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Drug Compounds (drug + compound)
Selected AbstractsDrug release phenomena within a hydrophobic starch acetate matrix: FTIR mapping of tablets after in vitro dissolution testingJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2008Jari Pajander Abstract The aim of this study was to assess the utility of Fourier transform infrared mapping to study the drug release phenomena within a hydrophobic matrix tablet. Starch acetate with a degree of substitution (2.7) was used as a hydrophobic matrix former. Anhydrous caffeine and riboflavin sodium phosphate were used as water soluble model drugs. The USP (XXVIII) paddle-method was selected as an in vitro dissolution test. Mapping of the diluted tablets' cross-section was performed by attenuated total reflection mode. Fourier transform infrared mapping can distinguish drug particles from the bulk matrix and it can be considered as a valuable method for obtaining both quantitative and qualitative information on drug release processes. The physicochemical properties of the drug compound strongly contribute to its release behavior when the USP paddle in vitro dissolution test is used. Mapping of the riboflavin product revealed a more homogenous matrix distribution due to its smaller particle size. Consequently, its dissolution release profile was more uniform than caffeine which possessed a wider particle size distribution and lower solubility. Mapping showed that caffeine became localized in the lower part of the tablet unlike riboflavin. The hydrodynamic conditions during the in vitro release test might contribute to this differentiation. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 3367,3378, 2008 [source] Multivariate chemometric approach to thermal solid-state FT-IR monitoring of pharmaceutical drug compoundJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2008Wei Jian Tan Abstract The study of thermal-related solid-state reaction monitored by spectroscopic method needs the use of advanced multivariate chemometric approach. It is because visual inspection of spectral data on particular functional groups or spectral bands is difficult to reveal the complete physical and chemical information. The spectral contributions from various species involved in the solid-state changes are generally highly overlapping and the spectral differences between reactant and product are usually quite minute. In this article, we demonstrate the use of multivariate chemometric approach to resolve the in situ thermal-dependent Fourier-transform infrared (FT-IR) mixture spectra of lisinopril dihydrate when it was heated from 24 to 170°C. The collected FT-IR mixture spectra were first subjected to singular value decomposition (SVD) to obtain the right singular vectors. The right singular vectors were rotated into a set of pure component spectral estimates based on entropy minimization and spectral dissimilarity objective functions. The resulting pure component spectral estimates were then further refined using alternating least squares (ALS). In current study, four pure component spectra, that is, lisinopril dihydrate, monohydrate, anhydrate, and diketopiperazine (DKP) were all resolved and the relative thermal-dependent contributions of each component were also obtained. These relative contributions revealed the critical temperature for each transformation and degradation. This novel approach provides better interpretation of the pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state. In addition, it can be used to complement the information obtained from differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 3379,3387, 2008 [source] Nano-level detection of naltrexone hydrochloride in its pharmaceutical preparation at Au microelectrode in flowing solutions by fast fourier transforms continuous cyclic voltammetry as a novel detectorJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2007P. Norouzi Abstract An easy and fast Fourier transform continuous cyclic voltammetric technique for monitoring of ultra trace amounts of naltrexone in a flow-injection system has been introduced in this work. The potential waveform, consisting of the potential steps for cleaning, stripping and potential ramp, was continuously applied on an Au disk microelectrode (with a 12.5 µm in radius). The proposed detection method has some of advantages, the greatest of which are as follows: first, it is no more necessary to remove oxygen from the analyte solution and second, this is a very fast and appropriate technique for determination of the drug compound in a wide variety of chromatographic analysis methods. The method was linear over the concentration range of 0.34,34000 pg/mL (r,=,0.9985) with a limit of detection 8.0,×,10,4 nM. The method has the requisite accuracy, sensitivity, precision, and selectivity to assay naltrexone in tablets. The influences of pH of eluent, accumulation potential, sweep rate, and accumulation time on the determination of the naltrexone were considered. