Apparent Zero-order Kinetics Research Articles

Development of a Large-Scale Copper(I)/TEMPO-Catalyzed Aerobic Alcohol Oxidation for the Synthesis of LSD1 Inhibitor GSK2879552

An improved process to an aldehyde en route to an LSD1 inhibitor was developed using an aerobic oxidation with a CuI and TEMPO (2,2,6,6-tetramethylpiperdine 1-oxyl) catalyst system. In this report, kinetic information is utilized to understand the generation a of number of key byproducts that affect catalyst performance and aldehyde yield. Insight into factors affecting the formation of these byproducts is presented. This CuI/TEMPO catalyst facilitates rapid conversion of the starting aliphatic alcohol in 1–2 h with apparent zero-order kinetics unprecedented for this substrate class with this catalyst system. Process optimization of catalyst components and reaction solvent led to the successful 400 g scale-up of this oxidation with bubbling air in a batch reactor.

Kinetic study of the photocatalytic degradation of the C-polymorph of a stearic acid microcrystal grown on an amorphous titania surface scattered with anatase microdomains

The photodegradation of a stearic acid (SA) microcrystal on an amorphous titania film surface scattered with submicrometric anatase domains is observed using a Reflected Light – Differential Interference Contrast (RL-DIC) microscopy. The SA microcrystal, grown from a saturated solution, is flat and rhombus-shaped with acute angle of 55° in agreement with the C-polymorph of SA crystal. We observe that the photodegradation initiates at the anatase microdomains under the microcrystal and creates SA holes in the shape of truncated-rhombus or elongated-hexagons having the same orientation and symmetry as the SA microcrystal. The expansion of the SA holes is ascribed to a photodegradation mechanism mediated by the photogeneration and surface diffusion of radical species across the gap between the anatase microdomain and the edges of the SA holes. A detail kinetic study of the SA holes expansion shows that the surface area of the SA holes scales almost linearly with UV exposure time in good agreement with an apparent zero-order kinetics. The morphology and the expansion kinetics of these holes are rationalized through the orientation dependence of the reactivity of the molecules with the radical species.

Characterization of the Sublimation and Vapor Pressure of 2-(2-Nitrovinyl) Furan (G-0) Using Thermogravimetric Analysis: Effects of Complexation with Cyclodextrins.

In the present work, the sublimation of crystalline solid 2-(2-nitrovinyl) furan (G-0) in the temperature range of 35 to 60 °C (below the melting point of the drug) was studied using thermogravimetric analysis (TGA). The sublimated product was characterized using Fourier-transformed-infrared spectroscopy (FT-IR) and thin layer chromatography (TLC). The sublimation rate at each temperature was obtained using the slope of the linear regression model and followed apparent zero-order kinetics. The sublimation enthalpy from 35 to 60 °C was obtained from the Eyring equation. The Gückel method was used to estimate the sublimation rate and vapor pressure at 25 °C. Physical mixtures, kneaded and freeze-dried complexes were prepared with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and analyzed using isothermal TGA at 50 °C. The complexation contributed to reducing the sublimation process. The best results were achieved using freeze-dried complexes with both cyclodextrins.

Thermogravimetric study of vapor pressure of TATP synthesized without recrystallization

This study aims at characterizing the vapor pressure signatures generated by triacetone triperoxide (TATP) that was synthesized without recrystallization by thermogravimmetric analysis (TGA) for exploitation by standoff detection technologies of explosive devices. The thermal behavior of the nonrecrystallized sample was compared with reported values. Any phase change, melting point and decomposition identification were studied by differential scanning calorimeter. Vapor pressures were estimated by the Langmuir method of evaporation from an open surface in a vacuum. Vapor pressures of TATP at different temperatures were calculated using the linear logarithmic relationship obtained from benzoic acid reference standard. Sublimation of TATP was found to follow apparent zero-order kinetics and sublimes at steady rates at 298K and above. While the enthalpy of sublimation found, 71.7kJmol−1, is in agreement with reported values the vapor pressures deviated significantly. The differences in the vapor pressures behavior are attributable to the synthesis pathway chosen in this study.

