Combining Mechanochemistry and Spray Congealing for New Praziquantel Pediatric Formulations in Schistosomiasis Treatment.

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-Povidone coground-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® 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.

Spray Congealing: An Emerging Technology to Prepare Solid Dispersions with Enhanced Oral Bioavailability of Poorly Water Soluble Drugs.

The low and variable oral bioavailability of poorly water soluble drugs remains a major concern for the pharmaceutical industry. Spray congealing is an emerging technology for the production of solid dispersion to enhance the bioavailability of poorly soluble drugs by using low-melting hydrophilic excipients. The main advantages are the absence of solvents and the possibility to obtain spherical free-flowing microparticles (MPs) by a relatively inexpensive, simple, and one-step process. This review aims to fully describe the composition, structure, physico-chemical properties, and characterization techniques of spray congealed-formulations. Moreover, the influence of these properties on the MPs performance in terms of solubility and dissolution enhancement are examined. Following, an overview of the different spray congealed systems developed to increase the oral drug bioavailability is provided, with a focus on the mechanisms underpinning the bioavailability enhancement. Finally, this work gives specific insights on the main factors to be considered for the rational formulation, manufacturing, and characterization of spray congealed solid dispersions.

A Novel Approach for Dry Powder Coating of Pellets with Ethylcellulose. Part II: Evaluation of Caffeine Release.

The objective of this study was to assess the efficacy and the capability of a novel ethylcellulose-based dry-coating system to obtain prolonged and stable release profiles of caffeine-loaded pellets. Lauric and oleic acids at a suitable proportion were used to plasticize ethylcellulose. The effect of coating level, percentage of drug loading, inert core particle size, and composition of the coating formulation including the anti-sticking agent on the drug release profile were fully investigated. A coating level of 15% w/w was the maximum layered amount which could modify the drug release. The best controlled drug release was obtained by atomizing talc (2.5% w/w) together with the solid plasticizer during the dry powder-coating process. SEM pictures revealed a substantial drug re-crystallization on the pellet surface, and the release studies evidenced that caffeine diffused through the plasticized polymer acting as pore former. Therefore, the phenomenon of caffeine migration across the coating layer had a strong influence on the permeability of the coating membrane. Comparing dry powder-coated pellets to aqueous film-coated ones, drug migration happened during storage, though more sustained release profiles were obtained. The developed dry powder-coating process enabled the production of stable caffeine sustained release pellets. Surprisingly, the release properties of the dry-coated pellets were mainly influenced by the way of addition of talc into the dry powder-coating blend and by the drug nature and affinity to the coating components. It would be interesting to study the efficacy of novel coating system using a different API.

Formulation of spray congealed microparticles with self-emulsifying ability for enhanced glibenclamide dissolution performance.

PURPOSE: To develop a novel preparation approach of solid Self-Emulsifying Drug Delivery System (s-SEDDS) based on spray congealing as potential drug delivery technology for poorly water-soluble drug Glibenclamide (GBD). METHODS: Several systems were formulated using suitable excipients, solid at room temperature, with different hydrophilic-lipophilic balance, such as Myverol, Myvatex, Gelucire®50/13 and Gelucire®44/14. Cremophor®EL and Poloxamer 188 were selected as surfactants and PEG 4000 as co-solvent. RESULTS: The screening of the best carrier for s-SEDDS manufacturing revealed that Gelucire®50/13 had greater performance. Then, surfactant-co-solvent systems were developed. Dissolution studies showed that all the formulations promoted the solubilisation performance of the GBD with respect to pure drug; in particular the formulation containing Gelucire®50/13 and PEG 4000 increased the drug solubilisation of five times. These microparticles showed self-dispersibility within 60 min and micelles dimensions around 360 nm. CONCLUSIONS: Spray congealing is a promising novel manufacturing technique of solid self-emulsifying systems.

Investigating the physicochemical properties of solid dispersions based on semicrystalline carriers: A case study with ketoprofen.