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:2009,2017, 2007 [source] Isobaric metabolite interferences and the requirement for close examination of raw data in addition to stringent chromatographic separations in liquid chromatography/tandem mass spectrometric analysis of drugs in biological matrixRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 13 2008Zhengyin Yan In addition to matrix effects, common interferences observed in liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses can be caused by the response of drug-related metabolites to the multiple reaction monitoring (MRM) channel of a given drug, as a result of in-source reactions or decomposition of either phase I or II metabolites. However, it has been largely ignored that, for some drugs, metabolism can lead to the formation of isobaric or isomeric metabolites that exhibit the same MRM transitions as parent drugs. The present study describes two examples demonstrating that interference caused by isobaric or isomeric metabolites is a practical issue in analyzing biological samples by LC/MS/MS. In the first case, two sequential metabolic reactions, demethylation followed by oxidation of a primary alcohol moiety to a carboxylic acid, produced an isobaric metabolite that exhibits a MRM transition identical to the parent drug. Because the drug compound was rapidly metabolized in rats and completely disappeared in plasma samples, the isobaric metabolite appeared as a single peak in the total ion current (TIC) trace and could easily be quantified as the drug since it was eluted at a retention time very close to that of the drug in a 12-min LC run. In the second example, metabolism via the ring-opening of a substituted isoxazole moiety led to the formation of an isomeric product that showed an almost identical collision-induced dissociation (CID) MS spectrum as the original drug. Because two components were co-eluted, the isomeric product could be mistakenly quantified and reported by data processing software as the parent drug if the TIC trace was not carefully inspected. Nowadays, all LC/MS data are processed by computer software in a highly automated fashion, and some analysts may spend much less time to visually examine raw TIC traces than they used to do. Two examples described in this article remind us that quality data require both adequate chromatographic separations and close examination of raw data in LC/MS/MS analyses of drugs in biological matrix. Copyright © 2008 John Wiley & Sons, Ltd. [source] Monitoring of Anti Cancer Drug Letrozole by Fast Fourier Transform Continuous Cyclic Voltammetry at Gold MicroelectrodeCHINESE JOURNAL OF CHEMISTRY, Issue 7 2010Parviz Norouzi Abstract A continuous cyclic voltammetric study of letrozole at gold microelectrode was carried out. The drug in phosphate buffer (pH 2.0) is adsorbed at ,200 mV, giving rise to change in the current of well-defined oxidation peak of gold in the flow injection system. The proposed detection method has some of advantages, the greatest of which are as follows: first, it is no more necessary to remove oxygen from the analyte solution and second, this is a very fast and appropriate technique for determination of the drug compound in a wide variety of chromatographic analysis methods. Signal-to-noise ratio has significantly increased by application of discrete Fast Fourier Transform (FFT) method, background subtraction and two-dimensional integration of the electrode response over a selected potential range and time window. Also in this work some parameters such as sweep rate, eluent pH, and accumulation time and potential were optimized. The linear concentration range was of 1.0×10,7,1.0×10,10 mol/L (r=0.9975) with a limit of detection and quantitation 0.08 nmol/L and 0.15 nmol/L, respectively. The method has the requisite accuracy, sensitivity, precision and selectivity to assay letrozol in tablets. The influences of pH of eluent, accumulation potential, sweep rate, and accumulation time on the determination of the letrozol were considered. [source] Biorelevant media simulating fed state intestinal fluids: Colloid phase characterization and impact on solubilization capacityJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2010Karen Kleberg Abstract The purpose of the present study was to study the impact of free fatty acid and monoglyceride level and ratio on the nanostructural composition and solubilizing capacity of media simulating fed state intestinal fluids (SIFs). SIFs, without or with oleic acid/monoolein (OA/MO) in ratios of 2:1 or 6:1 were composed and characterized by surface tension, dynamic light scattering, and cryogenic transmission electron microscopy. Additionally solubilizing capacities towards three poorly water-soluble