Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP,PVP/VA,and PVAc

A previous method for measuring solubilities of crystalline drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug-polymer dispersions, a strategy actively explored for delivering poorly soluble drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of solubility equilibrium. In this method, a drug-polymer mixture prepared by cryomilling is annealed at different temperatures and analyzed by differential scanning calorimetry to determine whether undissolved crystals remain and thus the upper and lower bounds of the equilibrium solution temperature. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temperatures, but revised slightly the previous results at lower temperatures. It also lowered the temperature of measurement closer to the glass transition temperature. For d-mannitol and IMC dissolving in PVP, the polymer’s molecular weight has little effect on the weight-based solubility. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less soluble than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory-Huggins model, yielding the relevant drug-polymer interaction parameters. The new annealing method yields more accurate data than the previous scanning method when solubility equilibrium is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate experimental data for developing predictive models. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4023–4031, 2010     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Differences in the interaction between aryl propionic acid derivatives and poly(vinylpyrrolidone) K30: A multi-methodological approach

The present work aims at the application of several methods to explain differences in the physical interaction of some aryl propionic acid derivatives (ibuprofen [IBP], ketoprofen [KET], flurbiprofen [FLU], naproxen [NAP], fenbufen [FEN]) with poly(vinylpyrrolidone) (PVP) K30, stored together at 298 ± 0.5 K and 22% RH. X-ray powder diffractometry and ¹³C-solid state NMR demonstrated that IBP was able to strongly interact with the polymer, while weak interaction was observed for KET, FLU, NAP, and the least for FEN. The interaction of comelted drug and PVP was studied by differential scanning calorimetry by applying the Gordon–Taylor equation, which revealed that small molar drug volumes may favour the drug diffusion through the PVP amorphous chains increasing the polymer free volume and decreasing the mixture T_g. The molecular docking study revealed that intermolecular energy is mainly due to the contribution of van der Waals energy component, causing the differences among the drugs, and is related to the drug–PVP surface contact area in the complex formed. Solid-state kinetic study demonstrated that IBP molecules are involved in a three-dimensional diffusion mechanism within the polymer favoured by its low molar volume that reduces molecular hindrance, and by the weakness of its crystal lattice, which facilitates crystallinity loss and stabilisation of the amorphous phase. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4216–4228, 2009     

Liquid-Liquid Miscibility Gaps and Hydrate Formation in Drug-Water Binary Systems: Pressure-Temperature Phase Diagram of Lidocaine and Pressure-Temperature-Composition Phase Diagram of the Lidocaine-Water System

The pressure-temperature (P–T) melting curve of lidocaine was determined (dP/dT = 3.56 MPa K^? 1), and the lidocaine–water system was investigated as a function of temperature and pressure. The lidocaine–water system exhibits a monotectic equilibrium at 321 K (ordinary pressure) whose temperature increases as the pressure increases until the two liquids become miscible. A hydrate, unstable at ordinary pressure, was shown to form, on increasing the pressure, from about 70 MPa at low temperatures (200–300 K). The thermodynamic conditions of its stability were inferred from the location of the three-phase equilibria involving the hydrate in the lidocaine–water pressure–temperature–mole fraction (P–T–x) diagram.     

Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression

Experimental data suggest that the endogenous cannabinoid system is involved in mood regulation, but no study has been performed so far to investigate the role of endocannabinoid genes in the susceptibility to major depression (MD) and/or bipolar disorder (BD). We assessed the CB1 receptor gene (CNR1) single nucleotide polymorphism (SNP) rs1049353 (1359 G/A) and the fatty acid amide hydrolase (FAAH) gene rs324420 SNP (cDNA 385C to A) for their associations with MD and/or BD in 83 Caucasian patients with recurrent MD, 134 Caucasian individuals with BD, and 117 Caucasian healthy subjects. The distribution of the CNR1 1359 G/A genotypes and alleles significantly differed among the groups (χ² = 12.595; df = 4, P = 0.01 for genotypes; χ² = 13.773; df = 2, P = 0.001 for alleles) with MD patients showing a higher frequency of both AG, GG genotypes and A allele as compared to healthy controls. The distribution of the FAAH cDNA 385C to A genotypes, according to the CC dominant model (AA + AC vs. CC), significantly differed among the groups (χ² = 6.626; df = 2, P = 0.04), with both BD patients and MD patients showing a non-significant slightly higher frequency of the AC genotype. These findings, although preliminary, suggest that the CNR1 1359 G/A and the FAAH cDNA 385C to A gene variants may contribute to the susceptibility to mood disorders.     

Relative Bioavailability of Three Different Solid Forms of PNU-141659 as Determined with the Artificial Stomach-Duodenum Model

The artificial stomach-duodenum (ASD) apparatus was designed and constructed to assess the in vitro performance of bulk drugs and their formulations in a device which is able to simulate different species and physiological conditions. As a continued demonstration of its application to a pharmaceutical problem, screening experiments were performed on three different solid forms of a drug candidate, PNU-141659. This compound exhibited poor solubility and permeability, and presented a significant problem in the development of a successful dosage form. Simple formulations of an anhydrous form, a hydrated form and an amorphous form of the drug were all assessed with the ASD set up to simulate dog physiology. The solubility ordering of these three forms was anhydrate < hemihydrate < amorphous and this is the first ASD study to directly compare amorphous and crystalline solid forms. However, the results of the ASD studies showed that the hydrated form, with the intermediate solubility should provide the highest bioavailability, not the more soluble amorphous form. This occurred because the more soluble amorphous form underwent a phase conversion to Form I during the ASD experiment. The results from the ASD compared favorably with those later obtained from in vivo dog studies. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3923–3930, 2010     

Determination of lamivudine and zidovudine permeability using a different ex vivo method in Franz cells

IntroductionThe major processes that control the absorption of orally administered drugs are dissolution and gastrointestinal permeation. These processes depend on two main properties: solubility and permeability. Based on these characteristics, the Biopharmaceutical Classification System (BCS) was proposed as a tool to assist in biowaiver and bioavailability prediction of drugs.MethodsThe purpose of the present study was to evaluate the permeability of lamivudine (3TC) and zidovudine (AZT) using a different ex vivo method in Franz cells. A segment of jejunum was inserted in a Franz cells apparatus, in order to assess drug permeability in the apical–basolateral (A–B) and basolateral–apical (B–A) directions. Each drug was added to the donor chamber, collected from the acceptor chamber and analyzed by HPLC. Fluorescein (FLU) and metoprolol (METO) were used as low and high permeability markers, respectively.ResultsThe apparent permeability (P_app) results for the A–B direction were: P_{app FLU A–B} = 0.54 × 10^? 4 cm·s^? 1, P_{app METO A–B} = 7.99 × 10^? 4 cm·s^? 1, P_{app 3TC A–B} = 4.58 × 10^? 4 cm·s^? 1 and P_{app AZT A–B} = 5.34 × 10^? 4 cm·s^? 1. For the B–A direction, the P_app results were: P_{app FLU B–A} = 0.56 × 10^? 4 cm·s^? 1, P_{app METO B–A} = 0.25 × 10^? 4 cm·s^? 1, P_{app 3TC B–A} = 0.24 × 10^? 4 cm·s^? 1 and P_{app AZT B–A} = 0.19 × 10^? 4 cm·s^? 1.DiscussionFor the A–B direction, the P_app results of fluorescein and metoprolol show low and high permeability, respectively, indicating that the membranes were appropriate for permeability studies. For the A–B direction, the P_app results of 3TC and AZT suggest that these antiretroviral drugs have permeability values close to metoprolol. Nevertheless, for the B–A direction the P_app results do not suggest efflux mechanism for any of the drugs. Thereby, the different ex vivo methods using Franz cells can be successfully applied in drug permeability studies, in particular for drug biopharmaceutical classification.     

