Structural and Luminescence Behavior of Nanocrystalline Orthophosphate KMeY(PO4)2: Eu3+ (Me = Ca, Sr) Synthesized by Hydrothermal Method.

KMeY(PO4)2:5% Eu3+ phosphates have been synthesized by a novel hydrothermal method. Spectroscopic, structural, and morphological properties of the obtained samples were investigated by X-ray, TEM, Raman, infrared, absorption, and luminescence studies. The microscopic analysis of the obtained samples showed that the mean diameter of synthesized crystals was about 15 nm. The KCaY(PO4)2 and KSrY(PO4)2 compounds were isostructural and they crystallized in a rhabdophane-type hexagonal structure with the unit-cell parameters a = b ≈ 6.90 Å, c ≈ 6.34 Å, and a = b ≈ 7.00 Å, c ≈ 6.42 Å for the Ca and Sr compound, respectively. Spectroscopic investigations showed intense 5D0 → 7F4 transitions connected with D2 site symmetry of Eu3+ ions. Furthermore, for the sample annealed at 500 °C, europium ions were located in two optical sites, on the surface of grains and in the bulk. Thermal treatment of powders at high temperature provided better grain crystallinity and only one position of dopant in the crystalline structure. The most intense emission was possessed by the KSrY(PO4)2:5% Eu3+ sample calcinated at 500 °C.

The cost-effectiveness of food consistency modification with xanthan gum-based Nutilis Clear® in patients with post-stroke dysphagia in Poland.

BACKGROUND: Dysphagia is a well-known stroke complication characterised by difficulty in swallowing. It may affect the majority of stroke patients and increases mortality and morbidity, due to aspiration pneumonia and malnutrition. Food thickening may help patients to feed themselves, and its effectiveness was demonstrated. However, the cost-effectiveness studies are lacking. We evaluate the cost-utility of xanthan gum-based consistency modification therapy (Nutilis Clear®) in adult post-stroke patients from the public payer perspective in Poland. METHODS: Routine clinical practice was used as a comparator, as no alternative specific treatment for dysphagia is available. To verify the robustness of the results against the modelling approach, we built two models: a static (a fixed simple-equations model, 8-week time horizon of dysphagia) and a dynamic one (Markov model, with a possible dysphagia resolution over a 1-year horizon). In both models, the treatment costs, health state utilities, and clinical events (i.e. aspiration, aspiration pneumonia, death) were included. Parameters were estimated jointly for both models, except for the duration of dysphagia and the risk of aspiration pneumonia (specific to the time horizon). We only assumed Nutilis Clear® to prevent aspirations, without affecting dysphagia duration. RESULTS: The average cost of one quality-adjusted life year (i.e. the incremental cost-utility ratios, ICURs) amounted to 21,387 PLN (€1 ≈ 4.5 PLN), and 20,977 PLN in static and dynamic model, respectively; far below the cost-effectiveness threshold in Poland (147,024 PLN). The one-way, scenario, and probabilistic sensitivity analysis confirmed these findings. CONCLUSIONS: Nutilis Clear® is highly cost-effective in Poland from the public payer perspective. Our approach can be used in other countries to study the cost-effectiveness of food thickening in stroke patients.

The cost-effectiveness of screening strategies for familial hypercholesterolaemia in Poland.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) elevates the cholesterol level and increases the risk of coronary events and death. Early detection and treatment reduce this risk. We aimed to determine the cost-effectiveness of FH screening in Poland in children, first job takers, and after an acute coronary syndrome (ACS) event, each followed by a cascade screening in the relatives of the positively-diagnosed subjects. METHODS: A decision tree was constructed to model the diagnosis process. We considered scenarios with and without genetic testing. A life-time Markov was built to investigate the effectiveness (life years gained, LYG; and quality-adjusted life years, QALY) and cost (public payer perspective) of treatment in FH-affected subjects. The clinical benefits result from early treatment reducing the risk of coronary heart disease (and death, in result). Model parameters were based on published data and experts' opinions. The costs (patients visits, tests, drugs) were estimated from the National Health Fund data and other publicly-available sources. RESULTS: Screening ACS patients below 55/65 years of age in men/women is the most cost-effective strategy: the cost of one LYG (QALY) amounts to 100 EUR (110 EUR). Removing the age limit or using genetic tests reduced cost-effectiveness; nonetheless, all strategies remained cost effective: the cost of one LYG or QALY was <5040 EUR, much lower than the official threshold of ca. 29,800 EUR/QALY. CONCLUSIONS: Screening for FH is highly cost-effective in Poland. The strategies are complementary, and using a combination thereof is recommended.

New high throughput screening method for drug release measurements.

In the field of drug delivery systems, microparticles made of polymeric matrix appear as an attractive approach. The in vitro release kinetic profile is crucial information when developing new particulate formulations. These data are essential for batch to batch comparison, quality control as well as for anticipation of in vivo behavior to select the best formulation to go further in preclinical investigations. The methods available present common drawbacks such as the time- and compound-consumption that does not fit with formulation screening requirements in early development stages. In this study, a new microscale high throughput screening (HTS) method has been developed to investigate drug release kinetic from piroxicam-loaded polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) microparticles. The method is a sample- and separation-based method where separation is performed by filtration using 96-well micro filter plates. 96 experiments can therefore be performed on one plate in one time in a fully automated way and with a very low sample and particle consumption. The influence of different parameters controlling release profiles was also investigated using this technique. The HTS method gave the same release profile than the standard dialysis method. Shaking, particle concentration, and the nature of the release medium were found to be of influence. The HTS method appears as a reliable method to evaluate drug release from particles with smaller standard deviation and less consumption of material.

Solubility and pKa determination of six structurally related phenothiazines.

