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In recent years there has been a growing interest in solid lipid-based systems, particularly in solid lipid microparticles (SLMs); however, only very few studies deeply investigated the dissolution behaviour of orally delivered-SLMs. The present study provides new insights about the release performance in different gastrointestinal fluids of SLMs containing a freely water soluble drug (caffeine, as BCS class I drug). Three different formulations of SLMs were prepared by spray congealing using lipid excipients belonging to three chemical classes: fatty acids, triglycerides and waxes. The dissolution profiles of caffeine were investigated using various updated biorelevant dissolution media simulating the conditions of the gastrointestinal tract (gastric tract and proximal human intestine). The profiles were statistically compared and the morphological changes of the particles after dissolution were assessed by SEM analysis. The influence of the SLMs composition resulted to be crucial on the dissolution behavior in the case of bigger particles (>250 μm), while smaller SLMs (100-250 μm) were mainly affected by the fluid composition. Moreover, regardless of the particle size, greater differences in drug release profiles were noted by using different intestinal media compared to those obtained in gastric media. In particular, the drug release from fatty acid and triglyceride-based SLMs was more controlled in the phosphate buffer than in the intestinal biorelevant media; while the opposite behavior was noticed for waxy-bases SLMs. Overall, the present study provides interesting insights which can be useful for the design of a multiparticulated solid lipid formulation.

Bacterial infections represent an important problem in the orthopaedic field as they can develop either immediately after the surgical intervention or after some years [1]. In particular, they can be very problematic in the case of implants as, often, their elimination requires the surgical removal of the infected implant. Accordingly, a possible solution strategy is to act locally by coating the implant by an antibacterial system that has to be easily applicable, biocompatible (it must not hinder implant osseointegration) and able to provide the desired release kinetics of the selected antibacterial drug. In this frame, this paper focuses the attention on a biphasic polymeric system made up by a thermos-reversible hydrogel, constituted by Poloxamer 407, hosting a dispersed phase represented by polylactic-co-glycolic acid 50:50 (PLGA) micro-particles containing the antibacterial drug (vancomycin hydrochloride). While below room temperature, the Poloxamer 407/water system behaves as a solution and it is easily spreadable on the implant surface, upon temperature rise to the physiological value, the Poloxamer 407/water solution undergoes gelation. Basically, gelation ensures that the PLGA micro-particles remain in situ, between the implant surface and the growing bone. On the contrary, the controlled drug delivery is due to vancomycin hydrochloride release from PLGA micro-particles, acting as the reservoir phase. The primary aim of this paper is to develop a mathematical model able to properly describe the in vitro vancomycin hydrochloride release from the biphasic system.

Praziquantel (PZQ) is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children. In this study, the association of mechanochemical activation (MA) and the spray congealing (SC) technology was evaluated for developing a child-friendly PZQ dosage form, with better product handling and biopharmaceutical properties, compared to MA materials. A 1:1 by wt PZQ&mdash, Povidone coground&mdash, was prepared in a vibrational mill under cryogenic conditions, for favoring amorphization. PZQ was neat ground to obtain its polymorphic form (Form B), which has an improved solubility and bioactivity. Then, activated PZQ powders were loaded into microparticles (MPs) by the SC technology, using the self-emulsifying agent Gelucire&reg, 50/13 as a carrier. Both, the activated powders and the corresponding loaded MPs were characterized for morphology, wettability, solubility, dissolution behavior, drug content, and drug solid state (Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction Studies (PXRD), and FT-IR). Samples were also in vitro tested for a comparison with PZQ against Schistosoma mansoni newly transformed schistosomula (NTS) and adults. MPs containing both MA systems showed a further increase of biopharmaceutical properties, compared to the milled powders, while maintaining PZQ bioactivity. MPs containing PZQ Form B represented the most promising product for designing a new PZQ formulation.

Praziquantel (PZQ) is an inexpensive, low toxicity BCS II class anthelmintic drug used for the treatment of neglected tropical diseases. In earlier papers a mechanochemical activation has been used to induce physical transformations on the drug which would ameliorate its solubility and hence its bioavailability and a systematic study of the effects of varying temperature, frequency and time of milling on drug melting enthalpy and drug recovery was given. In this communication, the focus is on the degradation products that are formed during this mechanical treatment of Praziquantel. In the cogrinding process with povidone and crospovidone several degradation products are formed. Different degradation products are formed, which depend on the type of polymer rather than the process conditions. Two of the most prominent degradation products were identified and their structure proposed on the basis of information obtained from GC-MS, UPLC-MS and 1H NMR techniques.

Praziquantel is an antiparasitic drug used for decades. Currently, the praziquantel commercial preparation is a racemic mixture, in which only the levo-enantiomer possesses anthelmintic activity. The knowledge of its properties in the solid state and other chemical-physical properties is necessary for improving its efficacy and applications. Drug solid dispersions were prepared with calcium carbonate at 1:5 drug to excipient weight ratio by solvent evaporation method. Then, the modification of the crystal structure of the racemic polymorph of praziquantel in presence of calcium carbonate has been studied by means of several analytical techniques (DSC, TGA, XRD, SEM, FTIR, Raman spectroscopy and chiral liquid chromatography). This study has been completed with atomistic calculations based on empirical interatomic force fields and quantum mechanics methods applied to the crystal structure of praziquantel and of intermolecular interactions. The results evidenced that calcium carbonate provoked a conformational change in the praziquantel molecule yielding the formation of different polymorphs of praziquantel crystal. These alterations were not observed replacing calcium carbonate with colloidal silica as excipient in the solid dispersion.

In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC-MS/MS method. The pharmacokinetic analysis revealed a 2-20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine.

Praziquantel, a BCS II class anthelmintic drug used for the treatment of schistosome infections, was coground in a vibrational mill with different polymers (linear and crosslinked povidone, copovidone and sodium starch glycolate). An explorative analysis of formulation variables (drug-polymer wt ratio and polymer type) and process parameters (type of grinding media, grinding time and frequency) was carried out with the help of an experimental screening design. The influence of the above mentioned factors on three PZQ characteristics (residual crystallinity, water solubility enhancement and drug recovery) was studied. The variation of carrier amount proved to be by far the most important variable affecting all the experimental responses. A lower impact and, in some cases, rather null effect, had the variation of the process variables. All coground systems were characterized by a high amorphous degree and a solubility significantly higher than the API. A very promising product was obtained by processing at 20 Hz for 4 h, using 3 spheres of 15 mm as grinding media, i.e. a coground having a 50% API content, showing a 4.6-fold greater solubility at 20 C than pure praziquantel. This product maintained the same antischistosomal activity of pure API and was both physically and chemically stable for at least 6 months. © 2017 Elsevier B.V. All rights reserved.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Microcrystalline vinpocetine, coground with cross-linked polyvinylpyrrolidone, affords hybrids containing nanosized drug nanocrystals, the size and size distributions of which depend on milling times and drug-to-polymer weight ratios. Using an innovative approach to microstructural characterization, we analyzed wide-angle X-ray total scattering data by the Debye function analysis and demonstrated the possibility to characterize pharmaceutical solid dispersions obtaining a reliable quantitative view of the physicochemical status of the drug dispersed in an amorphous carrier. The microstructural properties derived therefrom have been successfully employed in reconciling the enigmatic difference in behavior between in vitro and in vivo solubility tests performed on nanosized vinpocetine embedded in a polymeric matrix.