In situ amorphisation of indomethacin with Eudragit® E during dissolution

In this study, the possibility of utilising in situ crystalline-to-amorphous transformation for the delivery of poorly water soluble drugs was investigated. Compacts of physical mixtures of γ-indomethacin (IMC) and Eudragit® E in 3:1, 1:1 and 1:3 (w/w) ratios were subjected to dissolution testing at pH 6.8 at which IMC but not the polymer is soluble. Compacts changed their colour from white to yellow indicating amorphisation of IMC.X-ray powder diffractometry (XRPD) confirmed the amorphisation and only one glass transition temperature was observed (58.1 °C, 54.4 °C, and 50.1 °C for the 3:1, 1:1 and 1:3 (w/w) drug-to-polymer ratios, respectively). Furthermore, principal component analysis of infrared spectra resulted in clustering of in situ transformed samples together with quench cooled glass solutions for each respective ratio. Subsequent dissolution testing of in situ transformed samples at pH 4.1, at which the polymer is soluble but not IMC, led to a higher dissolution rate than for quench cooled glass solution at 3:1 and 1:1 ratios, but not for the 1:3 ratio.This study showed that crystalline drug can be transformed into amorphous material in situ in the presence of a polymer, leading to the possibility of administering drugs in the amorphous state without physical instability problems during storage.     

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (T_g) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated.FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a T_g of 101.2 °C, whereas the T_g for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days.The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively.The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster T_max compared to the solution and amorphous and crystalline free acid. C_max for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster T_max compared to the amorphous and crystalline free acid.     

The Effect of the Physical States of Binders on High-Shear Wet Granulation and Granule Properties: A Mechanistic Approach Toward Understanding High-Shear Wet Granulation Process. Part II. Granulation and Granule Properties

The objective is to provide mechanistic understanding of a preferred wet granulation process that a binder is added in a dry state. Blends of CaCO₃ and binders were prepared and used as model systems, and they were exposed to either 96% RH (rubbery/solution state) or 60% RH (glassy state) at room temperature to control the physical state of the binders, followed by high-shear granulation and particle size measurement. The blends of PVP K12, PVP K29/32, and HPC showed a significant increase in particle size after exposure to 96% RH. An increase of aspect ratio was also observed for the blend of HPC. In contrast, the blends being exposed to 60% RH did not exhibit any increase in particle size or aspect ratio. Regarding the effect of binder molecular weight on the mechanical strength of granules, granules of PVP K29/32 had higher strength than granules of PVP K12. This can be explained using polymer entanglement theory, in which the degree of polymerization (DP) of (N ～ 440–540) of PVP K29/32 is above the critical value (N_c ～ 300–600) for entanglement; while DP of PVP K12 (N ～ 20–30) is below it. Finally, a water sorption-phase transition-diffusion induced granule growth model for granulation has been suggested.     

Improved group contribution parameter set for the application of solubility parameters to melt extrusion

Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs toward their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison with established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r = −0.87 to −0.91) as well as for literature data on melt extrudates and casted films (r = −0.78 to −0.96).     

Influence of humidity on the phase behavior of API/polymer formulations

Amorphous formulations of APIs in polymers tend to absorb water from the atmosphere. This absorption of water can induce API recrystallization, leading to reduced long-term stability during storage. In this work, the phase behavior of different formulations was investigated as a function of relative humidity. Indomethacin and naproxen were chosen as model APIs and poly(vinyl pyrrolidone) (PVP) and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) as excipients. The formulations were prepared by spray drying. The water sorption in pure polymers and in formulations was measured at 25 °C and at different values of relative humidity (RH = 25%, 50% and 75%). Most water was absorbed in PVP-containing systems, and water sorption was decreasing with increasing API content. These trends could also be predicted in good agreement with the experimental data using the thermodynamic model PC-SAFT. Furthermore, the effect of absorbed water on API solubility in the polymer and on the glass-transition temperature of the formulations was predicted with PC-SAFT and the Gordon–Taylor equation, respectively. The absorbed water was found to significantly decrease the API solubility in the polymer as well as the glass-transition temperature of the formulation. Based on a quantitative modeling of the API/polymer phase diagrams as a function of relative humidity, appropriate API/polymer compositions can now be selected to ensure long-term stable amorphous formulations at given storage conditions.     