Hydrophilic semicrystalline carriers represent an alternative to amorphous polymers due to their low melting temperature, useful for the production of solid dispersions (SDs) by melting-based technologies. This research aims to compare SDs of ketoprofen (KET) and three different semicrystalline carriers (PEG, Poloxamer and Gelucire) regarding miscibility, phase behavior, molecular interactions and stability. KET was chosen owing to its low solubility and high glass forming ability. Estimation of drug-excipient miscibility was performed by Flory-Huggins theory. Negative Gibbs free energy indicated a spontaneous mixing of KET with the three carriers and miscibility in the order PEG > Poloxamer > Gelucire. SDs up to 40 % w/w of drug were produced by melting process at a temperature below KET melting point. Characterization of SDs was performed by differential scanning calorimetry, polarized light microscopy and powder X-ray diffraction. In case of PEG and Poloxamer, the drug incorporation did not affect carrier crystallinity, while KET was in the amorphous state. Differently, KET retarded the crystallization of Gelucire and at high drug loadings the SDs were amorphous and semisolid. FT-IR analysis revealed a strong interaction between KET and the three carriers. Finally, PEG-based SDs above 20 % KET loading displayed drug crystallization after 6 months of storage; while Poloxamer and Gelucire-based SDs showed KET crystallization only at 40 % KET. Due to its less hydrophilic character and limited water uptake, Gelucire showed the best stability among the three excipients.

Tailoring the release of drugs having different water solubility by hybrid polymer-lipid microparticles with a biphasic structure.

The aim of this study is to investigate the potential of hybrid polymer-lipid microparticles with a biphasic structure (b-MPs) as drug delivery system. Hybrid b-MPs of Compritol®888 ATO as main lipid constituent of the shell and polyethylene glycol 400 as core material were produced by an innovative solvent-free approach based on spray congealing. To assess the suitability of hybrid b-MPs to encapsulate various types of APIs, three model drugs (fluconazole, tolbutamide and nimesulide) with extremely different water solubility were loaded into the polymeric core. The hybrid systems were characterized in terms of particle size, morphology and physical state. Various techniques (e.g. optical, Confocal Raman and Scanning Electron Microscopy) were used to investigate the influence of the drugs on different aspects of the b-MPs, including external and internal morphology, properties at the lipid/polymer interface and drug distribution. Hybrid b-MPs were suitable for the encapsulation of all drugs (encapsulation efficiency > 90 %) regardless the drug hydrophobic/hydrophilic properties. Finally, the drug release behaviors from hybrid b-MPs were studied and compared with traditional solid lipid MPs (consisting of only the lipid carrier). Due to the combination of lipid and polymeric materials, hybrid b-MPs showed a wide array of release profiles that depends on their composition, the type of loaded drug, the drug loading amount and location, providing a versatile platform and allowing the formulators to finely balance the release performance of drugs intended for oral administration. Overall, the study demonstrates that hybrid, solvent-free b-MPs produced by spray congealing are an extremely versatile delivery platform able to efficiently encapsulate and release very different types of drug compounds.

Development and in vitro evaluation of mucoadhesive gelatin films for the vaginal delivery of econazole.