The aim of this research was to improve the oral bioavailability of Oxytetracycline hydrochloride, a broad spectrum antibiotic having poor oral bioavailability, through the formulation of double o/w/o microemulsion systems. The range of compositions forming a clear one-phase region (primary o/w microemulsion) was evaluated through the construction of the ternary diagram and then three different types of double microemulsions were prepared using the "two-step technology". The formulations were characterized for droplet size and zeta potential. DSC was used for determining the type of microemulsion and to verify the formation of double microemulsion systems. The physical characterization gave satisfactory results that were compatible with double microemulsion systems. Finally, the pharmacokinetics of microemulsions was evaluated after oral administration on rats and compared to that of an aqueous and an oily solution. Results indicated an oral bioavailability enhancement of 5.7 and 2 times over the aqueous and oily solutions, respectively.

In this study, the suitability as rapid release dosage forms for ibuprofen of cylindrically shaped extrudates based on Gelucire 50/13 and Polyethylene glycol 4000 was investigated. Several drug to carrier weight ratios were processed in a small-scale ram extruder at a temperature much lower than the melting point of the binders. Cylindrical extrudates, regular in shape and with a smooth surface were obtained. In the Gelucire 50/13/ibuprofen extrudates, only a slight reduction of drug crystallinity compared to the relative physical blends was found, which in any case, did not affect the stability of the systems. While in the Gelucire case the ibuprofen dissolution was improved even by a little percentage of carrier in the formulation, with Polyethylene glycol 4000 the introduction of additional hydrophilic excipients was found to be necessary to achieve a dissolution rate and extent of dissolution of the drug comparable to those of Gelucire/ibuprofen systems.

An attractive herbal product, softgel capsules containing 10 mg of Echinacea angustifolia lipophilic extract, was given in a single oral administration to 10 human volunteers to perform a pharmacokinetic and immunological study. The plasma concentration of the major constituent was monitored, quantifying at predetermined time points the dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides (tetraene). The plasmatic levels of IL-2, IL-6, IL-8, IL-10 and TNF-a in samples collected before and 24 h after drug administration were analyzed by cytokine assay. The total RNA was extracted from limpho-monocyte isolated from the same blood samples and the same cytokines in terms of gene expression were evaluated. With the help of proper statistical tests the differences between the values obtained at 0 and 24 h were evaluated. Results of pharmacokinetic studies attest an approximately 3.5-fold improvement of tetraene oral bioavailability compared with previously published studies. Dodeca-2E,4E-dienoic acid isobutylamide exerts immunomodulatory effects down-regulating the gene expression and reducing the protein plasmatic levels of pro-inflammatory cytokines such as IL-6, TNF-a and IL-8, and up-regulating the expression of anti-inflammatory molecules as IL-10. Student’s two-sided paired t-test and non-parametric Wilcoxon–Mann–Whitney signed rank test agree in the conclusions about the differences between the ln values at 24 h and corresponding ln values at 0 h.

Praziquantel (PZQ), an anthelminthic drug widely used in developing countries, is classified in Class II in the Biopharmaceutics Classification Systems; this means that PZQ has very low water solubility and high permeability, thus the dissolution is the absorption rate-limiting factor. The aim of this work was to evaluate the suitability of melt granulation and ultrasonic spray congealing as techniques for enhancing the dissolution rate of PZQ. Granules in high shear mixer were prepared by melt granulation, using polyethylene glycol 4000 or poloxamer 188 as meltable binders and alpha-lactose monohydrate as a filler. Quite regularly shaped granules having main size fraction in the range 200-500 microm were obtained using both formulations; however, only poloxamer 188 granules demonstrated a significant (P=0.05) increase of the PZQ dissolution rate compared to pure drug. To evaluate the potential of ultrasonic spray congealing, Gelucire 50/13 microparticles having different drug to carrier ratios (5, 10, 20 and 30%, w/w) were then prepared. The results showed that all the microparticles had a significant higher dissolution rate (P=0.05) respect to pure PZQ. The increase of the PZQ content considerably decreased the dissolution rate of the drug: 5 and 10% PZQ loaded systems evidenced dissolution significantly enhanced compared to 20 and 30% PZQ microparticles. The microparticle's characterisation, performed by Differential Scanning Calorimetry, Hot Stage Microscopy, X-ray powder diffraction and FT-Infrared analysis, evidenced the absence of both modifications of the solid state of PZQ and of significant interactions between the drug and the carrier. In conclusion, melt granulation and ultrasonic spray congealing could be proposed as solvent free, rapid and low expensive manufacturing methods to increase the in vitro dissolution rate of PZQ.

Loratadine-loaded microspheres were prepared by spray-drying of dispersions, emulsions and suspensions differing in polymeric composition and solvents used. Conventional microspheres were obtained by spray-drying of dispersions composed of chitosan (CM) as only polymer, while composed microspheres were obtained by spray-drying of two-phase systems composed of chitosan and ethylcellulose (EC). Microspheres differed in EC/CM weight ratio (0:1, 1:2 and 1:3) and in loratadine/polymers weight ratio (1:6 and 1:8). The entrapment efficiencies were between 67.9 and 86.1%; less loratadine was entrapped as polymer/drug ratio decreased. In comparison to one-phase systems composed of CM as only polymer, spray-drying of two-phase systems composed of both, CM and EC resulted in improved loratadine entrapment (80.1–86.1%). All microspheres were positively charged, indicating the presence of chitosan at the surface, regardless of the drug content and the type of spray-dried system. The highest zeta-potential was measured for loratadine-free conventional microspheres, consisting of chitosan only (32.7±1.3 mV). Tensile studies showed that both, EC/CM ratio and the type of spray-dried system influenced the bioadhesive properties of the microspheres in a way that the microspheres with higher chitosan content were more bioadhesive and microspheres prepared from suspensions were more bioadhesive than those prepared from emulsions, regardless of the same polymeric composition. The results suggested that the spray-drying method is useful to produce bioadhesive loratadine-loaded microspheres. © 2004 Elsevier B.V. All rights reserved.

