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The compatibility of kanamycin with sodium citrate for the formulation of kanamycin sulfate injection was determined, including optimization of the amount of sodium citrate in the injection and the sterilization process. An HPLC coupled with an evaporative light scattering detector (ELSD) was used to measure the amount of sodium citrate and the impurity profiles. A validated post-column derivatization HPLC coupled with a fluorescence detector (FLD) was used to determine the correlation between specific impurities in a domestic factory and sodium citrate, and then the formulation was evaluated by HPLC coupled with mass detector (MS) characterization of degradation products. The results show that the amount of sodium citrate in kanamycin sulfate injection from a domestic factory is about 40 times higher than that of the Meiji formulation. Several specific impurities can be detected in solutions heated under simulated sterilization conditions (121 ℃), which were correlated with the amount of sodium citrate. Impurities were characterized by HPLC-MS/MS, and data showed that the identified impurities were interaction products of kanamycin and sodium citrate. These results indicate that greater attention should be directed at formula optimization in domestic factories, as it is crucial to the safety and efficacy of the preparations. Drug-excipient chemical compatibility should also be evaluated in the development of pharmaceutical dosages forms especially when the active pharmaceutical ingredients have a primary amine group.
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OBJECTIVE: To characterize the impurity structures in vancomycin raw material. METHODS: Impurities were eluted gradiently on a Chromasil 100-5 C18(4.6 mm×250 mm, 5 μm) column, with triethylamine buffer solution (pH 3.2)-acetonitrile-tetrahydrofuran (92∶7∶1, V/V/V) as mobile phase A, and triethylamine buffer solution (pH 3.2)-acetonitrile-tetrahydrofuran (70∶29∶1, V/V/V) as mobile phase B. Stress tests were performed on the raw material to specify those impurities. By application of on-line LC/MSn method, the impurities were analyzed in positive mode and their structures were characterized based on the degradation mechanism and mass fragmentation regularity of sugar-lipopeptides. RESULTS: Totally 14 impurities were characterized in the raw material, seven of which were reported for the first time. The relationships between the chemical structures and chromatographic behaviors of vancomycin, demethylvancomycin and methylated vancomycin with their two β-isomers were summarized. CONCLUSION: The structures of related impurities in vancomycin raw material can be rapidly identified by on-line LC/MSn method together with stress degradation experiments.
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Impurity profiling is one of the most important activities in both assuring drug safety and improving the quality of domestic drugs. Since the basic strategy of impurity profile control was put forward in 2010, a mature control procedure for impurity profile in drugs has been formed in China after nearly ten years of continuous efforts. The progress in impurity profiling before 2010 and from 2010 to 2015 have been reviewed. Since 2015, the concepts, analytical techniques and the application of these techniques in this field have developed rapidly. As a result, the progress in impurity profiling of chemical drugs since 2015 was reviewed in this paper. And the views on future development of impurity profiling in drugs were also put forward.
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OBJECTIVE: To establish an HPLC-MS method for the analysis of the impurity profile of cefotaxime sodium. METHODS: Shimadzu-LCMS-IT-TOF was used with Waters XBridge Shield (RP18, 4.6 mm×250 mm, 5 μm) column. Mobile phase A was 20 mmol·L-1 ammonium acetate (pH adjusted to 6.25)-methanol (92: 8), and mobile phase B was set at 20 mmol·L-1 ammonium acetate-methanol (60: 40) (pH adjusted to 6.25).Gradient elution was performed at a flow rate of 1.0 mL·min-1. ESI source was used.Positive and negative ion scanning was conducted in the range of m/z 150-900.The heating temperature was 200℃, CDL temperature was maintained at 200℃, atomization gas flow rate was 1.5 L·min-1, dry gas pressure was 94.0 kPa, and the post-column diversion ratio was 1: 4.Some related substances in cefotaxime sodium were identified by comparing the retention time in chromatography, [M+H]+ spectrum and MS2 spectrum with those of reference substances, the others which haven't reference substances were deduced or speculated by analyzing the MS2 or MSn fragmentation with the help of a rule summarized from the MS2 fragmentation of cefotaxime sodium and the reference substances of system suitability impurities. RESULTS: Twenty-six related substances were separated and detected in the sample, all of which were identified or deduced. They were cefotaxime sodium isomeric compounds and homologs generated during the production process or degradation products. CONCLUSION: The method can be applied in the identification and qualitative analysis of the related substances of cefotaxime sodium and the quality control and optimization of the synthesis of cefotaxime sodium.