compounds: danazol, fenofibrate, and cinnarizine, were assessed. The surface tension of the media was not affected by the OA/MO ratio but only determined by the total surfactant concentration. The media with no lipolysis products only contained micelles, whereas media with lipolysis products also contained vesicles and other colloidal structures. The structures in the 6:1 media were more numerous and more well-defined regarding shape and size. The nanostructural composition of the media did influence the solubilizing capacity toward fenofibrate and cinnarizine, but not toward danazol. The relative composition of SIFs is important for the solubilizing capacity of some drug compounds. The findings in this study suggest that the affinity of the drug to the different colloidal structures is determining for the solubility of the compound in the media. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3522,3532, 2010 [source] A novel peroxy radical based oxidative stressing system for ranking the oxidizability of drug substancesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2006Paul A. Harmon Abstract A novel oxidative stressing system is described which generates high levels of peroxy radicals in solution at room temperature, without the use of azonitrile initiators. The oxidative stressing system is composed of a 10% solution of Tween 80 in water to which FeCl3,·,6H2O is added. The Tween 80 acts as a solubilizing agent for drug compounds, and also contains substantial amounts of organic hydroperoxides. It is shown that the Fe III/ Fe II couple operates on the hydroperoxide concentration to effectively generate new peroxy radicals, which then propagate in the Tween 80 solution. Key features of the Tween 80/Fe III system are investigated, and the oxidizability of seven known compounds and ten developmental compounds are examined. Relative reaction rates span a 300-fold range, from benzoic acid (nonreactive, defined as <0.5% reacted per day) to Vitamin D3 (7% reacted per hour). Oxidizability "rankings" thus generated are shown to agree well with azonitrile initiated oxidative stress. The potential for general correlations between this type of oxidizability data and actual oxidative performance in LFC and solid oral dosage forms is discussed. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 2014,2028, 2006 [source] Evaluation of the Effect of Ethanol's Toxic Metabolite Acetaldehyde on the Gastrointestinal Oligopeptide Transporter, PEPT1: In Vitro and in Vivo StudiesALCOHOLISM, Issue 1 2008Scott J. Fisher Background:, The effects of alcohol consumption and its subsequent metabolism on drug transport, absorption and pharmacokinetics are poorly understood. This study examines the effects of the ethanol metabolite, acetaldehyde, on the clinically relevant drug transporter, PEPT1. The metabolism of ethanol and the following acetaldehyde formation is thought to modulate the uptake capacity of PEPT1 within the gastrointestinal tract for a variety of clinically important peptidomimetic drug compounds. Methods:, Glycylsarcosine ([3H]-GlySar), a nonhydrolysable PEPT1 specific substrate was used in our studies. In vitro uptake studies were performed in the Caco-2 and Chinese hamster ovary (CHO)-hPEPT1 cell models, measuring cellular uptake of labeled compound against increasing levels of unlabeled compound in the presence of acetaldehyde. In vivo absorption of [3H]-GlySar was measured in male Sprague,Dawley rats that were treated with oral dose of ethanol/disulfiram (5 g/kg / 100 mg/kg) for 6 days. These results were compared to control rats treated with saline, ethanol alone or disulfiram alone. Results:, In vitro uptake of [3H]-GlySar in CHO-hPEPT1 cells treated with 1 mM acetaldehyde was significantly decreased (p < 0.05) as compared to untreated controls. The uptake of [3H]-GlySar in Caco-2 cell monolayers treated with 1 mM acetaldehyde was also significantly decreased as compared to the untreated control cells. In vivo absorption of [3H]-GlySar in ethanol treated rats, as measured by AUC0,12 hours were decreased by approximately 50% versus the control rat group. Conclusion:, The effects of acetaldehyde due to consumption of ethanol on the uptake and bioavailability of therapeutic drug compounds transported by the PEPT1 oligopeptide transporter have not been documented. In the present studies, we demonstrate that acetaldehyde significantly modulates PEPT1 function and, thereby, affects drug bioavailability. To our best knowledge, this is the first report on the effects of an ethanol metabolite on substrate absorption in the gastrointestinal tract, rather than interactions in the liver, which is an under-represented area of research in alcohol pathophysiology. [source] Determination of pKa values of nonsteroidal antiinflammatory drug-oxicams by RP,HPLC and their analysis in pharmaceutical dosage formsJOURNAL OF SEPARATION