4He dose- and track-averaged linear energy transfer: Monte Carlo algorithms and experimental verification.

Objective.In the present hadrontherapy scenario, there is a growing interest in exploring the capabilities of different ion species other than protons and carbons. The possibility of using different ions paves the way for new radiotherapy approaches, such as the multi-ions treatment, where radiation could vary according to target volume, shape, depth and histologic characteristics of the tumor. For these reasons, in this paper, the study and understanding of biological-relevant quantities was extended for the case of4He ion.Approach.Geant4 Monte Carlo based algorithms for dose- and track-averaged LET (Linear Energy Transfer) calculations, were validated for4He ions and for the case of a mixed field characterised by the presence of secondary ions from both target and projectile fragmentation. The simulated dose and track averaged LETs were compared with the corresponding dose and frequency mean values of the lineal energy,yD¯andy¯F, derived from experimental microdosimetric spectra. Two microdosimetric experimental campaigns were carried out at the Italian eye proton therapy facility of the Laboratori Nazionali del Sud of Istituto Nazionale di Fisica Nucleare (INFN-LNS, Catania, I) using two different microdosimeters: the MicroPlus probe and the nano-TEPC (Tissue Equivalent Proportional Counter).Main results.A good agreement ofL¯dTotalandL¯tTotalwithy¯Dandy¯Texperimentally measured with both microdosimetric detectors MicroPlus and nano-TEPC in two configurations: full energy and modulated4He ion beam, was found.Significance.The results of this study certify the use of a very effective tool for the precise calculation of LET, given by a Monte Carlo approach which has the advantage of allowing detailed simulation and tracking of nuclear interactions, even in complex clinical scenarios.

Air pollution deposition on a roadside vegetation barrier in a Mediterranean environment: Combined effect of evergreen shrub species and planting density.

Leaf deposition of PM10-100, PM2.5-10, PM0.2-2.5 and of 21 elements was investigated in a roadside vegetation barrier formed by i) two evergreen shrub species (Photinia × fraseri, Viburnum lucidum), with ii) two planting densities (0.5, 1.0 plant m-2), at iii) three distances from the road (2.0, 5.5, 9.0 m), at iv) two heights from the ground (1.5, 3.0 m), and on v) three dates (Aug, Sep, Oct). The presence of black and brown on-leaf PM10-100 and their element composition were detected by microscopy and image analysis. Pollutant deposition was also measured using passive samplers at five distances from the road (2.0, 5.5, 9.0, 12.5, 19.5 m) in the area of the barrier and in an adjacent lawn area. V. lucidum had more PM2.5-10 and PM0.2-2.5 on leaves than P. × fraseri, while most elements were higher in P. × fraseri. Most pollutants decreased at increasing distances from the road and were higher at 1.5 m from the ground compared to 3.0 m. Higher planting density in P. × fraseri enhanced the deposition of PM10-100 and PM2.5-10, while in V. lucidum, the planting density did not affect the depositions. Black PM10-100 decreased a long distance from the road and was entirely composed of carbon and oxygen, which was thus identified as black carbon from fuel combustion. The vegetation barrier had a higher deposition of most PM fractions at 5.5-12.5 m, while in the lawn area, depositions did not change. At 19.5 m, the PM10-100 was 32% lower behind the barrier than in the lawn area. In conclusion, the vegetation barrier changed the deposition dynamics of pollutants compared to the lawn area. These results strengthen the role of vegetation barriers and shrub species against air pollution and may offer interesting insights for the use of new road green infrastructures to improve air quality.

Nature based solutions to mitigate soil sealing in urban areas: Results from a 4-year study comparing permeable, porous, and impermeable pavements.