Extractive spectrophotometric assay of cyclizine in a pharmaceutical formulation and biological fluids

Two highly sensitive and simple spectrophotometric methods were developed to quantitate the drug cyclizine (CYC) in its pure form and in a pharmaceutical formulation. The two methods involved ion-associate formation reactions (method A) with mono-acid azo dyes, i.e., sudan (I) and sudan (II), as well as ion-pair reactions (method B) with bi-azo dyes, i.e., sudan (III), sudan (IV) and sudan red 7B (V). The reactions were extracted with chloroform, and the extraction products were quantitatively measured at 480, 550, 500, 530 and 570 nm using reagents I–V, respectively. The reaction conditions were monitored and optimised. The Beer plots for reagents I–V showed linear relationships for the concentrations of 4.2–52.0, 5.4–96.0, 3.5–43.0, 4.4–80.0 and 0.6–18.0 μg mL^?1, respectively, with molar absorptivities of 2.2 × 10⁴, 4.1 × 10⁴, 3.6 × 10⁴, 2.5 × 10⁴ and 1.3 × 10⁴ L mol^?1 cm^?1, respectively. Sandell sensitivities and detection limits were calculated and analysed. The implementation of the two methods to the analysis of a commercial tablet (Valoid) succeeded, and the recovery study suggested that there was no interference from common excipients in the tablet. Regarding the accuracy and precision of the methods, a statistical comparison of the results was performed using Student’s t-test and the F-test at the 95% confidence level. The accuracy and precision of the proposed methods were not significantly different.     

Molecular Dynamics Simulations of Hydrotropic Solubilization and Self-Aggregation of Nicotinamide

Hydrotropy is a phenomenon where the presence of a large quantity of one solute enhances the solubility of another solute. The mechanism of this phenomenon remains elusive and a topic of debate. This study employed molecular dynamics simulation to investigate the hydrotropic mechanism of a model system consisting of a hydrotropic agent, nicotinamide (NA), a poorly water-soluble solute, PG-300995 (PG), and water. Our study demonstrates that NA and PG undergo significant aggregation in the aqueous solution, a result correlating closely to the self-aggregation of NA under the same conditions. The correlations are found both structurally and dynamically, suggesting that the self-aggregation of NA may be a prerequisite, or at least a major contributor, to its hydrotropic effects. The self-aggregation of NA allows the segregation of the hydrophobic solute from water, a key step to ease the energy increase to the system. Energetic evidences directly show that the hydrotropic solubilization is favored in the presence of NA aggregation. These results are in strong support of the molecular aggregation hypothesis for hydrotropic solubilization. Additionally, it is found that the restoration of water-water HBs from the interference of the NA and PG molecules plays an important role for the aggregation. The HBs between the solute and the hydrotrope may contribute, but is not vital, to the aggregation and hence the hydrotropic effects. The dynamic data confirm that the aggregates, while remain in liquid state, are much more active dynamically than a pure NA amorphous/liquid phase under the same temperature and pressure. By equilibrating an NA amorphous agglomerate with water, it is found that the aggregation state, rather than an NA-water two phase system, is the equilibrium state of the NA + water system.     