This study investigates the application of melt extrusion for the development of an oral retard formulation with a precise drug release over time. Since adjusting the formulation appears to be of the utmost importance in achieving the desired drug release patterns, different formulations of laminar extrudates were prepared according to the principles of Experimental Design, using a design for mixtures to assess the influence of formulation composition on the in vitro drug release from the extrudates after 1 h and after 8 h. The effect of each component on the two response variables was also studied. Ternary mixtures of theophylline (model drug), monohydrate lactose and microcrystalline wax (as thermoplastic binder) were extruded in a lab scale vertical ram extruder in absence of solvents at a temperature below the melting point of the binder (so that the crystalline state of the drug could be maintained), through a rectangular die to obtain suitable laminar systems. Thanks to the desirability approach and a reliability study for ensuring the quality of the formulation, a very restricted optimal zone was defined within the experimental domain. Among the mixture components, the variation of microcrystalline wax content played the most significant role in overall influence on the in vitro drug release. The formulation theophylline:lactose:wax, 57:14:29 (by weight), selected based on the desirability zone, was subsequently used for in vivo studies. The plasma profile, obtained after oral administration of the laminar extruded system in hard gelatine capsules, revealed the typical trend of an oral retard formulation. The application of the mixture experimental design associated to a desirability function permitted to optimize the extruded system and to determine the composition space that ensures final product quality. 2015 Elsevier B.V. All rights reserved.

Improvements of the oral bioavailability of lipophilic drugs can be obtained using lipidic formulations such as the self-emulsifying drug delivery systems. The high shear wet granulation (HSWG), using microemulsions as binder, is a viable process to produce self-emulsifying granules. However only few information are present in the literature on the effect of process variables on the properties of the granules obtained with these binders. Consequently, this article compares the effects of some relevant experimental variables (impeller speed and massing time) on the final technological and pharmaceutical properties of the granules produced using simple water, or alternatively, a microemulsion as binder and containing simvastatin (SV) as model drug. The effects of the variables were determined by evaluating the granule median diameter, their particle size distribution, roundness, disintegration time and dissolution rate of SV. Results clearly demonstrated that the microemulsion-based process was less sensitive to operating conditions than the water-based process. With microemulsion the nucleation process and growth regimes were more difficult to control, resulting in products with broader PSDs. At the same operating conditions microemulsion-based granules were more brittle but rounder and showed smaller median diameter compared to water-based granules. The dissolution rate of simvastatin was not significantly affected by the operating conditions.

In this study, the immunomodulatory effect of a triply standardized Echinacea angustifolia root extract (Polinacea(®)) was evaluated in 10 healthy subjects. Ten ml of syrup containing one hundred mg of extract (corresponding to 4.7 mg of Echinacoside and 8.0mg of a high molecular weight-20,000 Da- polysaccharide) were administered as a herbal syrup once a day for one month. The immunomodulatory effect was evaluated before and after herbal syrup administration evaluating the expression levels of the cytokines IL-2, IL-8, IL-6 and TNF-α. Cytokine expression was studied in lympho-monocytes and in plasma samples measuring the mRNA and protein levels, respectively. The results were analysed by ANOVA and non-parametric Friedman rank sum tests; when possible it was adopted a pair-wise comparisons at different post-treatment times, using the paired t-tests with Holm correction. The correlation between the variations of cytokine plasma levels and the respective mRNA was carried out using a linear regression model. In lympho-monocytes our data indicate the up-regulation of the mRNA levels of IL-2 and IL-8 and the down regulation of the mRNA levels of the pro-inflammatory cytokines TNF-α and IL6. The differential regulation was maximal after 14 days of treatment. IL-2 up-regulation and IL-6 down-regulation were also confirmed at the protein level in plasma. Finally, the up-regulation of the mRNA of IL-2/IL-8 and the down-regulation of IL-6 positively correlated with the protein levels detected in the plasma. In conclusion, this pilot study suggests a relevant role for the standardized Echinacea angustifolia root extract in the control of cytokine expression. This first demonstration of the immuno-modulating activity of Echinacea angustifolia root extract in the healthy subject, supports at least in part the common use of such products as health promoting supplement.

The peculiar higher solubility of drug nanocrystals compared to macrocrystals appeals to the pharmaceutical field. Indeed, until now, about 70 % of the potential drug candidates are discarded due to low bioavailability related with poor solubility in water. Since a modern and efficient design strategy for nanocrystal-based delivery systems requires the knowledge of the theoretical relation between nanocrystal size and solubility, the aim of this paper is to build up a physically-oriented thermodynamic model relating to nanocrystal dimensions with their melting temperature, enthalpy, solubility and dissolution rate. In particular, the developed model will be applied to vinpocetine, a poorly soluble drug used in the treatment of various types of cerebrovascular circulatory disorders.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. In the present research a salt of vincamine, a poorly bioavailable indole alkaloid derived from the leaves of Vinca minor L., was synthesized in the solid state by means of a mechanochemical process employing citric acid as a reagent. The mechanochemical process was adopted as a solvent-free alternative to classical citrate synthetic route that involves the use of solvents. Since the mechanochemical salification is little studied to date and presents the disadvantage of offering a low yield, in this work, the influence of three process and formulation variables on the percentage of vincamine citrate was studied. In particular, the time of mechanical treatment (in planetary mill Fritsch P5) and the amount of citric acid were varied in order to evaluate their effect on the yield of the process, and the introduction of a solid solvent, a common pharmaceutical excipient (sodium carboxymethylcellulose, NaCMC), was considered. Due to the complexity of the resulting samples’ matrix, an appropriate experimental design was employed to project the experimental trials and the influence of the three variables on the experimental response was estimated with the help of a statistical analysis. The experimental response, that is, the yield of the process corresponding to the percentage of vincamine in the protonated form, was unconventionally calculated by means of X-ray photoelectron spectroscopy analysis (XPS). Out of 16 samples, the one with the highest yield was the coground sample containing vincamine and citric acid in a 1:2 molar ratio, treated for 60 min in the presence of NaCMC. Under the above conditions the salification reaction was completed highlighting the importance of a proper selection of process and formulation variables of the mechanochemical salification, and emphasizing the crucial role of the solid solvent in facilitating the salification. The second step of the research encompassed the characterization of the citrate salt obtained by solid excipient assisted mechanochemical salification (SEAMS) in comparison with the vincamine citrate obtained by classical synthetic route. The samples were characterized by, besides XPS, high resolution transmission electron microscopy (HRTEM), X-ray powder diffraction (XRPD), in vitro solubilization kinetics and in vivo oral pilot study in rats. Finally, in order to monitor over time possible disproportionation phenomena, stability studies have been performed by repeating XPS analysis after 8 months. As expected, the the SEAMS-vincamine salt consisted of particles both crystalline and amorphous. The solubilization kinetics was superior to the corresponding salt probably thanks to the favorable presence of the hydrophilic excipient although the two salts were bioequivalent in rats after oral administration. Furthermore, no evidence of disporportionation phenomena in the SEAMSvincamine salt was found after storage. In conclusion, in the case of forming salts of poorly soluble drugs, the SEAMS process may be an interesting alternative to both classical synthetic routes, eliminating the need for solvent removal, and simple neat mechanochemical salification, overcoming the problem of limited process yield.