Soil sealing is one of the most pervasive forms of soil degradation that follows urbanization and, despite innovative pavements (i.e. pervious) are being installed in urban areas to mitigate it, there is little research on the effects of pervious pavements on soil water and carbon cycle and on the physiology of urban trees. The aim of this 4-year experiment was to assess the effects of three pavements, differing in permeability to water and gases, on some soil physical parameters, and on growth and physiology of newly planted Celtis australis and Fraxinus ornus. Treatments were: 1) impermeable pavement (asphalt on concrete sub-base); 2) permeable pavement (pavers on crushed rock sub-base); 3) porous design (porous pavement on crushed rock sub-base); 4) control (unpaved soil, kept free of weed by chemical control). Soil (temperature, moisture, oxygen content and CO2 efflux) and plant (above- and below-ground growth, leaf gas exchange, chlorophyll fluorescence, water relations) parameters were measured. All types of pavements altered the water cycle compared to unpaved soil plots, but this disturbance was less intense in porous pavements than in other soil cover types. Porous pavements allowed both higher infiltration and evaporation of water than both pavers and asphalt. Reduction of evaporative cooling from soil paved with permeable and impermeable pavements contributed to significant soil warming: at 20cm depth, soils under concrete pavers and asphalt were 4 and 5°C warmer than soil covered by porous pavements and unpaved soils, respectively. Thus, enhancing evaporation from paved soil by the use of porous pavements may contribute to mitigating urban heat islands. CO2 greatly accumulated under impermeable and permeable pavements, but not under porous pavements, which showed CO2 efflux rates similar to control. Soil oxygen slightly decreased only beneath asphalt. Growth of newly planted C. australis and F. ornus was little affected by pavement type. Tree transpiration rapidly depleted soil moisture compared to the not-planted scenario, but soil moisture did not fall below wilting point (particularly in the deeper soil layers, i.e. 40-50cm) in any treatment. While C. australis showed similar leaf gas exchange and water relations in all treatments, F. ornus showed a depression in CO2 assimilation and slight signs of stress of the photosynthetic apparatus when planted in soil covered with impermeable pavement. The effects of soil cover with different materials on tree growth and physiology were little, because newly planted trees have most of their roots still confined in the unpaved planting pit. Still, the reduction of soil sealing around the planting pit triggered the establishment of sensitive species such as ash. Further research is needed to assess the effects of different pavement types on established, larger trees.

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: long term results of the Italian Tamoxifen Anastrozole trial.

The Italian Tamoxifen Anastrozole (ITA) trial investigated the efficacy of switching to anastrozole for women who were already on adjuvant tamoxifen since 2-3years. Relapse-free survival (RFS) was the primary end-point; event-free survival (EFS), overall survival (OS) and safety were secondary end-points. Herein, we report an update on the long term results of this trial. At a median follow-up time of 128 months (range 14-168 months), 94 events have been recorded in the tamoxifen group compared with 71 events in the anastrozole group (hazard ratio (HR)=0.71; 95% confidence interval (CI), 0.52-0.97; p=0.03). RFS was also significantly longer in the anastrozole group (HR=0.64; 95% CI, 0.44-0.94; p=0.023); no statistically significant difference between study arms concerning OS was shown, but the trial was not powered enough in respect to this end-point. The incidence of serious adverse events (SAE) like bone fractures was comparable (four in each arm), while gynaecological problems were still significantly more numerous among the women continued on tamoxifen (21 patients developed a SAE in this group, including eight endometrial cancers, compared to three patients who suffered from a SAE, including one endometrial cancer, in the anastrozole group: p<0.000). Present data confirm that switch is safe and can provide long-term gain in terms both of RFS and of EFS, which persists even several years since treatment discontinuation.

Enhancement of oleyl alcohol anti tumor activity through complexation in polyvinylalcohol amphiphilic derivatives.