Stability Indicating Liquid Chromatographic Method for the Determination of Fenofibrate and its Application to Kinetic Studies

A stability-indicating LC assay method was developed for the quantitative determination of fenofibrate (FFB) in pharmaceutical dosage form in the presence of its degradation products and kinetic determinations were evaluated in acidic, alkaline and peroxide degradation conditions. Chromatographic separation was achieved by use of Zorbax C18 column (250 × 4.0 mm, 5 μm). The mobile phase was established by mixing phosphate buffer (pH adjusted 3 with phosphoric acid) and acetonitrile (30:70 v/v). FFB degraded in acidic, alkaline and hydrogen peroxide conditions, while it was more stable in thermal and photolytic conditions. The described method was linear over a range of 1.0-500 μg/ml for determination of FFB (r= 0.9999). The precision was demonstrated by relative standard deviation (RSD) of intra-day (RSD= 0.56– 0.91) and inter-day studies (RSD= 1.47). The mean recovery was found to be 100.01%. The acid and alkaline degradations of FFB in 1M HCl and 1M NaOH solutions showed an apparent zero-order kinetics with rate constants 0.0736 and 0.0698 min−1 respectively and the peroxide degradation with 5% H2O2 demonstrated an apparent first-order kinetics with rate constant k = 0.0202 per min. The t1/2, t90 values are also determined for all the kinetic studies. The developed method was found to be simple, specific, robust, linear, precise, and accurate for the determination of FFB in pharmaceutical formulations.

Mechanical grinding effect on thermodynamics and inclusion efficiency of loratadine-cyclodextrin inclusion complex formation.

The interaction of poor water-soluble drug loratadine (LOR) with β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous or solid state was investigated. Mechanical grinding effect on the inclusion steps, thermodynamic kinetics and inclusion efficiency of inclusion complex formation of LOR with β-CD or HP-β-CD was quantitatively investigated by DSC and FT-IR microspectroscopy with curve-fitting analysis. The phase solubility profiles of LOR with β-CD and HP-β-CD were classified as AL-type phase diagram. The grinding-induced reduction in LOR crystallinity in the presence of β-CD or HP-β-CD was found to be apparent zero-order kinetics. The inclusion efficiency of solid inclusion complex for LOR/β-CD or LOR/HP-β-CD was significantly correlated with the reduction in LOR crystallinity and the grinding time. The mechanism of inclusion complex formation for LOR/β-CD or LOR/HP-β-CD was proposed through the progressive reduction in LOR crystallinity, the promoted LOR amorphization, and molecular inclusion processes in the continuous energy input process of mechanical grinding.

Hydrolysis of Surfactants Containing Ester Bonds: Modulation of Reaction Kinetics and Important Aspects of Surfactant Self-Assembly

The effects of self-assembly on the hydrolysis kinetics of surfactants that contain ester bonds are discussed. A number of examples on how reaction rates and apparent reaction orders can be modulated by changes in the conditions, including an instance of apparent zero-order kinetics, are presented. Furthermore, it is shown that the examples on reaction kinetics display parallels and connections to important physicochemical aspects of surfactant aggregates, namely, the “reservoir function” of micelles and the fact that the headgroup region of micelles constitutes an aqueous environment largely distinct from the bulk solution. The examples presented can be used in teaching organic as well as physical chemistry. The text is written with the intention to be largely self-contained, in order to make it accessible for readers with different background experience.

