Journal of Pharmaceutical Analysis

Development of cell metabolite analysis on microfluidic platform

Luyao Lin, Jin-Ming Lin

2015, (6): 337-347. doi: 10.1016/j.jpha.2015.09.003

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abstract Cell metabolite analysis is of great interest to analytical chemists and physiologists, with some meta-bolites having been identified as important indicators of major diseases such as cancer. A high-throughput and sensitive method for drug metabolite analysis will largely promote the drug discovery industry. The basic barrier of metabolite analysis comes from the interference of complex components in cell biological system and low abundance of target substances. As a powerful tool in biosample analysis, microfluidic chip enhances the sensitivity and throughput by integrating multiple functional units into one chip. In this review, we discussed three critical steps of establishing functional microfluidic platform for cellular metabolism study. Cell in vitro culture model, on chip sample pretreatment, and microchip combined detectors were described in details and demonstrated by works in five years. And a brief summary was given to discuss the advantages as well as challenges of applying microchip method in cell metabolite and biosample analysis.

Thermal stability and hydration behavior of ritonavir sulfate:A vibrational spectroscopic approach

Kaweri Gambhir, Parul Singh, Deepak K Jangir, Ranjana Mehrotra

2015, (6): 348-355. doi: 10.1016/j.jpha.2015.05.001

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abstract Ritonavir sulfate is a protease inhibitor widely used in the treatment of acquired immunodeficiency syndrome. In order to elucidate the inherent stability and sensitivity characteristics of ritonavir sulfate, it was investigated under forced thermal and hydration stress conditions as recommended by the Inter-national Conference on Harmonization guidelines. In addition, competency of vibrational (infrared and Raman) spectroscopy was assessed to identify structural changes of the drug symbolizing its stress de-gradation. High performance liquid chromatography was used as a confirmatory technique for both thermal and hydration stress study, while thermogravimetric analysis/differential thermal analysis and atomic force microscopy substantiated the implementation of vibrational spectroscopy in this frame-work. The results exhibited high thermal stability of the drug as significant variations were observed in the diffuse reflectance infrared Fourier transform spectra only after the drug exposure to thermal ra-diations at 100 °C. Hydration behavior of ritonavir sulfate was evaluated using Raman spectroscopy and the value of critical relative humidity was found to be 4 67%. An important aspect of this study was to utilize vibrational spectroscopic technique to address stability issues of pharmacological molecules, not only for their processing in pharmaceutical industry, but also for predicting their shelf lives and suitable storage conditions.

Identification, synthesis and characterization of process related desfluoro impurity of ezetimibe and HPLC method validations

Esen Bellur Atici, Bekir Karl??a

2015, (6): 356-370. doi: 10.1016/j.jpha.2015.04.002

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Ezetimibe, which selectively inhibits cholesterol absorption across the intestinal wall and is used as an antihyperlipidemic agent, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of ezetimibe, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in reverse phase gradient high performance liquid chro-matography (HPLC) method and its molecular weight was determined by LC–MS analysis. The impurity was identified as (3R,4S)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)-1-phenyla-zetidin-2-one which is called desfluoro ezetimibe (lactam-related) impurity, synthesized and char-acterized, the mechanism of its formation was discussed in detail. After all standardization procedures, it was used as a reference standard during validation of HPLC method and routine analyses. In addition, content of Eze-1 desfluoro impurity in Eze-1 intermediates was specified as 0.10%to keep the formation of desfluoro ezetimibe impurity under control and the related substances HPLC method was validated accordingly.

Quantification of tolvaptan in rabbit plasma by LC-MS/MS:Application to a pharmacokinetic study

Kumar S. Moola, Bala Sekhara Reddy Challa, Chandrasekhar Kothapalli Bannoth

2015, (6): 371-377. doi: 10.1016/j.jpha.2014.09.001

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A sensitive, selective and high-throughput liquid chromatography–tandem mass spectrometry (LC–ESI–MS/MS) method was developed and validated for the quantitation of tolvaptan in rabbit plasma. Sample clean-up involved liquid–liquid extraction (LLE) and chromatography was performed on Zorbax SB C18 analytical column (50 mm ? 2.1 mm, 3.5 mm) using 0.1%formic acid:methanol (20:80, v/v) as the mobile phase. The parent-product ion transitions for the drug (m/z 449.2-252.1) and IS (m/z 456.2-259.2) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and positive ion mode. The method was validated over the concentration range of 0.10–1000.00 ng/mL and successfully applied to a pharmacokinetic study of healthy rabbits.

Antimicrobial and antiproliferative prospective of kosinostatin-a secondary metabolite isolated from Streptomyces sp.