Oleyl alcohol was complexed with new amphiphilic polyvinylalcohol derivatives with the aim of increasing its aqueous solubility, thus improving bioavailability and favoring its antitumor activity. Water-soluble amphiphilic polymers were prepared by polyvinyl alcohol (PVA) substitution with oleyl chains through a succinyl spacer at 2% and 3% substitution degree. The complexes were obtained by spray-drying hydroalcoholic solutions of the substituted polymers and free oleyl alcohol at different weight ratios (3:1; 5:1; 10:1 w/w). The main physicochemical characteristics of the complexes were analyzed and correlated to the cytotoxic activity of oleyl alcohol toward tumor cell lines. The complexes strongly increased the aqueous solubility of oleyl alcohol and provided oleyl alcohol release in the presence of extractive conditions (simulating in vivo absorption). The complexes obtained by 10:1 polymer:fatty alcohol weight ratio offered higher release rates than the 5:1 and 3:1 ratios, respectively. Complexation also increased oleyl alcohol cytotoxicity toward tumor cells due to increased availability of the active molecule in the aqueous phase. Pure polymers were found to be biocompatible and no toxic effect was detected up to the highest concentration used in the present study (500 mu g/ml). The complexation of oleyl alcohol with the polymers analyzed here efficiently increased the availability of the fatty alcohol in aqueous environment. The enhanced cytotoxicity toward tumor cells of the complexed oleyl alcohol and the polymer biocompatibility make these amphiphilic PVA derivatives interesting candidates for soluble pharmaceutical formulations containing hydrophobic drugs whose therapeutic potential is often underestimated due to unsuitable levels of their aqueous solubilization.

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial.

BACKGROUND: Tamoxifen, for many years the 'gold standard' in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here. PATIENTS AND METHODS: This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2-3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety. RESULTS: A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12-93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group [HR 0.57 (95% CI 0.38-0.85) P = 0.005]. Relapse-free and overall survival were also longer in the anastrozole group [HR 0.56 (95% CI 0.35-0.89) P = 0.01 and 0.56 (95% CI 0.28-1.15) P = 0.1]. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7). CONCLUSIONS: Switching to anastrozole after the first 2-3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen.

Design and evaluation in vitro of controlled release mucoadhesive tablets containing chlorhexidine.

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity. Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa. Similar tests have also been carried out on a commercial product, Corsodyl gel, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.

Modified doxorubicin for improved encapsulation in PVA polymeric micelles.

Polyvinylalcohol, partially substituted with lipophilic acyl chains, generates polymeric micelles in aqueous phase, containing a hydrophobic core able to encapsulate lipophilic drugs. Two types of polymers were obtained by conjugation of polyvinylalcohol with oleoyl or linoleoyl chains as pendant groups. The polymers, at a substitution degree of approximately 1%, are soluble in water and form polymeric micelles whose size increases with polymer concentration. Doxorubicin was hydrophobized, by linking an oleoyl chain via amide bond, to make the drug more similar to the substituted polymers and promote its encapsulation into the inner core of the micelles. The properties of the drug-polymer systems were evaluated in solution by dynamic light scattering technique and correlated to the physicochemical characteristics of the drug and the substituted polymers. Solubilization tests revealed that the similarity of the chain, in both the polymer and the drug, promotes better drug encapsulation in the oleoyl than linoleoyl derivative. The drug-polymer systems are stable in phosphate buffer saline (pH 7.4) at 37 degrees C, and the release of the drug is activated by the presence of the proteolytic enzyme pronase-E. The enzyme activated drug release and the size of the polymeric micelles, compatible with the pore dimensions of the tumor vessels, make these systems interesting for targeting lipophilic drugs to solid tumors, where the proteolytic enzyme concentration strongly raises with respect to the other body compartments.

Modified polyvinylalcohol for encapsulation of all-trans-retinoic acid in polymeric micelles.