Modeling and experimental evaluation of vacuum-UV photoreactors for water treatment

Vacuum-UV (VUV) radiation is a promising and effective technology for the oxidation of organic contaminants. The VUV-induced degradation of a model pollutant, Formic Acid (FA), was modeled and experimentally investigated. Experimental work involved an annular flow-through reactor operated in batch mode with complete recycle of the reactants. Ozone-producing low-pressure Hg lamps were used as the source of VUV radiation. FA concentrations of up to 0.55 mmol L −1 were completely degraded after 40 min of irradiation. FA degradation was accompanied by the formation of H 2O 2 at concentrations of about 0.3 mmol L −1. Kinetic and radiation models were combined with the corresponding mass balances to describe the experimental results. The kinetic model accounted for the most important reactions occurring in the system, including photolysis of water and H 2O 2, side reactions between radicals, and degradation of FA. The radiation model, which was solved using the Monte Carlo method, described the propagation of photons in the reactor volume and took into account the optical properties of the solution and the emission power of the lamps, obtained by actimometry. Modeling simulations fit experimental data of FA degradation using VUV, H 2O 2/VUV, and H 2O 2/UV with a root mean square error of 7.4%. According to modeling and experimental results, the VUV-induced degradation of FA followed an apparent zero order kinetics, a fact that may suggest the reaction was limited by the availability of hydroxyl radicals (HO ).

Stress Degradation Studies and Kinetic Determinations of Duloxetine Enteric-Coated Pellets by HPLC

A stability-indicating HPLC assay method was developed for the quantitative determination of duloxetine (DLX) in a pharmaceutical dosage form in the presence of its degradation products, and kinetic determinations were evaluated in acid conditions and UV-C radiation exposure. Chromatographic separation was achieved by use of an ACE C18 column (250 x 4.0 mm id, 5 microm particle size). The mobile phase was prepared by mixing aqueous 50 mM potassium phosphate buffer (pH 6.0 containing 0.3% triethylamine) and acetonitrile (60 + 40, v/v). DLX was rapidly degraded in an acid medium and in the presence of hydrogen peroxide and UV-C radiation; it was more stable in alkaline medium. The described method was linear over a range of 4.0-14.0 microg/mL for determination of DLX (r = 0.9998). The precision was demonstrated by the RSD of intraday (0.79-1.07%) and interday (0.85%) studies. The mean recovery was found to be 100.56%. The acid degradation of DLX in 0.1 M HCI solution showed an apparent zero-order kinetics (k = 0.177 microg/mL/min), and the photodegradation demonstrated an apparent first-order kinetics (k = 0.082 microg/mL/min). The developed method was found to be simple, specific, robust, linear, precise, and accurate for the determination of DLX in enteric-coated pellets.

Generalized regression neural networks in prediction of drug stability

This study had two aims. Firstly, we wanted to model the effects of the percentage of Eudragit RS PO and compression pressure as the most important process and formulation variables on the time course of drug release from extended-release matrix aspirin tablets. Secondly, we investigated the possibility of predicting drug stability and shelf-life using an artificial neural network (ANN). Ten types of matrix aspirin tablets were prepared as model formulations and were stored in stability chambers at 60 degrees C, 50 degrees C, 40 degrees C and 30 degrees C and controlled humidity. Samples were removed at predefined time points and analysed for acetylsalicylic acid (ASA) and salicylic acid (SA) content using stability-indicating HPLC. The decrease in aspirin content followed apparent zero-order kinetics. The amount of Eudragit RS PO and compression pressure were selected as causal factors. The apparent zero-order rate constants for each temperature were chosen as output variables for the ANN. A set of output parameters and causal factors were used as training data for the generalized regression neural network (GRNN). For two additional test formulations, Arrhenius plots were constructed from the experimentally observed and GRNN-predicted results. The slopes of experimentally observed and predicted Arrhenius plots were tested for significance using Student's t-test. For test formulations, the shelf life (t(95%)) was then calculated from experimentally observed values (t(95%) 82.90 weeks), as well as from GRNN-predicted values (t(95%) 81.88 weeks). These results demonstrate that GRNN networks can be used to predict ASA content and shelf life without stability testing for formulations in which the amount of polymer and tablet hardness are within the investigated range.

