Exploratory Study on Lercanidipine Hydrochloride Polymorphism: pH-Dependent Solubility Behavior and Simulation of its Impact on Pharmacokinetics.

This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 µm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.

Adaptation of a commercial ion selective fluoride electrode to a tubular configuration for analysis by flow methodologies.

The determination of fluoride ions in water samples is accomplished by using a tubular flow through detector constructed by drilling a channel through a commercially available LaF(3) crystal electrode in such a way that the original contacts of the non-modified unit are maintained. Its performance when incorporated in both FIA and SIA systems was evaluated and the results show that the tubular unit retains the characteristics of the non-modified electrode. In SIA conditions an extended linear range of response and lower detection limit were achieved when compared with the electrode performance in FIA conditions. These aspects together with the additional advantage of low sample and reagent consumptions in SIA when compared to FIA, makes the incorporation of the proposed tubular ISE in a SIA system the preferred approach for on line determination and monitoring of fluoride content in natural water samples.

Can sample treatments based on advanced oxidation processes assisted by high-intensity focused ultrasound be used for toxic arsenic determination in human urine by flow-injection hydride-generation atomic absorption spectrometry?

Two advanced oxidation processes (AOPs), based on high-intensity focused ultrasound (HIFU), namely, KMnO(4)/HCl/HIFU and H(2)O(2)/HCl/HIFU are studied and compared for the determination of toxic arsenic in human urine [As(III)+As(V)+MMA+DMA] by flow-injection hydride-generation atomic absorption spectrometry (FI-HG-AAS). The KMnO(4)/HCl/HIFU procedure was found to be adequate for organic matter degradation in human urine. l-cysteine (letra minuscula) was used for As reduction to the trivalent state. The new procedure was assessed with seven urines certified in different As species. Results revealed that with KMnO(4)/HCl/HIFU plus l-cysteine the toxic arsenic can be accurately measured in human urine whilst the H(2)O(2)/HCl/HIFU procedure underestimates toxic As. DMA and MMA degradation in urine were observed, due to the effects of the ultrasonic field. Recoveries for As(III), As(V), MMA and DMA were within the certified ranges. Arsenobetaine was not degraded by the AOPs. The new procedure adheres well to the principles of analytical minimalism: (i) low reagent consumption, (ii) low reagent concentration, (iii) low waste production and (iv) low amount of time required for sample preparation and analysis.

Sequential flow injection analysis system on-line coupled to high intensity focused ultrasound: green methodology for trace analysis applications as demonstrated for the determination of inorganic and total mercury in waters and urine by cold vapor atomic absorption spectrometry.

A new concept is presented for green analytical applications based on coupling on-line high-intensity focused ultrasound (HIFU) with a sequential injection/flow injection analysis (SIA/FIA) system. The potential of the SIA/HIFU/FIA scheme is demonstrated by taking mercury as a model analyte. Using inorganic mercury, methylmercury, phenylmercury, and diphenylmercury, the usefulness of the proposed methodology for the determination of inorganic and total mercury in waters and urine was demonstrated. The procedure requires low sample volumes and reagents and can be further applied to all chemical reactions involving HIFU. The inherent advantages of SIA, FIA, and HIFU applications in terms of high throughput, automation, low reagent consumption, and green chemistry are accomplished together for the first time in the present work.

Flow amperometric determination of pharmaceuticals with on-line electrode surface renewal.

In this article, a flow system developed for the amperometric determination of a great variety of pharmaceuticals that are known to lead the rapid poisoning of the working electrode surface is described. The referred system was made up of two parallel flow channels that shared the voltammetric detector of tubular configuration, whose movement in the manifold followed the concept of multi-site location of detector. In this way, after each measurement, the conditioning of the working electrode was possible through the passage by its surface of a regeneration solution without implying the alteration of the carrier that flowed in the analytical channel of the manifold. The methodology proposed was evaluated through the determination of two drugs belonging to two distinct therapeutic groups: an antihypertensive (diltiazem) and a non-steroid anti-inflammatory (nimesulide). The results obtained after evaluation of various pharmaceutical formulations on the Portuguese market were in the case of diltiazem compared with those supplied by the reference US Pharmacopoeia XXIV method, with no statistically significant differences having been observed for a confidence interval of 95%. In the case of nimesulide, since no official reference method exists, a series of recovery experiments were proceeded with and a mean value of 101.1% with a R.S.D. of 0.7% was obtained.