Statistically designed enzymatic hydrolysis of an icariin/β-cyclodextrin inclusion complex optimized for production of icaritin

This study focuses on the preparation and enzymic hydrolysis of an icariin/β-cyclodextrin inclusion complex to efficiently generate icaritin. The physical characteristics of the inclusion complex were evaluated by differential scanning calorimetry (DSC). Enzymatic hydrolysis was optimized for the conversion of icariin/β-cyclodextrin complex to icaritin by Box–Behnken statistical design. The inclusion complex formulation increased the solubility of icariin approximately 17-fold, from 29.2 to 513.5 μg/mL at 60 °C. The optimum conditions were predicted by Box–Behnken statistical design as follows: 60 °C, pH 7.0, the ratio of enzyme/substrate (1:1.1) and reaction time 7 h. Under the optimal conditions the conversion of icariin was 97.91% and the reaction time was decreased by 68% compared with that without β-CD inclusion. Product analysis by melting point, ESI-MS, UV, IR, ¹H NMR and ¹³C NMR confirmed the authenticity of icaritin with a purity of 99.3% and a yield of 473 mg of icaritin from 1.1 g icariin.     

Binding of new aminopropan-2-ol compounds to bovine serum albumin, α1 acid glycoprotein and rat serum using equilibrium dialysis and LC/MS/MS

BackgroundThe binding of three new aminopropan-2-ol compounds briefly called 2F109, ANBL and TWo8 with potential cardiovascular activity to bovine serum albumin (BSA), α₁-acid glycoprotein (AGP) and to rat serum was studied. The chemical structures of these compounds are related to carvedilol. They possess an antiarrhythmic and hypotensive activity, and β- and α-adrenolytic mechanism of action. All analogues are weak bases with pKa values 8.65,8.85 and 8.26 for 2F109, ANBL and TWo8, respectively, and they possess lipophilic character (log P > 1.9584).MethodsThe extent of protein binding was determined using equilibrium dialysis in the range 2.5 – 900 μM, and 2.5 – 300 μM for binding of investigated compounds to BSA and AGP, respectively, and the quantitative measurement was done by LC/ESI-MS/MS assay.ResultsThe studied compounds bound to a single class of binding sites on BSA which was characterized by low affinity (K_d for 2F109 = 8.49 × 10^–5 M, for ANBL = 1.92 × 10^–5 M, and for TWo8 = 1.71 × 10^–5 M) and low capacity(n = 0.53 for 2F109,0.132 for ANBL and 0.13 for TWo8). The binding of 2F109, ANBL and TWo8 to AGP revealed one class of binding sites, with moderate affinity (K_d for 2F109 = 4.67 × 10^–6 M, for ANBL = 3.48 × 10^–5 M, and for TWo8 = 1.13 × 10^–5 M) and higher capacity (n = 2.21 for 2F109, 2.76 for ANBL and 2.28 for TWo8).ConclusionThe obtained data indicate that 2F109, ANBL and TWo8 moderately bind to BSA (34.2 – 71.2%) with low capacity (K_a = 6.21 × 10³–7.61 × 10³ M^–1)and strongly bind to AGP(71.5–85.5%)with moderate affinity (K_a = 7.94 × 104⁴.73 ×10⁵ M^–1).     

Upgrading bio-oil produced from the catalytic pyrolysis of sugarcane (Saccharum officinarum L) straw using calcined dolomite

In this study, the catalytic pyrolysis of sugarcane straw (SCS) into bio-oil and chemicals using calcined dolomite was applied for upgraded bio-oil production. Experiments were performed in a custom-built SS316 tube reactor, and the effects of the pyrolysis parameters, including the different dolomite calcination conditions, temperature (400-600 °C), biomass feed rate (0.3–1.2 kg h^?1), sweeping gas flow rate (80–200 cm³ min^?1) and average size distribution (250–1000 µm), were systematically investigated. The results showed that the SCS catalytic pyrolysis process obtained liquid yields of 36.15 wt%, gas yields of 52.09 wt% and solid yields of 11.76 wt% when using a pyrolysis temperature, biomass feed rate, nitrogen sweep gas, and average biomass size of 450 °C, 0.6 kg h^?1, 80 cm³ min^?1 and 500 µm, respectively, with 10 wt% calcined dolomite. The calcined dolomite influenced the bio-oil components from the carbonylation and the cracking of volatile vapor and resulted in an upgraded bio-oil with a lower oxygen content, higher gross calorific value and decreased acid corrosion.     