Development and Evaluation of Ethyl Cellulose-Based Transdermal Films of Furosemide for Improved In Vitro Skin Permeation

Transdermal films of the furosemide were developed employing ethyl cellulose and hydroxypropyl methylcellulose as film formers. The effect of binary mixture of polymers and penetration enhancers on physicochemical parameters including thickness, moisture content, moisture uptake, drug content, drug-polymer interaction, and in vitro permeation was evaluated. In vitro permeation study was conducted using human cadaver skin as penetration barrier in modified Keshary-Chein diffusion cell. In vitro skin permeation study showed that binary mixture, ethyl cellulose (EC)/hydroxypropyl methylcellulose (HPMC), at 8.5:1.5 ratio provided highest flux and also penetration enhancers further enhanced the permeation of drug, while propylene glycol showing higher enhancing effect compared to dimethyl sulfoxide and isopropyl myristate. Different kinetic models, used to interpret the release kinetics and mechanism, indicated that release from all formulations followed apparent zero-order kinetics and non-Fickian diffusion transport except formulation without HPMC which followed Fickian diffusion transport. Stability studies conducted as per International Conference on Harmonization guidelines did not show any degradation of drug. Based on the above observations, it can be reasonably concluded that blend of EC-HPMC polymers and propylene glycol are better suited for the development of transdermal delivery system of furosemide.

Fomepizole: A Critical Assessment of Current Dosing Recommendations

Fomepizole, 4-methylpyrazole (4-MP), is a competitive antagonist of alcohol dehydrogenase with a binding affinity >8000 times that of ethanol. The drug is currently labeled by the United States Food and Drug Administration for the treatment of adult patients with known or suspected ethylene glycol or methanol poisoning. Fomepizole's wide therapeutic dose range and safety profile confer several advantages over standard ethanol therapy for the treatment of toxic alcohol exposures, including the lack of ethanol-associated side effects. Published data and data obtained from the drug's manufacturer implies that the dose escalation after 48 hours is to compensate for fomepizole-induced increased body clearance resulting from autoinduction of the cytochrome P450 (CYP) drug metabolizing enzyme CYP2E1. However, we were unable to identify any evidence of fomepizole's metabolism occurring via CYP2E1 in humans while the data most frequently cited as evidence for induction do not appear to support this claim. Based on this data along with the apparent zero-order kinetics, the current dose increase recommendations may be unnecessary and considering the safety margin described for fomepizole, an extremely conservative constant higher dose administered every 12 hours would appear to assure efficacy and tolerability. Despite the evidence, dose changes should only be implemented after careful clinical trials.

Nitric oxide (NO) scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle.

The flavonoid quercetin reduces blood pressure and endothelial dysfunction in animal models of hypertension. However, the results concerning the relationship between quercetin and NO present a complex picture. We have analyzed the mechanisms involved in the NO scavenging effects of quercetin and its repercussion on NO bioactivity in vascular smooth muscle. Quercetin scavenged NO with apparent zero-order kinetics with respect to NO. This effect was strongly dependent on the O(2) concentrations, so that NO decay at pH 7.4 could be fitted to the equation -d[NO]/dt = k x [O(2)] x [quercetin], where k was 0.15 M(-1) s(-1). The NO scavenger effects were prevented by superoxide dismutase (SOD), reduced by lowering pH, accompanied by O(2)(.) production and correlated with decreased NO bioactivity in rat aortic rings. However, under conditions of increased O(2)(.) concentrations, quercetin was a better scavenger of O(2)(.) than of NO. When NO scavenging by quercetin was prevented by addition of SOD, NO bioactivity was increased. Quercetin also prevented the inhibitory effects of the SOD inhibitor diethyldithiocarbamic acid (DETCA) on NO bioactivity. In the presence of DETCA, quercetin reduced tissue O(2)(.) as measured by nitro blue tetrazolium staining. In conclusion, quercetin exerts dual effects on O(2)(.) and NO. At physiological conditions of pH, O(2) concentrations and NO, quercetin effectively scavenged NO in the low micromolar range, and the rate-limiting step was the autooxidation of quercetin and the formation of O(2)(.). When the extracellular NO scavenging effect was prevented, quercetin increased the biological activity of NO, an effect related to its O(2)(.) scavenger properties and/or its inhibitory effect on tissue O(2)(.) generation.