There is a need for innovation in plant-derived pharmaceuticals, food supplements and nutraceutical products regarding the use of more eco-sustainable solvents for their extraction. Furthermore, the poor oral bioavailability of several phytochemicals with health promoting effects stimulates the research in the field of pharmaceutical formulations. Natural Deep Eutectic Solvents (NADES) are formed by natural compounds, and can be considered as future solvents being especially useful for the preparation of nutraceuticals and food-grade extracts. In this paper various NADES were prepared using sugars, aminoacids and organic acids. Rutin (quercetin-3-O-α-l-rhamnopyranosyl-(1→6))-β-d-glucopyranose) was used as a model compound to study NADES. Moreover, the effect of various eutectic mixtures on rutin’s water solubility was studied. Proline/glutamic acid (2:1) and proline/choline chloride (1:1) mixtures have a solubility comparable to ethanol. The proline/glutamic acid (2:1) eutectic containing rutin was used in a pharmacokinetic study in Balb/c mice while bioavailability was compared to oral dosing of water suspension. Plasmatic levels of rutin were measured by HPLC-MS/MS showing increased levels and longer period of rutin permanence in plasma of NADES treated animals. This paper reports the possible use of non-toxic NADES for pharmaceutical and nutraceutical preparations.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. The aims of this research were to prepare highly bioavailable binary cogrounds (vincamine–AcDiSol® or PVP-Cl) by means of a mechanochemical process and to study the mediation of each polymer in the induction of physical transformations of the drug. From a set of fifteen cogrounds for each crosslinked polymer, two samples were selected in each group on the basis of the AUC of in vitro dissolution profiles with the help of a statistical comparison. The chosen samples were analysed by means of TEM, XRPD, Raman-spectroscopy/imaging, SSNMR, also including the study of 1H spin–lattice relaxation times. The research encompassed in vivo oral absorption studies in rats, pharmacokinetic analysis and physical stability studies during 1 year. An intimate drug–polymer mixing was found in the coground samples with domain average dimensions smaller than 100A˚ ; this reflected in a remarkable enhancement of the in vitro and in vivo bioavailability. Different disordered states were detected in the coground samples as a function of cogrinding time and the type and amount of polymer used. Though both crosslinked polymers produced a remarkable enhancement of the oral bioavailability, coground systems based on AcDiSol® are preferable in terms of pharmacokinetic performance and physical stability.

The aim of the work was to produce a delivery system for Silybum Marianum dry extract with enhanced oral bioavailability by combining two technologies (mechanochemical activation and spray congealing). Initially, the active was coground with sodium croscarmellose in a planetary mill in order to reach an activated state more prone to dissolution. DSC, XRD, FT-IR and LD analyses showed the formation of nanosized particles of dry extract, with reduced degree of crystallinity of the main crystalline flavolignans (silybine A and B). Then, microparticles containing the activated coground and, as comparison, the corresponding physical mixture of extract and polymer and the dry extract alone were produced by spray congealing technology using Gelucire (R) 50/13 as a hydrophilic low m.p. carrier. Microparticles containing the activated coground were produced spherical in shape, achieved satisfactory yield and high encapsulation efficiency. These microparticles, in addition to a favourable in vitro solubilisation kinetic, in a preliminary in vivo study in five rats demonstrated their ability to improve very significantly the oral bioavailability of the main flavolignans of Silybum Marianum dry extract (silybin A and B). These results suggested that the association of mechanochemical activation and spray congealing could be considered an innovative and very useful approach to the oral delivery of Silybum Marianum. Furthermore, for the first time the possibility of successfully applying the spray congealing technology for the preparation of a herbal drug delivery system was shown.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. The aim of this research was to prepare helical and cylindrical extrudates by melt extrusion and to evaluate their potential as sustained release dosage form. The systems contained theophylline as water-soluble model drug and microcrystalline wax as thermoplastic binder. The temperature suitable to ensure a successful extrusion process of formulations containing the wax in three different percentages was found to be below the melting point of the excipient. After the production of the extrudates in three different helical shapes (having 2, 3 and 4 blades) and a classical cylindrical shape, the systems were studied by means of X-ray powder diffraction and differential scanning calorimetry to check possible variations of the solid state of the drug during the thermal process. The morphology and chemical composition of the surface of the extrudates were examined by Scanning Electron Microscopy/Energy Dispersive X-ray Microanalysis to evaluate the presence of the drug on the surface of the extrudates and to monitor changes on the aspect of the waxy matrix during dissolution. Then, the different systems were analysed from the in vitro dissolution point of view to study the influence of the shape and of the composition on the drug release. An in vivo pilot study on the best performing system (helix with 3 blades) was carried out on five healthy volunteers and monitoring the intestinal transit by X-ray images. The resulting plasma profiles were analysed by means of a suitable pharmacokinetic analysis. Finally, an ad hoc mathematical model was developed to perform an accurate description of the in vitro release and in vivo performance of the 3-blades helical system.

The objective of this study was to develop new solid self-emulsifying pellets to deliver milk thistle extract (silymarin). These pellets were prepared via extrusion/spheronisation procedure, using a self-emulsifying system or SES (Akoline MCM®, Miglyol®, Tween 80®, soy lecithin and propylene glycol), microcrystalline cellulose and lactose monohydrate. To select the most suitable formulations for extrusion and spheronisation, an experimental design of experiences was adopted. The screening amongst formulations (13 different blends) was performed preparing pellets and evaluating extrusion profiles and quality of the spheronised extrudates. The pellets were characterised for size and shape, density, force required to crush them. Although more than one type of pellets demonstrated adequate morphological and technological characteristics, pellets prepared from formulation 7 revealed the best properties and were selected for further biopharmaceutical investigations, including in vitro dissolution and in vivo trials on rats to study serum and lymph levels after oral administration of the pellets. These preliminary technological and pharmacokinetic data demonstrated that extrusion/spheronisation is a viable technology to produce self-emulsifying pellets of good quality and able to improve in vivo oral bioavailability of main components of a phytotherapeutic extract of more than 100 times by enhancing the lymphatic route of absorption.

