters of these subtypes correlated to crystallization process of ceftriaxone sodium, such as salification rate, water content in different subtypes, as well as by studying different lattice stabilities, different compatibilities with rubber closures during accelerated stability tests, the key point to improve the quality of domestic ceftriaxone sodium was disclosed. The results of this paper indicated that the fine structure of the products could be controlled well by improving the salification and crystallization process. As a result, the subtype II of ceftriaxone sodium with high stability can be produced.
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Objective: To study whether domestic chloramphenicol eye drops with different ethylparabenin content meet the re-quirements in Chinese Pharmacopoeia. Methods:Antimicrobial effect test was used to examine the antimicrobial effect of the different eye drops. Results:The antimicrobial effect of the eye drops was in compliance with the requirements in the pharmacopoeia. Conclu-sion:The ethylparabenin concentration in the eye drops is higher than necessary. Boric acid and borax not only can adjust pH, but also show antimicrobial effect.
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Macrolide antibiotics are broad-spectrum, with activity against a range of Gram-positive, Gram-negative organisms and some anaerobes. The components of macrolide antibiotics are generally complicated. Therefore, it is very important to establish impurity profiles of these antibiotics to ensure their safety and process control. Compared with classical methods, the liquid chromatography-mass spectrometry method is particularly advantageous to characterize minor components at trace levels in terms of sensitivity, efficiency and selectivity, thus more and more widely used in establishments of impurity profiles. In this study, the general approaches to characterize minor components in complex pharmaceutical matrix, fragmentation pathways of 14- and 16-membered macrolide antibiotics and the establishment of the impurity profile of acetylspiramycin were given to provide valuable enlightenments to establish the impurity profiles of pharmaceutical products.
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The quality of some earlier developed antibiotics is usually ensured by the combination of HPLC purity and microbiological potency measurement in the pharmacopoeias of various countries because the relationship between their purity and potency is not clearly quantified. Due to potency is assessed using certain units of measurement, it can not be directly traced to the international system of units (SI unit). This has become a hotspot in the study of the quantitative relationship between purity and potency of antibiotics. It would be quite an achievement to simultaneously determine both purity and potency using HPLC methods during quality control. This study evaluated a multicomponent antibiotic product, gentamycin, as a test sample. First, pure samples of the C components of gentamycin: C1a, C2, C2a and C1 were prepared, separately. Second, quantitative relationship (theoretical potency) between the purity and potency of each C component of gentamycin were determined using 1H NMR, HPLC-ELSD and microbiological assay method. One milligram of gentamycin C1a, C2, C2a and C1 was equal to 1 286.98, 1 095.74, 1 079.52 and 739.61 gentamycin units, respectively. Finally, a method for the determination of gentamycin potency was established based on the proportion and content of C components of gentamycin. The unification of purity and potency for gentamycin was achieved using only HPLC-ELSD. It is also demonstrated that C components of gentamycin and micronomicin produce the same responses under ELSD, which means that it is not necessary to prepare separate reference standards for each C component of gentamycin and that quantitative testing can be performed accurately using only one micronomicin reference standard. This study simplified the previous method for the determination of the content of C components of gentamycin using HPLC-ELSD. The developed method is suitable for regular use as a part of quality control and can simplify the rigmarole quality control procedures provided in current pharmacopeias.
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Aminoglycoside antibiotics, due to their strong antibacterial effects and broad antimicrobial spectra, have been very commonly used in clinical practice in the past half century. However, aminoglycoside antibiotics manifest severe ototoxicity and nephrotoxicity, and are one of top factors in hearing loss. In this study, three members of the aminoglycoside antibiotics family, gentamycin, neomycin and streptomycin, were chosen as the representatives to be investigated for their toxicity to the embryonic development and the larva hair cells in zebrafish, and also to their target genes associated with hearing-related genes. The results showed that: (1) the lethal effect of all three drugs demonstrated a significant dependence on concentration, and the severity order of the lethal effect was streptomycin > neomycin > gentamycin; (2) all the three drugs caused the larva trunk bending in resting state at 5 dpf (day past fertilization), probably due to their ototoxicity in the physical imbalance and postural abnormalities; (3) impairment and reducing of the hair cells were observed in all three cases of drug treatment; (4) four genes, eya1, val, otx2 and dlx6a, which play an important role in the development of hearing organs, showed differential and significant decrease of gene expression in a drug concentration-dependent manner. This study for the first time reports the relevance between the expression of hearing genes and the three ototoxic antibiotics and also proved the feasibility of establishing a simple, accurate, intuitive and fast model with zebrafish for the detection of drug ototoxicity.