P.3.035 Generalized anxiety and major depression in a Belgian primary care setting, influence by socio-economic factors. The GADIS II study

The effect of ultraviolet radiation on the photolability of nitrofurazone in aqueous solutions was followed by a stability-indicating paper chromatographic method. Various factors including the pH of the medium, the presence of surfactants, polyethylene glycols, metal ions or ultraviolet light absorbers influenced the rate of photodecomposition of the drug. The photodecomposition of nitrofurazone in aqueous solution followed apparent zero-order kinetics. In the polyethylene glycol or aqueous solution the rate was much lower than that in the surfactants. The process of photodecomposition was accelerated by ferric ions while slightly inhibited by cupric ions. It was found that the rate constant increased initially with the incorporation of a small amount of the ultraviolet light absorbers. Subsequently, the rate constant decreased with increasing concentration of ultraviolet light absorber. Uvinul D-50 shows a higher stabilizing effect than Uvinul N-35. There was little thermal degradation of the drug in comparison to the decomposition by irradiation with ultraviolet light at the temperature of the study. Thermal degradation followed a first order rate process.

Kinetics of paclitaxel 2'-N-methylpyridinium mesylate decomposition.

This study was designed to examine the kinetics of decomposition of paclitaxel 2'-N-methylpyridinium mesylate (PNMM), a derivative of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies of PNMM were conducted over a pH range of 4.0 to 8.0 at 25 degrees C. The critical micelle concentration (CMC) of PNMM was determined by pulsating bubble surfactometry. Studies of the conversion of PNMM to paclitaxel were conducted in vitro in human plasma. Decomposition of PNMM followed apparent zero-order kinetics. The pH-rate profile exhibited no evidence of acid catalysis down to pH 4.0, while the rate was accelerated under base conditions. Surface tension studies suggested that PNMM formed micelles with a CMC of approximately 34 micro g/mL. Conversion studies in phosphate buffer showed that no more than 5% of PNMM converted to paclitaxel, while in human plasma the conversion was about 25%. The degradation of PNMM was via apparent zero-order kinetics and was dependent upon pH. The observed apparent zero-order kinetics of decomposition of PNMM was consistent with the formation of micelles in phosphate buffer. In buffered aqueous media alone or in human plasma, PNMM did not convert quantitatively to paclitaxel. Thus, the limiting factor in the application of PNMM as a prodrug would appear to be the poor potential to convert to paclitaxel.

Sublimation characterization and vapor pressure estimation of an HIV nonnucleoside reverse transcriptase inhibitor using thermogravimetric analysis.

The purpose of this research is to investigate the sublimation process of DPC 963, a second-generation nonnucleoside reverse transcriptase inhibitor for HIV-1 retrovirus, and to better understand the effect of sublimation during active pharmaceutical ingredient (API) manufacture and formulation development, especially the drying processes. Sublimation of DPC 963 at 150 degrees C and above was determined by thermogravimetric analysis-Fourier transform infrared (TGA-FTIR). The rates of sublimation at different temperatures were measured using isothermal TGA. Condensed material was collected and analyzed by differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and infrared (IR) spectrometry. Benzoic acid was used as a reference standard to derive a linear logarithmic relationship between sublimation/evaporation rate and vapor pressure specific to the TGA system used in this study. Sublimation and evaporation of DPC 963 were found to follow apparent zero-order kinetics. Using the Eyring equation, the enthalpy and entropy of the sublimation and evaporation processes were obtained. The enthalpies of sublimation and evaporation were found to be 29 and 22 kcal/mol, respectively. The condensed material from the vapor phase was found to exist in 2 physical forms, amorphous and crystalline. Using benzoic acid as a reference standard, vapor pressure of DPC 963 at different temperatures was calculated using the linear logarithmic relationship obtained. DPC 963 undergoes sublimation at appreciable rates at 150 degrees C and above but this is not likely to pose a serious issue during the manufacturing process. Vapor pressure estimation using thermogravimetric analysis provided sufficient accuracy to be used as a fast, simple, and safe alternative to the traditional methods of vapor pressure determination.