SCIENCE, JSS, Issue 17 2009Ebru Cubuk Demiralay Abstract In this study, pKa values were determined by using the dependence of the capacity factor on the pH of the mobile phase for four ionizable substances, namely, tenoxicam, piroxicam, meloxicam, and naproxen (I.S.). The effect of the mobile phase composition on the ionization constant was studied by measuring the pKa at different ACN concentrations, ranging from 30 to 40%. The adequate condition for the chromatographic determination of these compounds in pharmaceutical dosage forms was established based on the different retention behaviors of the species. An octadecylsilica Nucleosil C18 column (150×4.6 mm, 5 ,m) was used for all the determinations. The chromatographic separation of oxicams was carried out using acetonitrile (ACN)/water at 35% v/v, containing 65 mM phosphoric acid and UV detection at a wavelength of 355 nm. The method developed was successfully applied to the simultaneous determination of these drug compounds in laboratory-prepared mixtures and their commercial pharmaceutical dosage forms. Each analysis requires no longer than 12 min. [source] Characterisation of indomethacin and nifedipine using variable-temperature solid-state NMRMAGNETIC RESONANCE IN CHEMISTRY, Issue 11 2005David C. Apperley Abstract We have characterised the stable polymorphic forms of two drug molecules, indomethacin (1) and nifedipine (2) by 13C CPMAS NMR and the resonances have been assigned. The signal for the CCl carbon of indomethacin has been studied as a function of applied magnetic field, and the observed bandshapes have been simulated. Variable-temperature 1H relaxation measurements of static samples have revealed a T1, minimum for indomethacin at 17.8 °C. The associated activation energy is 38 kJ mol,1. The relevant motion is probably an internal rotation and it is suggested that this involves the COCH3 group. Since the two drug compounds are potential candidates for formulation in the amorphous state, we have examined quench-cooled melts in detail by variable-temperature 13C and 1H NMR. There is a change in slope for and at the glass transition temperature (Tg) for indomethacin, but this occurs a few degrees below Tg for nifedipine, which is perhaps relevant to the lower real-time stability of the amorphous form for the latter compound. Comparison of relaxation time data for the crystalline and amorphous forms of each compound reveals a greater difference for nifedipine than for indomethacin, which again probably relates to real-time stabilities. Recrystallisation of the two drugs has been followed by proton bandshape measurements at higher temperatures. It is shown that, under the conditions of the experiments, recrystallisation of nifedipine can be detected already at 70 °C, whereas this does not occur until 110 °C for indomethacin. The effect of crushing the amorphous samples has been studied by 13C NMR; nifedipine recrystallises but indomethacin does not. The results were supported by DSC, powder XRD, FTIR and solution-state NMR measurements. Copyright © 2005 John Wiley & Sons, Ltd. [source] Improved detection of reactive metabolites with a bromine-containing glutathione analog using mass defect and isotope pattern matchingRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 9 2010André LeBlanc Drug bioactivation leading to the formation of reactive species capable of covalent binding to proteins represents an important cause of drug-induced toxicity. Reactive metabolite detection using invitro microsomal incubations is a crucial step in assessing potential toxicity of pharmaceutical compounds. The most common method for screening the formation of these unstable, electrophilic species is by trapping them with glutathione (GSH) followed by liquid chromatography/mass spectrometry (LC/MS) analysis. The present work describes the use of a brominated analog of glutathione, N -(2-bromocarbobenzyloxy)-GSH (GSH-Br), for the invitro screening of reactive metabolites by LC/MS. This novel trapping agent was tested with four drug compounds known to form reactive metabolites, acetaminophen, fipexide, trimethoprim and clozapine. Invitro rat microsomal incubations were performed with GSH and GSH-Br for each drug with subsequent analysis by liquid chromatography/high-resolution mass spectrometry on an electrospray time-of-flight (ESI-TOF) instrument. A generic LC/MS method was used for data acquisition, followed by drug-specific processing of accurate mass data based on mass defect filtering and isotope pattern matching. GSH and GSH-Br incubations were compared to control samples using differential analysis (Mass Profiler) software to identify adducts formed via the formation of reactive metabolites. In all four cases, GSH-Br yielded improved results, with a decreased false positive rate, increased sensitivity and new adducts being identified in contrast to GSH alone. The combination of