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OBJECTIVE: To study the impurity profile of cefradine dihydrate. METHODS: The impurity peaks of cefradine dihydrate were identified using column-switching technique and LC-MS, and the origination of the impurities were investigated by the forced degradation study. RESULTS: The impurity profile of cefradine dihydrate included fourteen impurities, nine of them were structure known impurities controlled by EP, two of them were newly identified impurities and three of them were structure unknown impurities. CONCLUSION: The origination and influence factors of the impurities are investigated though the impurity profile study of cefradine dihydrate, and it can provide reference for the quality control of cefradine dihydrate.
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OBJECTIVE: To establish an HPLC-UV-ESI-MSn method for the study of impurity profile of amoxicillin and clavulanate potassium tablets. METHODS: Agilent 1100 LC/MSD Trap liquid chromatography-mass spectrometry was used, and the column was Shim pack CLC-ODS RP18(4.6 mm×250 mm, 5 μm). The mobile phase A was 20 mmol·L-1 ammonium acetate (pH adjusted to 6.0), and the mobile phase B was 20 mmol·L-1 ammonium acetate-acetonitrile (20∶80) (pH adjusted to 6.0). Gradient elution was performed at a flow rate of 1.0 mL·min-1. ESI source was used. Positive and negative ion scan was conducted with a scanning range of m/z 100-1 500. The nebulizing pressure was 275.8 kPa, dry gas flow was 9 L·min-1, and post-column diversion ratio was 1∶5. Some related substances were identified by comparing the retention time in the chromatography, [M+H]+ spectrum and MS2 spectrum with those of the reference substances, while the others which do not have reference substances were deduced or speculated by analyzing the MS2 or MSn fragmentation with the help of a rule summarized from the MS2 fragmentation of amoxicillin, clavulanic acid and system suitability impurity reference substances. RESULTS: A total of 15 related substances were separated and characterized including nine known impurities like amoxicilloic acid, amoxicillin dimer, etc. and six unknown impurities. CONCLUSION: The method can be applied in the identification and qualitative analysis of the related substances in amoxicillin and clavulanate potassium tablets and is helpful for the quality control and optimization of the synthetic process.
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Objective To establish HPLC determination method and impurity profile of the related substances in metronidazole.Methods A Welch Ultimate(R)XB-C1s (4.6 mm× 250 mm,5 μm)was used with a mobile phase consisting of methanol-1.36 g· L-1 solution of potassium dihydrogen phosphate (20∶ 80).The detection wavelength was 315 nm and the flow rate was 1 mL· min-1.Its related substances were determined by principal component self-contrast method.Results Good separation of metronidazole and the impurities could be achieved.Twenty batches of samples in the past six years were determined which meet quality standards.The study of impurity profiles could effectively monitor the synthetic process and the change of impurities in metronidazole.Conclusion The method is simple,quick and sensitive,which can be used to control the related substances in metronidazole.Meanwhile,the impurity profiles ensure the quality stability of metronidazole.
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The critical attribute was analyzed in clavulanate potassium tablet of amoxicillin according to the principle QbD. By investigation of the drug impurity profile, the cycle-closed dimer and penicilloic acid of amoxicillin were considered to be the critical impurities, and the sources and the degradation pathways of these two impurities were discussed. The research confirmed that crystal form was the critical attribute of drug substance. The drying process in the tablet granulation was regarded as the critical process parameter. The tablet formulation was also another factor in the impurity generation. This study provides a new idea for the evaluation of drug quality.