Vinayagam Rambabu, Subramaniyan Suba, Suburamaniyan Vijayakumar

2015, (6): 378-382. doi: 10.1016/j.jpha.2014.11.002

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Cancer is a communal health hazard worldwide. The present investigation attempts to evaluate anti-microbial and anticancer potential of kosinostatin on mammary carcinoma cell line (MCF-7). The an-ticancer and antiproliferative activities of kosinostatin were analyzed on MCF cell line by MTT assay and cytotoxicity assays like lactate dehydrogenase (LDH) and glutathione (GSH). The secondary metabolite kosinostatin exhibited its apoptotic nature by expressing p53 protein. Collectively, the results acquired from this study promise that kosinostatin shows the potent anticancer activity.

Optimization, validation and application of an assay for the activity of HMG-CoA reductase in vitro by LC-MS/MS

Jing Wang, Ji-Ye Sun, Chun-Jie Sha, Yu-Feng Shao, Yan-Hong Liu, You-Xin Li, Zhen-Wen Duan, Wan-Hui Liu

2015, (6): 383-388. doi: 10.1016/j.jpha.2015.06.002

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A stable HMG-CoA reductase (HMGR) reaction in vitro was developed by a sensitive, selective and precise liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. The optimized enzyme reac-tion condition contained 1.5μg of HMGR, 20 nM of NADPH with 50 min of reaction time. The method was validated by several intra-and inter-day assays. The production transitions of m/z 147.0/59.1 and m/z 154.0/59.1 were used to detect and quantify mevalonolactone (MVAL) and MVAL-D7, respectively. The accuracy and precision of the method were evaluated over the concentration range of 0.005–1.000μg/mL for MVAL and 0.010–0.500μg/mL for lovastatin acid in three validation batch runs. The lower limit of quantitation was found to be 0.005μg/mL for MVAL and 0.010μg/mL for lovastatin acid. Intra-day and inter-day precision ranged from 0.95%to 2.39%and 2.26%to 3.38%for MVAL, 1.46%to 3.89%and 0.57% to 5.10% for lovastatin acid, respectively. The results showed that the active ingredients in Xuezhikang capsules were 12.2 and 14.5 mg/g, respectively. This assay method could be successfully applied to the quality control study of Xuezhikang capsule for the first time.

In vitro-in vivo studies of the quantitative effect of calcium, multivitamins and milk on single dose ciprofloxacin bioavailability

Baishakhi Dey, Prakash Katakam, Fathi H. Assaleh, Babu Rao Chandu, Shanta Kumari Adiki, Analava Mitra

2015, (6): 389-395. doi: 10.1016/j.jpha.2015.02.003

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Ciprofloxacin, commonly used in India as an anti-microbial for prolonged use in chronic and non-specific indications, may affect the bioavailability of the drug. The drug prescribed is commonly taken with multivitamins, calcium and milk. A simple and reliable analytical methodology obtaining a correlation with in vivo urinary excretion studies using UV and HPLC and in vitro dissolution studies (IVIVC) has shown a significant increase in elimination rate of ciprofloxacin co-administered with multivitamins, calcium and milk. Appreciable IVIVC results proved that dissolution studies could serve as an alternative to in vivo bioavailability and also support bio-waivers.

Comparative study of adsorptive role of carbonaceous materials in removal of UV-active impurities of paclitaxel extracts

Jaber Nasiri, Elaheh Motamedi, Mohammad Reza Naghavi

2015, (6): 396-399. doi: 10.1016/j.jpha.2015.04.004

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Graphite oxide (GO) and reduced graphene oxide (rGO) nanosheets were synthesized with a low-cost manufacturing method. The morphology and structures of the synthesized samples were studied using X-ray diffraction (XRD), atomic force microscopy (AFM), Fourier-transform infrared (FTIR) and Raman spectroscopy. The efficiencies of GO and rGO as novel candidate adsorbents in the pre-purification of paclitaxel were compared and contrasted with those of commercial graphite (Gt), graphene (G) and multi-wall carbon nanotube (MWCNT). According to UV–vis and HPLC analyses, rGO was evaluated as the best absorbent for the removal of impurities in pre-purification of paclitaxel from plant cell cultures. In contrast, the GO had the poorest proficiency for paclitaxel pre-purification in comparison with the other carbonaceous adsorbents. This is attributed to the existence of many localized defects in the π-structure of GO that is related to weakness ofπ–πstacking interactions between crude extract impurities and GO.

Application of analytical instruments in pharmaceutical analysis

2015, (6): 400-403.

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JPA Prize in 2014

2015, (6): 404-404.

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2015 Vol. 5, No. 6