In this investigation, the preparation of solid self-emulsifying drug delivery systems (solid-SEDDS) by means of a wet granulation process was optimized in a lab-scale high shear mixer in order to improve the dissolution rate of piroxicam, a poorly water-soluble model drug. With this aim, the classic liquid granulation binder was replaced with an oil-in-water microemulsion, loaded with the drug. The microemulsion formulations were first selected on the basis of phase diagrams and their physicochemical properties, such as viscosity and droplet size. The best microemulsions were then used to prepare solid-SEDDS while maintaining the composition of the solid carrier and the operating conditions of the lab-scale high shear mixer used in this study. These pellets demonstrated an emulsifying capability and their piroxicam release was significantly enhanced with respect to pure drug. Since their dissolution was a function of pellet size fraction, in the subsequent step the yield of the best performing fraction was further increased by modifying experimental conditions for pellet production (impeller speed and amount of povidone). In this way, the 400 μm pellet size fraction of the selected formulation was produced with a percentage yield of 42.5 by wt., with satisfactory technological properties and unchanged drug dissolution performance.

The aim of this work was to enhance the bioavailability of erythromycin base when administered orally in rainbow trout (Oncorhynchus mykiss). Since erythromycin is normally given in the form of medicated feed, in this study three new types of feed formulation were developed. A self-emulsifying system and two types of double microemulsions (O/W/O) were prepared, characterized and adsorbed on a commercial extruded diet for fish. The emulsified systems were based on saturated polyglycolized glycerides and mono- and diglycerides of medium-chain fatty acids (as oily phase), Tween 80 (as surfactant) and, in the case of double microemulsions, distilled water. The systems differed in percentage composition and for the amount and position of erythromycin in different phases. The three medicated feed were then administered orally by means of a gastric probe to rainbow trout and their relative bioavailability was estimated in comparison with that obtained after oral administration of feed with erythromycin powder. For each medicated feed, 80 fish were tested. Finally, plasma profiles of erythromycin after single administration of medicated feeds were used to predict profiles obtainable by administering once-daily medicated feeds for 7 consecutive days. The results proved that the feeds containing microemulsified erythromycin provided largely superior oral bioavailability and the advantage of obtaining the same efficacy against bacterial infections with a much lower dose of drug.

The importance of studying oral drug absorption is well recognized by both research facilities/institutions and the pharmaceutical industry. The use of mathematical models can represent a very profitable and indispensable tool to understand oral drug absorption. Indeed, mathematical models can verify the correctness of the mechanisms proposed to describe drug release, absorption, distribution and elimination thus reducing the number of expensive and time-consuming experiments. In this paper we develop a mathematical approach able to model both the polymeric particle mediated delivery and the gastrointestinal absorption-metabolism-excretion (ADME) of a given drug. As a model drug a poorly water-soluble drug (vinpocetine) in both the amorphous and nanocrystalline state is considered. The delivery system is obtained by drug cogrinding with a polymer (cross-linked polyvinilpyrrolidone). As the proposed mathematical model can properly fit the in vivo data on the basis of information obtained in vitro, it represents a powerful theoretical tool connecting in vitro and in vivo behavior.

Silybum marianum dry extract, whose therapeutic use is partially restricted by the insolubility in water of its main flavonolignans, was subjected to a mechanochemical activation process in planetary mill using betacyclodextrins as carriers. After optimization of the operating conditions according to an established theoretical model, the best active-to-carrier proportion was selected from the preliminary trials. When using the optimized conditions, the mechanochemical process permits an improvement of the physico-chemical properties of the active, which reaches an “activated” solid state, that is stable for at least 1 year. In fact, XRD, DRIFT and Raman spectroscopy analyses showed that the main extract component, Silybin, completely lost its crystalline structure after co-grinding with betacyclodextrins and formed weak interactions with the carrier. The powder characteristics remarkably changed after co-grinding, leading to a sample with a very small mean diameter and with a twofold increase of the specific surface area in comparison to the dry extract. The activated solid state of the coground systems remarkably enhanced the in vitro drug dissolution kinetics with consequent improved oral bioavailability. Furthermore, the in vivo studies on rats revealed a 6.6-fold bioavailability increase respect to the S. marianum Italian commercial product used as reference (Silirex® 200 capsules). © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4119–4129, 2009

The relative bioavailability of the major alkamides, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, from Echinacea purpurea phytotherapeutic lozenges at three different dose levels (0.07, 0.21 and 0.9 mg) was evaluated in a pharmacokinetic study in humans and the possible effects on the immunological system were measured. Alkamides were found to be rapidly absorbed and measurable in plasma 10 min after administration of 0.21 and 0.9 mg lozenges and remained detectable for 3h for the 0.21 mg lozenges and for more then 3h for the 0.9 mg lozenges; 0.07 mg lozenges were measurable 20 min after administration and remained detectable for only 2h after the administration. A significant dose-independent down-regulation of the pro-inflammatory cytokines IL-12p70, IL-8, IL-6, IL-10 and TNF was observed 24h after oral administration. The results of non-compartmental pharmacokinetic analysis revealed that a C(max) of (0.65+/-0.41 ng/ml) was reached at 32 min with the 0.07 mg lozenges, (1.00+/-0.21ng/ml) at 25 min with the 0.21 mg lozenges and (8.88+/-5.89 ng/ml) at 19 with the 0.9mg lozenges. As evidenced by the dose-exposure relationship, no significant departure from dose proportionality was observed, indicating linearity in pharmacokinetics. To get a further insight in pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides a compartmental population pharmacokinetic model was developed applying mixed effect modelling procedure. The results demonstrate that within the dose range studied pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides are linear and that absorption is very rapid (t(1/2)=6 min) with apparently no lag time, thus indicating the possibility that a fraction of the drug is absorbed through the oral mucosa.

Aim of this work was to develop a cylindrical co-extrudate characterised by an in vivo sustained release profile by means of a hot-melt extrusion process. Co-extrudate was made up of two concentric extruded matrices: an inner one having a hydrophilic character, based on polyethylene glycol, and an outer one with lipophilic character, based on microcrystalline wax. Both segments contained theophylline as a model drug. A screening between several devices differing for dimensions (diameter and length) and relative proportions of the inner and outer part was carried out on the basis of their in vitro drug release and the release mechanism was studied by means of a mathematical model. The co-extrudate exhibiting the desired sustained release was selected for in vivo bioavailability studies. In vivo studies confirmed the achievement of the purpose of the research, demonstrating the desired release of theophylline on four healthy volunteers. Accordingly, hot-melt extrusion process is a viable method to produce in a single step co-extrudates showing a sustained release. In addition, the developed mathematical model proved to be a reliable descriptor of the both in vitro and in vivo experimental data.