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Objective To study on plasmid-mediated quinolone-resistant in Escherichia coli strains isolated from fecal samples of chicken and swine from the nine farms around our country.Methods Antimi-crobial susceptibility testing was carried out by broth microdilution testing,gyrA,gyrB,parC,qnr and aac (6')- Ⅰ b-cr were examined by PCR,and the products were sequenced.Conjugation experiment was carried out to proved that the plasmid-mediated quinolone resistance was transferable.Results In the total 818 animal isolates,qnr and aac genes were detected in 38 (4.6%) and 75 (9.2%) strains.The qnrA,qnrB,and qnrS genes were detected in 1 (0.1%),9 (1.1%) and 28 (3.4%) of the isolates.All isolates were negative for qnrC,qnrD genes.Conclusion There is a close relationship between high level quinolone resistance and plasmid-mediated quinolone resistance.The results of the current study highlight food-producing animals as a potential reservoir of antimicrobial-resistant bacteria and clinically important resistance genes.More attention should be paid to the surveillance of such strains.
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In recent years, more and more researchers focus on the selectivity of RP-HPLC columns. Among these columns, C18 column is the most commonly used the column. Yet even the same filler can not give us the same separation effect with the columns of different brands and different types, therefore, it is important to choose the suitable HPLC column for carrying out an experiment. After study in recent years, some column classification, selection methods (e.g.: column parameter method, F value method) have been achieved and contributed to the finding of suitable columns and reducing the blindness of column selection. This paper summarizes the advantages of these methods and their limitations in the application process, and gives some advices and expectations to pharmaceutical analysis works based on the works of other researchers.
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Abstract: Construction of a successful near infrared analysis model is a complex task. It spends a lot of manpower and material resources, and is restricted by sample collection and model optimization. So it is important to study on the extended application of the existing near infrared (NIR) models. In this paper, cephradine capsules universal quantitative model was used as an example to study on the feasibility of its extended application. Slope/bias correction and piecewise direct standardization correction methods were used to make the universal model to fit to predict the intermediates in manufacturing processes of cephradine capsules, such as the content of powder blend or granules. The results showed that the corrected NIR universal quantitative model can be used for process control although the results of the model correction by slope/bias or piecewise direct standardization were not as good as that of model updating. And it also indicated that the model corrected by slope/bias is better than that by piecewise direct standardization. Model correction provided a new application for NIR universal models in process control.
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With the establishment of HPLC and LC-MS methods to determine the related substances and the content of active pharmaceutical ingredient (API) in ipratropium bromide aerosol products, several packing material-related impurities were identified, including antioxygen BHT and antioxygen 2246. Results showed that these leachable additives from the packing materials may present at a relative high level in the drug solution, and the low content of API in the drug products is usually due to the adsorption of the packing material as well as the leaking of contents. The current available assay methods for the control of ipratropium bromide aerosol products are often lack of specificity and unable to assure the drug quality effectively. To meet the increasing attention on the regulations of drug packing materials, our research would be a pilot study, indicating that the inappropriate packing materials could cause the migration and adsorption of the active ingredients, and the importance to have compatibility studies between packing materials and drugs.
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A near infrared (NIR) method for the detection of illegal addition of sildenafil citrate in capsules of Chinese traditional medicine was constructed. The diffuse reflectance near infrared spectra were recorded using integrated sphere and fiber optics respectively. Using the spectra of the sildenafil citrate standard as Reference spectra, the threshold of the correlation coefficient was set up based on the minimum effective concentration of the sildenafil citrate. By comparing the threshold with the correlation coefficient between the tested spectra and the Reference spectra in the selected spectral range, the tested sample contains sildenafil citrate is determined. For the integrated sphere method, the spectral range of 6070-5800 cm~(-1) and 4170-4070 cm~(-1) were selected, and 70% was set as threshold. For the fiber method, 6070-5800 cm~(-1) and 65% were used. 79 and 247 batches of the Chinese traditional medicines contained sildenafil citrate collected from the Chinese market were used to validate the two methods separately. The accuracy of the integrated sphere method was 91.14%, and that of f iber method was 87.45%.