All-trans-retinoic acid (ATRA) is now included in many antitumor therapeutic schemes for the treatment of acute promyelocytic leukaemia, Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer and neuroblastoma. Unfortunately its poor aqueous solubility hampers its parenteral formulation. To date, there is no parenteral formulation of ATRA commercially available and oral administration of ATRA is associated with progressively diminishing ATRA levels in plasma, which is related to induction of retinoic acid-binding protein and increased drug catabolism by cytochrome P-450-mediated reaction. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects. To this purpose we prepared an amphiphilic polymer by polyvinylalcohol (PVA) substitution with oleyl amine at 1.5% substitution degree (mol substituent per 100 mol hydroxyvinylmonomer) and evaluated its functional properties with regard to ATRA complexation. The substituted polymer displayed ability to interact with ATRA both in aqueous solution and in the solid state following spray-drying of drug-polymer hydro-alcoholic solutions. The spray-dried complexes rapidly dissolved in water providing high levels of ATRA solubilization as a function of the drug-polymer weight ratio. The complexes characterized by 1:5 drug-polymer weight ratio provided higher levels of ATRA solubilization than 1:3 and 1:10 drug-polymer weight ratios respectively. Pre-formed polymeric micelles in water equilibrated in the presence of excess solid ATRA provided the lowest levels of solubilization. The drug release from the complexes was very slow in PBS, indicating their suitability in antitumor drug targeting where a fundamental requirement is stability towards drug release for at least 24 h, corresponding to the average circulation time period of macromolecular carriers. The cytotoxicity studies against neuroblastoma cell lines outlined increased cytotoxicity of complexed ATRA with respect to free ATRA, likely due to the increased bioavailability of the hydrophobic drug from the complex. We conclude that ATRA entrapped into self-assembling polymer micelles may be a useful parenteral ATRA formulation overcoming the unwanted pharmacological mechanism that lead to acquired retinoid resistance.

Elaboration and "in vitro" characterization of 5-ASA beads.

The purpose of this research was to perform the design and in vitro evaluation of alginate beads containing 5-ASA in order to achieve an oral system that protects the drug until it reaches the colon. Alginate beads were prepared by the well-known ionic gelation reaction (Ca2+). The influence of the incorporation of several polymers (Eudragit FS 30D, Eudragit S100, and chitosan) in the initial formulation was studied. In all formulations, entrapment efficiencies of the drug higher than 70% were obtained. The scanning electron microscopy (SEM) study of beads showed homogeneous sizes and shapes in all cases. Finally, the release behavior of these polymeric beads were also studied and compared. The results indicated that Eudragit FS 30D (26%) showed the most favorable dissolution behavior in terms of achieving a controlled release of 5-ASA. To determine the mechanism of drug release from these beads, the Korsmeyer equation was applied. Qt/Qinfinity <0.9 can be described using a Higuchi model and Qt/Qinfinity=0.7 showed a zero-order release period. This formulation was assayed at other different pH values (pH=6; 6.8; 7.2) to assure that there is no release of 5-ASA until the system reaches the colon. No release was observed at pH 6.0. Release was very slow at pH 6.8; averages about 20% an hour at pH 7.2 and was complete within 4 hour at pH 7.4. So, these Eudragit FS beads exhibited interesting dissolution profiles for the therapy of colon pathologies.

A factor analysis for complex systems containing nimesulide.

Binary systems containing Nimesulide and PEG 4000 were prepared by the melting method in the concentration range 3-25% w/w of the drug. The systems are homogeneous in the molten state, while, after cooling, two phases were formed of different density. They were manually separated and separately studied. Upper phases are richer in PEG 4000, while the lower ones contain the drug at levels even higher than those of the starting mixtures. The two phases were examined by DSC and UV techniques; high dissolution rates were observed with upper phases, while lower phases did not display improvement with respect to a physical mixture or micronized drug. With the aim to avoid phase separation, a third component was added to the binary system containing 5% w/w drug, during the melting. The ternary systems were prepared containing sodium dodecyl sulfate, triethanolamine, polysorbate 80, poloxamer, and cetomacrogol: a homogeneous phase was obtained only in two cases (with the addition of sodium dodecyl sulfate and triethanolamine), but only in the presence of triethanolamine dissolution rate was improved. Finally, a factor analysis was performed for complex systems containing a combination of the four additives, each one at two concentrations (1.25 and 2.5% w/w), to evaluate the optimum system in terms of both kinetic and composition parameters. Results suggest that additives affect mainly the physical aspect of the formulation rather than the kinetic behavior, which appears little improved only in a few cases.