Dietary fumonisin exposure in a rural population of South Africa

A validated culturally specific dietary assessment method was used to determine the habitual maize intakes of black Xhosa-speaking Africans living in the Centane region of the Eastern Cape Province to assess their exposure to the carcinogenic fumonisin mycotoxins. The mean total dry weight maize intakes of home-grown, commercial or combined (both maize sources) were 474, 344, 462 g day^?1, respectively. When considering the total mean levels of fumonisin in home-grown maize (1142 μg kg^?1) and commercial maize (222 μg kg^?1), the probable daily intakes (PDI’s), expressed as μg kg^?1 body weight day^?1 were 12.1 (95%CI: 0.3–4926.5) and 1.3 (95%CI: 1.0–1.8) for men and 6.7 (95%CI: 1.0–457.8) and 1.1 (95%CI: 0.9–1.3) for women, consuming home-grown and commercial maize, respectively. Based on the different maize-based beer drinking frequencies the PDI’s varied between 6.9 and 12.0 μg kg^?1/drinking event. Depending on the maize intake patterns an exposure “window” exists where fumonisin exposure is below the recommended group provisional maximum tolerable daily intake (PMTDI) for fumonisins of 2 μg kg^?1 bw day^?1. The assessment of fumonisin exposure and development of preventative strategies depend, not only the accurate determination of total fumonisin levels in maize, but also on the distinct dietary patterns of a specific population.     

Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats

Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n = 8) or 80% of AL (CR, n = 8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10^− 9 to 10^− 4 M) was reduced in fa/fa AL compared to control lean AL rats (p < 0.001), and restored by CR. The AMPK activator AICAR (10^− 5 to 8·10^− 3 M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p < 0.001). Inhibition of PI3K (wortmannin, 10^− 7 M), Akt (triciribine, 10^− 5 M), or eNOS (L-NAME, 10^− 4 M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK–PI3K–Akt–eNOS pathway.     

Dry Powder Aerosols Generated by Standardized Entrainment Tubes From Drug Blends With Lactose Monohydrate: 1. Albuterol Sulfate and Disodium Cromoglycate

The major objective of this study was: discriminatory assessment of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs. Drug/lactose interactive physical mixtures (2%w/w) were prepared. Their properties were measured: solid-state characterization of phase behavior and molecular interactions by differential scanning calorimetry and X-ray powder diffraction; particle morphology and size by scanning electron microscopy and laser diffraction; aerosol generation by SETs and characterization by twin-stage liquid impinger and Andersen cascade impactor operated at 60 L/min. The fine particle fraction (FPF) was correlated with SET shear stress (τ_s), using a novel powder aerosol deaggregation equation (PADE). Drug particles were < 5 μm in volume diameter with narrow unimodal distribution (Span < 1). The lowest shear SET (τ_s = 0.624 N/m²) gave a higher emitted dose (ED ~ 84–93%) and lower FPF (FPF_6.4 ~ 7–25%). In contrast, the highest shear SET (τ_s = 13.143 N/m²) gave a lower ED (ED ~ 75–89%) and higher FPF (FPF_6.4 ~ 15–46%). The performance of disodium cromoglycate was superior to albuterol sulfate at given τ_s, as was milled with respect to sieved lactose monohydrate. Excellent correlation was observed (R² ~ 0.9804–0.9998) when pulmonary drug particle release from the surface of lactose carriers was interpreted by PADE linear regression for dry powder formulation evaluation and performance prediction.