The purpose of this preliminary study was to investigate the physico-chemical properties of nimesulide precipitated by continuous supercritical antisolvent (SAS) from different organic solvents like acetone, chloroform and dichloromethane at 40 degrees C and 80, 85 and 88 bar, respectively. Scanning electron microscopy, differential scanning calorimetry, X-Ray diffractometry and in vitro dissolution tests were employed to study how the technological process and the solvent nature would affect the final product. SAS-processed nimesulide particles showed dramatic morphological change in crystalline structure if compared to native nimesulide, resulting in needle and thin rods shaped crystals. The solid state analysis showed that using chloroform or dichloromethane as a solvent the drug solid state remained substantially unchanged, whilst if using acetone the applied method caused a transition from the starting form I to the meta-stable form II. So as to identify which process was responsible for this result, nimesulide was further precipitated from the same solvent by conventional evaporation method (RV-sample). On the basis of this comparison, the solvent was found to be responsible for the re-organization into the different polymorphic form and the potential of the SAS process to produce micronic needle shaped particles, with an enhanced dissolution rate if compared to the to the pure drug, was ascertained. Finally, the stability of the nimesulide form II, checked by DSC analysis, was ruled on over a period of 15 months.

Several controlled release systems of drugs have been elaborated using a supercritical fluid process. Indeed, recent techniques using a supercritical fluid as a solvent or as an antisolvent are considered to be useful alternatives to produce fine powders. In this preliminary study, the effect of Supercritical Anti Solvent process (SAS) on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC) was investigated. Two grades of HPMC (HPMC E5 and K100) as carriers were considered in order to prepare a sustained delivery system for theophylline which was used as a model drug. The characterization of the drug before and after SAS treatment, and the coprecipitates with carriers, was performed by X-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC). The dissolution rate of theophylline, theophylline-coprecipitates, and matricial tablets prepared with coprecipitates were determined. The physical characterizations revealed a substantial correspondence of the drug solid state before and after supercritical fluid treatment while drug-polymer interactions in the SAS-coprecipitates were attested. The dissolution studies of the matrices prepared compressing the coprecipitated systems showed that the matrices based on HPMC K100 were able to promote a sustained release of the drug. Further, this advantageous dissolution performance was found to be substantially independent of the pH of the medium. The comparison with the matrices prepared with untreated substances demonstrated that matrices obtained with SAS technique can provide a slower theophylline release rate. A new mathematical model describing the in vitro dissolution kinetics was proposed and successfully tested on these systems.

Atenolol is a β-blockers drug commonly used in the prevention of heart diseases. The aim of this work is to improve its bioavailability modifying its particle morphology by using supercritical carbon dioxide as antisolvent agent. Saturation conditions, at different temperatures, for ternary systems made up with carbon dioxide and solutions of atenolol in methanol, ethanol and isopropanol have been investigated using a variable volume cell. The effect of the presence of the active principle on the vapor–liquid equilibrium for the organic solvent–carbon dioxide system have been considered in order to choose the best operative conditions to perform the antisolvent precipitation process. Atenolol was then processed from different solutions (5%, w/w atenolol–methanol; 5%, w/w atenolol–ethanol and 1.65%, w/w atenolol–isopropanol) by sending the streams in a precipitation chamber firstly in counter current and later on in equicurrent. Various characterization analyses have been made on the precipitated powders. It is important to note that the release profiles of the precipitated atenolol show a general enhancement of the dissolution rate, compared to the one of the untreated drug.

A method of producing self-emulsifying pellets by wet granulation of powder mixture composed of microcrystalline cellulose, lactose and nimesulide as model drug with a mixture containing mono- and di-glycerides, polisorbate 80 and water, in a 10-l high shear mixer has been investigated. The effects of the formulation variables on pellets characteristics were evaluated by mixtures experimental design and by a polynomial model, in order to describe the phenomenon, to verify eventual interactions among components of the mixture and to investigate the feasibility of scaling-up. After determination of size distribution, the pellets were characterised by scanning electron microscopy, dissolution and disintegration tests, and by in vitro absorption test. Such an approach, applied to the development of a self-emulsifying system for nimesulide as poorly water-soluble model drug, resulted in different formulations with improved drug solubility and permeability characteristics. The data demonstrate that pellets composed of oil to surfactant ratio of 1:4 (w/w) presented improvement in performance in permeation experiments.

The purpose of this study was to apply the supercritical CO(2) impregnation process for preparing solvent-free nimesulide (NMS)-betacyclodextrins (BCD) association systems with enhanced drug dissolution rate. Several drug-to-carrier molar ratios were tested (1:1; 1:2.5; 1:3.5) at different conditions of temperatures (40, 100, and 130 degrees C) and pressures (140, 190 or 220 bar). The physical and morphological characterisation of the systems using powder X-ray diffraction, thermal analysis, diffuse reflectance Fourier transform-infrared spectroscopy and scanning electron microscopy was carried out to understand the influence of this technological process on the physical status of single components and binary systems and to detect possible interactions between drug and carrier. These analyses provided no evidence of a complete inclusion of NMS in the carrier but the existence of interactions between drug and carrier together with a partial dehydration of the BCD and the formation of drug crystallites with lower melting point and heat of fusion than the native NMS. These phenomena were more intense when severe conditions of pressure and temperature (220 bar and 130 degrees C) were used during impregnation trials and when the amount of BCD augmented in the systems. These activated solid state of the impregnated systems promoted an enhancement of drug dissolution rate that, in keeping with the results of the physical characterisation, was function of the process conditions and BCD content.

Theophylline-loaded microparticles of a lipid carrier, Precirol® ATO 5, were prepared by the ultrasonic spray-congealing method. The goal of the work was to investigate the effect of different concentrations and kind of colloidal silicon dioxide (Aerosil® 90, 200 and 300) on the microparticle characteristics (particle size, drug loading, morphology and kinetics of release). The results showed that the introduction of Aerosil® improved the drug distribution in the different particle sizes and that the mean diameter of the microparticles decreased with the viscosity of the suspension to be nebulized, especially that with Aerosil® 300. Whatever the microparticles formulation is, SEM and image analysis did not reveal any remarkable difference of the microparticle shape and surface area, suggesting that other parameters could influence the dissolution behaviour. Actually, the dissolution profiles of all the formulations appeared to be closely related to the physico-chemical properties of Aerosil®, especially to its gelation properties, which are a function of its specific surface area. In particular, microparticles having high concentration of Aerosil® 200 and 300 approached a zero order release kinetics, while Aerosil® 90 microparticles followed a first order release kinetics. Therefore, the drug release rate is controlled by the extent and rate of water absorption/swelling of the Aerosil® employed. Finally, DSC, HSM, XRD and FT-IR evidenced the permanence of the drug in its original state.