Mucoadhesive tablets for buccal administration containing sodium nimesulide.

The possibility of improving the flux of nimesulide across the buccal mucosa using the drug in the form of a sodium salt was investigated in our study. The salt form may increase to flux across buccal membrane, starting from a suspension; its lower permeation coefficient is compensated by a higher concentration gradient. The salt was inserted into a mucoadhesive tablet for buccal administration. The tablets were designed to prevent the loss of the drug into the saliva by means of a protective layer and placed on the area not in contact with the mucosa. Ten volunteers were used. The in vitro release from mucoadhesive tablets was examined through a porcine buccal mucosa, using a standard Franz cell, modified for present purposes. The advantages of a higher concentration gradient for the flux, related to a higher solubility of the salt, and to a sufficiently high permeation coefficient of the drug, despite the ionized form, could not be completely exploited, because the composition of the formulation destroys the chemical form of the drug.

Ultrasound-compacted and spray-congealed indomethacin/polyethyleneglycol systems.

The product obtained by ultrasound (US)-assisted compaction was compared with a solid dispersion for systems containing polyethyleneglycols (PEGs) of different molecular weights and indomethacin (IMC), at the weight ratio 9:1, obtained by traditional melting and followed by a new US-assisted spray-congealing technique. US-discharge during compaction affects crystallinity of both IMC and PEG: pure IMC changes to an amorphous form and, when in mixture with PEG, partially dissolves in the excipient: this causes an increase of the dissolution rate of the drug. Differential scanning calorimetry (DSC) thermograms do not reveal any endothermic peak associated with the melting of the drug, while X-ray diffractograms show a loss of crystallinity of both IMC and PEG in the US-compacted granules. The extent of a back-crystallisation, which reduces the dissolution rate, as a function of the ageing of the material, depends on the type of the selected PEG. When a molten IMC/PEG mixture was transformed into microspheres by an US-assisted spray-congealing technique, the behaviour at dissolution almost recalls that of US-compacted granulates and some differences are briefly discussed.

Preparation and characterization by morphological analysis of diclofenac/PEG 4000 granules obtained using three different techniques.

The steam granulation is a new wet granulation technique, which involves the use of steam water instead of traditional liquid water as granulation liquid. The aim of this work was to evaluate the possibility of using this new technique to prepare diclofenac-polyethylene glycol 4000 accelerated-release granules. Steam granules were prepared in a laboratory scale high-shear mixer, and their properties were then compared to those of granules, having the same composition, obtained by traditional granulation techniques (wet and melt granulation). The results showed that, selecting the proper process parameters, it was possible to obtain granules using all the three methods; however, the total process time was significantly shorter for steam granulation (30 min) in comparison to traditional wet granulation (70 min), due to the lower amount of used water. The morphological characterization of steam, water and melt granules, performed by scanning electron microscopy (SEM) and image analysis, revealed that steam granules had a more spherical shape and a larger surface area with respect to water and melt ones, suggesting a possible difference in dissolution behavior. Moreover, differential scanning calorimetry (DSC) and X-ray powder diffraction analysis evidenced the transformation of the drug from its originally crystalline form into the amorphous one. Finally, the in vitro dissolution tests showed an increased dissolution rate of the drug from the granules (in particular steam granules) in comparison to pure drug and physical mixture. In conclusion, the results of this study suggested that the steam granulation technique could be considered an interesting alternative to traditional wet granulation to improve the dissolution rate of diclofenac.

Alginate/chitosan particulate systems for sodium diclofenac release.