Effects of natural polysaccharide addition on drug release from calcium-induced alginate gel beads.

Calcium-induced alginate gel beads (Alg-Ca) containing various polysaccharides, including an alginate hydrolysate, were prepared and the drug release profiles were investigated. Hydrocortisone (HC) was gradually released from Alg-Ca into the mimic gastric fluid, while in intestinal fluid, it was quickly released with the dissolution of Alg-Ca. However, with Alg-Ca containing 5% chitin (CT), dissolution of Alg-Ca was not observed, and release of HC showed apparent zero-order kinetics. Furthermore, addition of the alginate hydrolysate altered the HC-release profile for Alg-Ca.

The Pharmaceutical Use of Captisol®: Some Surprising Observations

The purpose of this paper is to share some recent observations on the pharmaceuticaluses and properties of Captisol® or SBE7M-β-CD in controlled porosity osmotic pump tablets (CP-OPT) and the underlying mechanism/sthat lead to apparent zero-order drug release pattern. It would have been simple toattribute the apparent zero-order release mechanism/s of poorly water-soluble drugsfrom CP-OPTs and pellets utilizing Captisol®as both a solubilizing andosmotic agent, to purely osmotic and diffusional components. However, the mechanismmay be more related to a counterbalancing of physical properties as the concentration of Captisol®changes within the matrix. Specifically, the initial concentration of Captisol®within a core is 0.3–0.4M. When this drops to lower values an osmotic pressure drop occurs across the membrane. Therefore, drug release should not follow apparent zero-order kinetics if all the drug is solubilized. However, as the viscosity within the tablet also drops, the apparent diffusion coefficient of both Captisol® and drug increases. Therefore, it appears that there is an initial resistance (hydraulic pressure) to fluid flow from the tablet through the rate-limiting microporous membrane. This resistance decreases so that even as osmotic pressure and concentration differences drop with time, counterbalancing faster release occurs. Osmotic driving force appears to be the most important initial driving force but a diffusional component becomes more significant with time.

Sustained-release hydrophilic matrix tablets of zileuton: formulation and in vitro/in vivo studies

Zileuton is a new active 5-lipoxygenase inhibitor which has been shown to be clinically effective in the treatment of asthma. It is a racemic mixture of S- and R-enantiomers. In the present study, hydrophilic polymer matrix tablets were used for oral controlled delivery of zileuton. The prototype formulations with drug loading of 50–60% were prepared and tested in vitro using USP apparatus I, II and III. In vivo absorption of three formulations with differing release rates was evaluated using crossover designs in beagle dogs. Plasma concentrations of the two enantiomers of zileuton were analyzed by a chiral HPLC method. The results indicated that the release of zileuton from the matrix tablets followed apparent zero-order kinetics when tested using USP apparatus I and II. Prolonged absorption of zileuton was achieved using the hydrophilic matrix system. In vivo drug release estimated by deconvolution based on the data of both S- and R-enantiomers was correlated with in vitro release. Linear relationships between in vitro and in vivo release were obtained with more rapid in vivo release than in vitro.

Topical liposomal system for localized and controlled drug delivery

A liposomal reservoir system bearing the local anesthetic, benzocaine, was developed for controlled and localized delivery via topical route. The liposomal suspension was incorporated into an ointment and gel base. The developed systems were studied for various physical and kinetic attributes in vitro. The systems delivered the drug at a controlled rate over 24 h, whereas plain drug ointment showed a rapidly decreased release rate over 24 h, with more than 92% released. The drug delivery across human cadaver skin following liposomal ointment application was noted to be considerably slow. The in vivo study revealed a longer duration of action in the case of liposomal formulations. An effort was made to study the effect of ultrasound as a reversible means to effect pulsatile delivery of the drug from the liposomal depot. The work proved the potential of liposomes as a slow release vehicle which follows apparent zero order kinetics and its use in modulating drug input via skin.