The purpose of this study is to evaluate the possibility of developing a cylindrical sustained-release dosage form for theophylline directly by means of a ram extrusion process. In particular, the formulations contained: stearic acid as a low melting binder, morrohydrate lactose and polyethylene glycol 6000 as hydrophilic fillers. The influence of type and percentage of the components was studied considering different parameters such as the time required for 50% of the drug release (t(50%))and the drug diffusion coefficient in the delivery system. The choice of the different formulations to be tested is carried out employing an axial design with constraint domains. The limits of each component were fixed on the basis of preliminary trials. The analysis of the t50% values revealed that the release kinetics is mainly affected by stearic acid and theophylline content, whilst lactose effect is almost negligible. A substantial correspondence between the experimental results and the analysis of the drug release kinetics performed by means of an ad hoc developed mathematical model was found. The proposed mathematical model allows to conclude that wherever the release mechanism is initially ruled by dissolution, then diffusion plays the most important role. (C) 2003 Elsevier B.V. All rights reserved.

The purpose of this study was to investigate the influence of supercritical CO2 processing on the physico-chemical properties of carbamazepine, a poorly soluble drug. Using the gas anti-solvent (GAS) technique, this drug was precipitated from three different solvents (acetone, ethylacetate and dichloromethane) to study, in addition, the effect of these vehicles on the properties of the final product. The samples were analysed before and after treatment by scanning electron microscopy analysis (SEM) and laser granulometer for possible changes in the appearance of the crystals. Furthermore, the solid state of the samples was studied by means of X-Ray powder diffraction (XRD), differential scanning calorimetry (DSC), diffuse reflectance Fourier-transform infrared spectroscopy (DRIFT) and hot stage microscopy (HSM). Finally, the in vitro dissolution tests were carried out. The solid state analysis of treated and untreated with CO2 samples, illustrated that the applied methodology caused a transition from the starting form I to the form I as well as a dramatic change on crystal morphology, resulting in a final product mainly consisting of needle-shaped crystals, regardless of the chosen solvent. Furthermore, to investigate whether this phenomenon was due to the GAS process or the vehicles used, carbamazepine was precipitated from the same three solvents by traditional evaporation method (RV-samples). On the basis of this comparison, the solvents used were found to be responsible for the reorganisation into a different polymorphic form, whereas the potential of the GAS process to produce micronic needle shaped particles, having a enhanced dissolution rate compared to the RV-carbamazepine, was stated.

In this work, the potential of waxes for preparing with the ultrasonic spray congealing technique microparticles for controlling the in vitro release of verapamil HCl was investigated. The first part of the study encompassed the optimisation of the formulation to achieve an efficient drug incorporation together with a satisfactory in vitro drug release rate. In particular, microcrystalline wax, stearyl alcohol and mixtures of the two were used. Also a surfactant (soya lecithin) was added to the formulations. After the particle size analysis, the characterisation of the microparticles involved the study of the solid state of drug and carriers in the systems (DSC, HSM and XRD) and the morphological and chemical analyses of the microparticle surface (SEM and XPS). Finally, the drug release mechanism from these devices was evaluated using the statistical moment analysis. The results of this study show that by selecting the type and the amount of the carriers, microparticles with a spherical shape and a good encapsulation efficiency were observed. These particles showed a zero-order release for 8 h, without modifying the solid state properties of the drug. Therefore, waxy microparticles prepared by the ultrasonic spray congealing technique are promising solvent-free devices for controlling the release of verapamil HCl. © 2003 Elsevier Science B.V. All rights reserved.

This work describes a new approach to prepare a fast-release dosage form for carbamazepine (CBZ), involving the use of melt granulation process in high shear mixer for the production of tablets. In particular, the granules containing CBZ were prepared using polyethylene glycol (PEG) 4000 as a melting binder and lactose monohydrate as a hydrophilic filler. The potential of the intragranular addition of crospovidone as a dissolution enhancer and a disintegrant agent was also evaluated. After the analysis of their solid state performed by means of X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC), the granules were characterised from the technological and dissolution point of view. The subsequent step encompassed the preparation and the evaluation of the tablets, including the effect of the extragranular introduction of crospovidone. Besides the remarkable enhancement of drug dissolution rate of the granulates in comparison to physical mixtures and pure drug, no significant differences were found between the dissolution profiles of the granulates containing lactose or crospovidone. However, the difficult disintegration and bad dissolution performance of the tablets not containing intragranular crospovidone highlight the necessity of this disintegrant in the granulating mixture. Moreover, the extragranular addition of a small amount of crospovidone gave rise to a further amelioration of the disintegration and dissolution performances. © 2003 Elsevier Science B.V. All rights reserved.

In this study, the potential of the spray-drying technique for preparing microspheres able to modify the release profile of carbamazepine was investigated. Low-, medium- and high-molecular-weight chitosan and hydroxypropyl methylcellulose (HPMC) in different drug–polymer ratios were used for the preparation of microspheres. The microspheres, characterized by X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC), were also studied with respect to particle size distribution, drug content and drug release. The results indicated that the entrapment efficiency (EE), as well as carbamazepine release profile, depended on polymeric composition and drug– polymer ratios of the microspheres prepared. The best entrapment efficiencies were obtained when chitosan of low-molecular-weight (CL) or HPMC were used for the microencapsulation. For all types of polymer used, the microspheres with low carbamazepine loading (6.3% w/w) showed better control of drug release than the microspheres with higher drug loadings. The HPMC microspheres showed the slowest carbamazepine release profile with no initial burst effect. Carbamazepine release profiles from ternary systems, carbamazepine–CL–HPMC microspheres, depended mostly on HPMC content and showed similar carbamazepine release profile as CL microspheres when HPMC content was low (9:1 CL–HPMC ratio, w/w). Otherwise, the carbamazepine release from CL–HPMC microspheres was remarkably faster than from either chitosan or HPMC microspheres. The release profile of carbamazepine from the microspheres was highly correlated with the crystalline changes occurring in the matrix.

The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. The chosen formulation was based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler. After determination of the size distribution, the pellet characterisation included scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence, the in vitro release from every single size fraction (2000, 1250, 800, 630,630 microm) was evaluated and the release mechanism was analysed with the help of an appropriate mathematical model. The results of drug content and superficial atomic composition were found to be constant in all pellets size fractions, attesting the ability of melt pelletisation in a high shear mixer to form a product with homogeneous composition. The mathematical model is built on the hypotheses that drug diffusion and solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Smaller classes apart (particles are not perfectly spherical), the comparison between model best fitting and experimental data indicated the reasonability of these hypotheses. Moreover, model reliability is proved by its ability of predicting drug release from a known mixture of the above mentioned particles classes.