Alginate/chitosan particles were prepared by ionic gelation (Ca2+ and Al3+) for the sodium diclofenac release. The systems were characterized by electron microscopy and differential scanning calorimetry. The ability to release the active substance was examined as a function of some technological parameters and pH of dissolution medium. The release of sodium diclofenac is prevented at acidic pH, while is complete in a few minutes when pH is raised up to 6.4 and 7.2. The alginate/chitosan ratio and the nature of the gelifying cation allow a control of the release rate of the drug. The release mechanism was briefly discussed.

Diclofenac salts. I. Fractal and thermal analysis of sodium and potassium diclofenac salts.

Sodium and potassium diclofenac salts form hydrates when crystallized from water; the sodium salt contains four crystallization water molecules, while the potassium salt precipitates as a dihydrate. Crystallization from organic solvents occurs with a change of the crystal habit. The fractal dimension of the particle surface of both salts obtained from water is low and is in agreement with the formation of smooth and regular surfaces during crystallization. The fractal dimension for dissolution is relatively high and comparable for hydrate and anhydrate forms of both salts, and the result was interpreted as being due to the surfactant behavior of diclofenac anions. Thermograms of both salts show a couple of endotherms in the range 30-100 degrees C, which disappear when the salts have been previously heated at 100 degrees C, but slowly reappear when the anhydrate forms are stored in a humid environment. Both salts present a complex exotherm of decomposition at 284 and 314 degrees C, respectively. The results are briefly discussed with regard to the formulations of the anti-inflammatory agent diclofenac.

Improvement of the synthesis of diphenylmethyl 7beta-(o-hydroxy)benzylideneamino-3-hydroxymethyl-3-cephem-4-carboxylate.

The title product (I) is synthesized currently from 7-aminocephalosporanic acid, and diphenyldiazomethane (DDM) is used as a protective reagent of the acid function for further reactions. When DDM was prepared from benzophenone hydrazone by reaction with chloramine T, it was resulted impure by p-toluenesulfonamide, formed as side product, which cannot be removed during the final purification step carried out according to the literature procedure. Two simple methods are proposed here to obtain I with the suitable degree of purity necessary for a drug.

Channeling agent and drug release from a central core matrix tablet.

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance--polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.

Interaction between indomethacin and heavy metal ions in aqueous solution.

The interaction between indomethacin anions and heavy metal ions, such as cadmium, zinc and copper(II) ions, was studied in aqueous solution by polarographic techniques. Indomethacin anions form complexes with these heavy metal ions: the complex formed with cadmium ions is sparingly soluble, while more soluble and also stronger complexes are formed with zinc and copper(II). At high concentrations, where indomethacin anions undergo self-aggregation, these last compounds are solubilised. This property is briefly discussed and compared to that of bile salts. In the presence of calcium ions, indomethacin forms a poorly soluble salt and no evidence was detected for the formation of complex species.

Percolation thresholds in ultrasound compacted tablets.

Twenty matrix systems with different KCl content (as drug model, from 10 to 90% w/w) and Eudragit RS-PM (as inert excipient) were prepared using an ultrasound-assisted press and a traditional eccentric machine. The release behavior from both types of matrices was examined; the kinetic parameters for the release (intrinsic dissolution) and the technological properties of the final tablets (total porosity) were used to estimate the percolation threshold for the drug model and the excipient in both systems. For the systems compacted by ultrasound (US) the estimated value for the excipient percolation threshold ranges from 13.4 to 20.2% v/v (lower than that found for traditional tablets), that agrees with a continuum percolation model suggesting the presence of a continuum phase inside the tablet. This depends on a thermoplastic deformation of Eudragit RS-PM under ultrasound, that destroyed the particulate system of the excipient and transform it into a continuum medium. The percolation threshold for KCl ranged from 58.6 to 61.0% v/v for US and from 26.7 to 42.2% v/v for the traditional tablets. The higher value for ultrasound compacted tablets can be explained by the difficulty of KCl to outcome from a matrix containing insoluble phase that surrounds KCl crystals.