Solubilities of six structurally related phenothiazines, namely chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride at constant pH were measured in the temperature range from 290 K to 350 K in three important drugs solvents: water, ethanol and 1-octanol using the dynamic method and UV-vis method. Dissociation constants and corresponding pK(a) values of drugs were obtained with Bates-Schwarzenbach method at temperature 298.15K in the buffer solutions. Our experimental pK(a) values for chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride are 9.15, 10.01, 9.37, 8.89, 8.97, and 9.03, respectively. The basic thermal properties of pure drugs i.e. melting and solid-solid phase transition as well as glass-transition temperatures, the enthalpy of melting and phase transitions and the molar heat capacity at glass transition (at constant pressure) were measured with differential scanning microcalorimetry (DSC) technique. Molar volumes were calculated with Barton group contribution method. The experimental solubility data were correlated by means of three commonly known G(E) equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here have revealed simple eutectic mixtures. The root-mean-square deviations of temperature were used for the precision of the correlation. The activity coefficients of drugs at saturated solutions in each correlated binary mixture were calculated from the experimental data. These new data will help in all prediction-methods and their precision.

Effect of 2-hydroxypropyl-ß-cyclodextrin on solubility of sparingly soluble drug derivatives of anthranilic acid.

Guest-host complex formation of three drug derivatives of anthranilic acid, mefenamic acid, niflumic acid, and flufenamic acid with 2-hydroxypropyl-ß-cyclodextrin (2HP-ß-CD) in aqueous solutions was investigated using "Phase solubility study" with UV-vis spectrophotometry. Solubility of sparingly soluble drugs has been improved by addition of 2HP-ß-CD at two temperatures 298.15 K and 310.15 K and two pH values 2 and 7. The influence of different 2HP-ß-CD concentration on solubility of drugs at different pH and temperatures has been investigated. The 2HP-ß-CD-drug complex stability constants (K(s)), and dissociations constants (K(d)), as well as the thermodynamic parameters of reaction, i.e., the free energy change (ΔG), the enthalpy change (ΔH) and the entropy change (ΔS), were determined. The experimental data indicated formation of 1:1 inclusion complexes, which were found effective binders increasing the solubility of drugs.

Solubility of sparingly soluble drug derivatives of anthranilic acid.

This work is a continuation of our systematic study of the solubility of pharmaceuticals (Pharms). All substances here are derivatives of anthranilic acid, and have an anti-inflammatory direction of action (niflumic acid, flufenamic acid, and diclofenac sodium). The basic thermal properties of pure Pharms, i.e., melting and glass-transition temperatures as well as the enthalpy of melting, have been measured with the differential scanning microcalorimetry technique (DSC). Molar volumes have been calculated with the Barton group contribution method. The equilibrium mole fraction solubilities of three pharmaceuticals were measured in a range of temperatures from 285 to 355 K in three important solvents for Pharm investigations: water, ethanol, and 1-octanol using a dynamic method and spectroscopic UV-vis method. The experimental solubility data have been correlated by means of the commonly known G(E) equation: the NRTL, with the assumption that the systems studied here have revealed simple eutectic mixtures. pK(a) precise measurement values have been investigated with the Bates-Schwarzenbach spectrophotometric method.

Modelling, solubility and pK(a) of five sparingly soluble drugs.

Drug solubility is an important aspect of drug development. The objective of this investigation was to measure solubilities of five drugs (cimetidine, phenylbutazone, fenbufen, nitrofurantoin, triamterene) at constant pH in range of temperature from 270 to 340K in three solvents: water, ethanol and 1-octanol with the dynamic-visual method and the saturation shake-flask method using spectrophotometric analysis. The Barton group contribution method was used for the calculations of molar volumes of solutes. The thermodynamic description of the solubility curves was made using the thermophysical properties obtained with the differential scanning microcalorimetry technique (DSC). The DSC measurements have shown different than existing in the literature enthalpies of melting for phenylbutazone and fenbufen. The experimental solubility data also differ from the literature data, normally measured at one, or two temperatures only. The solubility data have been correlated by means of three commonly known excess Gibbs energy, G(E) equations. The activity coefficients of drugs at saturated solutions were calculated from the experimental data. Reexamination of the pK(a) values using diluted solutions was made with the Bates-Schwarzenbach method for the pK(a) measurements. The association constants and corresponding pK(a) values of drugs were close to the most of the literature data. We hope that our new solubility data, thermophysical data, and pK(a) values will improve all prediction-methods and their precision.

pKa and solubility of drugs in water, ethanol, and 1-octanol.

Dissociation constants and corresponding pK(a) values of five drugs were obtained with the Bates-Schwarzenbach method using a Perkin-Elmer Lambda 35 UV/vis spectrophotometer at temperature 298.15 K in the buffer solutions. Atropine, promethazine hydrochloride, ibuprofen, flurbiprofen, and meclofenamic acid sodium salt exhibited pK(a) values of 10.3, 6.47, 5.38, 4.50, and 4.39, respectively. The equilibrium mole fraction solubilities of six drugs were measured in a range of temperatures from 240 to 340 K in three important solvents for drugs: water, ethanol, and 1-octanol using the dynamic method. The basic thermal properties of pure drugs, i.e., melting and glass-transition temperatures, as well as the enthalpy of melting and the molar heat capacity at glass transition (at constant pressure) have been measured with the differential scanning microcalorimetry technique (DSC). Molar volumes have been calculated with the Barton group contribution method. The experimental solubility data have been correlated by means of three commonly known G(E) equations: the Wilson, NRTL, and UNIQUAC, with the assumption that the systems studied here have revealed simple eutectic mixtures. As a measure of goodness of correlation, the root-mean-square deviations of temperature have been used. The activity coefficients of the drugs in saturated solutions for each correlated binary mixture were calculated from the experimental data.