In this work, the utilization of a spray-congealing technique using a new ultrasonic atomizer to prepare enhanced-release, solvent-free microspheres of carbamazepine (CBZ)–Gelucire 50/13 in different drug-to-polymer ratios was considered. Scanning electron microscopy analysis showed that it was possible to obtain spherically shaped and nonaggregated microparticles; the prevalent particle size was in the range 150–250 μm and the microspheres had a good encapsulation efficiency (> 90% in the prevalent size fraction). The in vitro dissolution tests displayed a significant increase of the CBZ dissolution rate from microspheres compared with pure drug and to drug–Gelucire 50/13 physical mixture. Differential scanning calorimetry, hot stage microscopy, X-ray powder diffractometry, and diffuse reflectance Fourier transform infrared spectroscopy demonstrated phase stability of the original polymorph of CBZ in all the systems; moreover, no interactions between the drug and Gelucire 50/13 were found. The results of this study suggested that the spray-congealing technique using the ultrasonic atomizer could be considered as a new and interesting method to enhance the dissolution rate of a poorly water-soluble drug as CBZ. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:699–707, 2002

It is well known that carriers can affect the dissolution of poorly soluble drugs. In this study, our aim was to investigate the dissolution enhancement of carbamazepine solid dispersed or mixed at different loading ratios in crospovidone, polyvinylpyrrolidone, and sodium starch glycolate. The physical state of the drug and the drug-polymer interactions in the solid state were investigated using differential scanning calorimetry (DSC) and x-ray diffraction analysis (XRD). Through the solubilization kinetics and dissolution rates studies, the in vitro drug availability of the systems was evaluated. An improved in vitro dissolution of the drug was obtained in all the binary systems that increased as the polymer content increased.

The purpose of this study was to apply the attractive technique of the supercritical fluid to the preparation of solvent-free solid dispersions. In particular, the gas antisolvent crystallisation technique (GAS), using supercritical carbon dioxide as processing medium, has been considered to prepare an enhanced release dosage form for of the poorly soluble carbamazepine, employing PEG 4000 as a hydrophilic carrier. The physical characterisation of the systems using laser granulometer, powder X-ray diffraction, thermal analyses, and scanning electron microscopy was carried out in order to understand the influence of this technological process on the physical status of the drug. The results of the physical characterisation attested a substantial correspondence of the solid state of the drug before and after treatment with GAS technique, whereas a pronounced change in size and morphology of the drug crystals was noticed. The dramatic reduction of the dimensions and the better crystal shape, together with the presence of the hydrophilic polymer determined a remarkable enhancement of the in vitro drug dissolution rate.

The effects of process conditions and the apparatus variables on the granulometric characteristics of a formulation containing a hydrophobic binder (stearic acid), lactose and paracetamol prepared by melt pelletization process were investigated in a 10-litre high shear mixer. The factors under investigation were: impeller speed, massing time, type of impeller blades and presence of the deflector and their reciprocal interactions. Two granule characteristics were analysed: the percentage of aggregates larger than 3000 microm (Y(1)) and the yield of the 2000-microm pellet size fraction (Y(2)). In order to estimate simultaneously the above-mentioned factors, a particular experimental design was adopted, that allowed the reduction of the number of trials from 378 to 35 and took into consideration other uncontrolled factors with the aid of a block variable. Using the postulated model, we found the optimal operating conditions to minimize Y(1) and increase Y(2) by selecting the type of impeller, and by using an impeller speed lower than 300 rpm, a massing time of 8-9 min and by not using the deflector. Finally, the validity of the adopted strategy has been proved with an additional check point.

The preparation of sustained-release pellets by melt pelletisation was investigated in a 10-l high shear mixer and ternary mixtures containing stearic acid as a melting binder, anhydrous lactose as a filler and theophylline as a model drug. A translated Doehlert matrix was applied for the optimisation of process variables and quality control of pellets characteristics. After determination of size distribution, the pellets were characterised with scanning electron microscopy, X-ray photoelectron spectroscopy and porosimetric analysis. Finally, the in vitro release from every single size fraction was evaluated and the release mechanism was analysed. Since the drug release rate decreased when enhancing the pellet size fraction, the 2000-mm fraction, exhibiting a substantially zero-order release, was selected for further in vivo biovailability studies. These data demonstrated that pellets based on the combination of stearic acid and lactose can be used to formulate sustained release pellets for theophylline. © 2000 Elsevier Science B.V. All rights reserved.

For poorly soluble orally administered drugs, the rate of absorption is often controlled by the rate of dissolution of the drug in the gastrointestinal tract. In literature many technological metho...

The objective of this study was to design atenolol tablets with fast in vitro release rates. Different polymers were screened as possible carriers to enhance atenolol dissolution. Binary systems using povidone (PVP), crospovidone (PVP-CL), polyvinilpyrrolidone/vinylacetate (PVP/VA), and Eudragit ® E were prepared. The physical properties of solid dispersions, compared to physical mixtures, were analysed using X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The solubility and the release rate of atenolol from solid dispersions were compared to the drug alone. The influence of various parameters (type of polymer, drug to polymer ratio, pH) on the solubility and dissolution rate of the drug was also evaluated. The results of DSC and X-ray analyses of solid dispersions attested that the drug was always present in a crystalline form in the PVP-CL and Eudragit ® E systems, while with the high content of PVP and PVP/VA an amorphisation of the atenolol was detectable. On the other hand, the diffraction patterns and the DSC thermograms of the physical mixtures revealed that to some extent the drug was always present in a crystalline form. An improvement in solubility and dissolution rate of atenolol with PVP and PVP-CL was obtained.

One of the possible causes of failure of the mechanochemical activation of poorly soluble drugs relies on the scarce drug wettability. Indeed, the mechanochemical process comports the disposition of drug nano-crystals and amorphous drug, generated by the destruction of original drug macro-crystals, on the surface of the carrier (acting as stabiliser), usually represented by crosslinked polymeric particles. Accordingly, the scarce drug wettability can reduce the beneficial action of mechanochemical activation (nano-crystals and amorphous drug are characterised by a higher solubility with respect to the original macro-crystals). In this light, this paper is focussed on the use of surfactants for the increase of delivery system (drug plus carrier) wettability. In particular, the surfactant-polymer systems are characterised for what concerns their bulk and surface properties. This allows to select the best surfactant and to experimentally verify its effect on the release kinetics of a poorly soluble and wettable drug.