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OBJECTIVE: To investigate the impurity profile of cloxacillin sodium for injection and study the source of major impurities. METHODS: The impurities in samples from seven manufacturers were profiled by an optimized reversed-phase HPLC method and a newly established normal-phase HPLC method. The major impurities were prepared by semi preparation technology and identified by LC-QTOF-MS, 1H-NMR and 13C-NMR. RESULTS: Two new impurities relating with the salt-forming reaction and the purification process respectively, and four other new impurities were all successfully identified in this study. CONCLUSION: The study is suitable for profiling the impurities in cloxacillin sodium for injection and is quite useful for enhancing the quality control.
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OBJECTIVE: To investigate the impurity profile of raloxifene thus to lay a foundation for the establishment of drug quality standard. METHODS: HPLC-IT-TOF-MS was adopted to analyze destroyed raloxifene and reference substances of impurities. According to the mass spectrometry fragmentation patterns of known impurities, the structures of unknown impurities were speculated. RESULTS: Destroyed raloxifene totally produced three impurities, one of which was unknown. Based on the regular mass spectrometry fragmentation patterns of raloxifene and known impurities, the unknown impurity was speculated to be a sulfone that was generated through further oxidation of raloxifene. CONCLUSION: The methods and results of this study could lay a foundation for the impurity control during production and in vivo analysis of raloxifene.
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OBJECTIVE: To investigate the impurity profile of ceftizoxime sodium for injection and develop the impurity control strategy.
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OBJECTIVE: To identify and analyze the potential impurities of methocarbamol on the basis of its synthetic route and starting materials.
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A simple gradient Ultra Performance liquid chromatographic method (UPLC) was developed for determination of lopinavir and ritonavir from its related impurities and assay for the first time. This method involves the use of a C18 (Acquity UPLC BEH C18, 50 × 2.1 mm, 1.7 µm) column thermostated at 30 oC using triethylamine (pH 2.2): 0.1% H3PO4 in acetonitrile and methanol (85:15) as mobile phase in gradient elution mode. A Photo Diode Array (PDA) detector set at 215 nm was used for detection with flow rate 0.4 mL/min. This method was validated over the range of limit of quantitation (LOQ) to 50 to 150% of impurity specification limit and of working concentration for assay. The developed method was validated for linearity, range, precision, accuracy and specificity. This method was successfully applied for content determination of lopinavir and ritonavir in pharmaceutical formulations. This method can be conveniently used in quality control laboratory for routine analysis for assay and related substances as well as for evaluation of stability samples of bulk drugs and pharmaceutical formulations.
Desenvolveu-se, pela primeira vez, método de cromatografia líquida de ultra-eficiência (UPLC), com gradiente simples, para a determinação de lopinavir e ritonavir e suas impurezas relativas. Esse método envolve o uso de C18 (Acquity UPLC BEH C18, 50 × 2,1 mm, 1,7 µm), termostatizada a 30 oC, utilizando-se trietilamina (pH 2,2) e fase móvel de H3PO4 0,1% em acetonitrila e metanol (85:15), em eluição por gradiente. Detector de arranjo de fotodiiodo (PDA), fixado a 215 nm, foi utilizado para a detecção, com fluxo de 0,4 mL/min. Esse método foi validado em faixa de limite de quantificação (LOQ) de 50 a 150% de limite de impureza e da concentração de trabalho para o ensaio. O método desenvolvido foi validado quanto à linearidade, faixa, precisão, exatidão e especificidade. Esse método foi aplicado com sucesso para a determinação de lopinavir e de ritonavir em formulações farmacêuticas. Tal método pode ser convenientemente utilizado em laboratório de controle de qualidade, não só para análise de rotina e ensaio de substâncias relacionadas, como também para a avaliação da estabilidade de amostras a granel ou em formulações farmacêuticas.