using this novel trapping agent with powerful processing routines for filtering accurate mass data and differential analysis represents a very reliable method for the identification of reactive metabolites formed in microsomal incubations. Copyright © 2010 John Wiley & Sons, Ltd. [source] Product ion mass spectra of amphetamine-type substances, designer analogues, and ketamine using ultra-performance liquid chromatography/tandem mass spectrometry,RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 15 2006Luigino G. Apollonio This paper describes the application of ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) technology to separate and identify amphetamine-type substances (amphetamine, methamphetamine), common and novel designer analogues (MDA, MDMA, PMA, 4-MTA, MBDB), and ketamine using Acquity UPLC/Micromass Quattro Micro API mass spectrometer instrumentation (Waters Corporation, USA). From injection of drug reference standards, it was demonstrated that these compounds can be identified by product ion mass spectra in less than 4,min total analysis time, indicating that the technological advancements associated with UPLC/MS/MS allow it to serve as a powerful analytical tool for high-throughput testing. In addition to demonstrating the separation and response of these drug compounds under the stated UPLC/MS/MS conditions, we believe the acquired product ion spectra will be a beneficial reference to laboratories interested in incorporating the use of this technology in the routine analysis of drugs of abuse. Copyright © 2006 John Wiley & Sons, Ltd. [source] Beta-3 versus beta-2 adrenergic agonists and preterm labour: in vitro uterine relaxation effectsBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 6 2001Michael C. Dennedy Objective 1. To investigate the effects of the selective beta-3 adrenoreceptor agonist, BRL 37344, on human pregnant myometrial contractility in vitro. 2. to compare these effects with those of the beta-2 adrenoreceptor agonist, ritodrine. Methods Isometric tension recording was performed under physiological conditions in isolated myometrial strips from biopsies obtained at elective caesarean section. Following pre-incubation with oxytocin (10 -9 M), the effects of cumulative additions of BRL 37344 or ritodrine (10 -8,10 -3.5 M) on myometrial contractility were investigated. Results were expressed as -log EC50 (pD2) and mean maximal inhibition achieved for both drug compounds. Results BRL 37344 exerted a concentration dependant relaxant effect on myometrial contractions in all strips exposed [pD2, 7.26 (0.48) (SEM); mean maximal inhibition 61.98 (4.89%); n= 6]. Similarly, ritodrine exerted a concentration dependant inhibition of myometrial contractility in all strips exposed [pD2= 7.40 (0.28); mean maximal inhibition 59.49 (3.97%); n= 6]. There was no significant difference between calculated pD2 values (P= 0.65) or mean maximal inhibition achieved (P= 0.79). Conclusions The beta-3 adrenoreceptor agonist BRL 37344 induced relaxation of human myometrial contractions with similar potency to that of the most commonly used tocolytic agent ritodrine. This raises the possibility that the novel beta-3 adrenoreceptor agonists may have potential as therapeutic agents for human preterm labour. In view of their reported reduced cardiovascular side effects their potential clinical use requires further evaluation. [source] Antibiotic Resistance in Bacteria: Novel Metalloenzyme InhibitorsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2009Sung-Kun Kim ,-Lactam antibiotics are among the most important drugs used to fight bacterial infection. Overuse and misuse of ,-lactam antibiotics has caused the evolution of resistance mechanisms, allowing pathogenic bacteria to survive antibiotic treatment. The major source of resistance to ,-lactam antibiotics occurs through production of enzymes called ,-lactamases capable of catalyzing hydrolysis of the ,-lactam rings in these drug compounds. The metallo-,-lactamases have become a major threat due to their broad substrate specificities; there are no clinically useful inhibitors for these metalloenzymes. We have obtained single-stranded DNA's that are potent inhibitors of the Bacillus cereus 5/B/6 metallo-,-lactamase. These are rapid, reversible, non-competitive inhibitors of the metalloenzyme, with Ki and Ki, values in the nanomolar range. The inhibition patterns and metal ion dependence of their inhibition suggest that the oligonucleotides alter the coordination of the active site metal ion(s); inhibition is efficient and highly specific. Microbiological growth experiments, using combinations of ssDNA with the ,-lactam antibiotic cephalexin, reveal that the inhibitor is capable of causing cell death in liquid cultures of both Gram-positive and Gram-negative metallo-,-lactamase producing bacteria in the micromolar concentration range. [source] | |||||||||||||