Several strategies have been explored to obtain effective econazole nitrate (ECN) concentrations at the site of application for a prolonged time. In this paper, different gelatin-based film formulations for vaginal application were investigated, containing ECN (10% w/w with respect to gelatin) as pure drug or as drug-solid dispersions (SD). For the production of SD, different polymers were evaluated: polyvinylpyrrolidone (PVP), Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) and Gelucire® 50/13 (mixture of mono-, di- and triglycerides of fatty acids, esters of PEG 1500 and free PEG). Gelucire®-SD showed the best solubility enhancement, increasing 9.2 times the ECN solubility in pH 4.5 solution respect to pure drug; DSC and XRD analysis confirmed the crystalline form of the drug. XRD results evidenced that all gelatin-based films, containing either the drug or the SD, underwent the topotactic transformation of ECN into crystalline econazole (EC), owing to a strong interaction between the drug and the gelatin. Films containing Gelucire®-based SD displayed lower brittleness and rigidity with respect to the other samples; moreover they demonstrated good structural integrity after 24 h of incubation in the acidic solution (swelling degree of about 350%). Then, Gelucire®-SD based films were compared with the corresponding formulations cross-linked by genipin (2% w/w). The addition of genipin did not interfere with the drug-gelatin interaction. Gelucire®-SD based films showed similar release profiles to neat gelatin films, enhancing the drug release in the first 5 h and controlling the EC release over time, avoiding the use of a crosslinking additive. Finally, gelatin films containing Gelucire® solid dispersion displayed good adhesiveness and anti-Candida activity. Overall, results support the potential use of this film formulation as noncytotoxic EC delivery system for the treatment of vaginal candidiasis.

Modulation of Alendronate release from a calcium phosphate bone cement: An in vitro osteoblast-osteoclast co-culture study.

In this study, we loaded a biomimetic calcium phosphate bone cement (CPC) with relatively high amounts of a bisphosphonate through the use of Solid Lipid Microparticles (MPs) and investigated bone cells response to the composite cements. 10, 20 and 30% w/w of Alendronate (AL) were successfully introduced into microparticles of Cutina HR and Precirol, which were prepared by means of spray-congealing technique. Addition of AL-loaded MPs to the cement composition provoked a lengthening of the setting and of the hardening processes. However, setting times were still in a range useful for clinical applications, except for the cements at the highest Alendronate content. The composite cements displayed a sustained drug release over time. Cements with the best performances in terms of setting, hardening, mechanical properties and drug release were submitted to in vitro tests using a co-culture model of osteoblast and osteoclast. The results showed that the use of MPs to enrich the cement composition with Alendronate provides materials able to inhibit osteoclast viability and activity, while promoting osteoblast viability and earlier differentiation, indicating that the MPs-cements are good delivery systems for bisphosphonates.

Spray-congealed solid lipid microparticles as a new tool for the controlled release of bisphosphonates from a calcium phosphate bone cement.

The aim of this work was to develop an innovative drug delivery system potentially useful for the local delivery of Bisphosphonates to bone tissue. We propose the use of Solid Lipid Microparticles (MPs), up to now mainly used for oral and topical drug delivery, as carrier for bisphosphonates due to the favourable biocompatibility and lower toxicity of the lipids compared with many polymers. The delivery platform consisted of a biomimetic α-tricalcium phosphate-gelatin cement (CPC) enriched with alendronate loaded MPs (MPs-AL) produced by the spray congealing technology. Alendronate direct addition to cement composition is limited since Alendronate is able to sequester calcium from calcium phosphates, thus preventing the setting of the cements. At variance, this approach permitted to load a relatively high amount of the drug on the CPC and allowed the controlled release of the highly water soluble alendronate. A Design of Experiment (DoE) was employed for the screening of the effects of the formulation variables related to the presence of unloaded microparticle (MPs) on the cement most important mechanical properties. Then, MPs loaded with 10% w/w of alendronate were produced using five different carriers (Stearic Acid, Stearilic Alcohol, Cutina HR, Tristearin and Precirol ATO5). All MPs-AL exhibited a spherical shape, encapsulation efficiency higher than 90% and prevalent particle size ranging from 100 to 150µm. Solid state characterization (DSC, HSM and X-ray powder diffraction) demonstrated that encapsulation of alendronate into MPs did not alter its crystal structure. MPs-AL addition to the cement provoked a modest lengthening of the setting times and of the hardening reaction leading to the complete transformation of α-tricalcium phosphate into calcium-deficient hydroxyapatite, without significantly affect the cement mechanical properties. Moreover, the results of in vitro AL release study performed on cements enriched with MPs-AL showed that the system allows a controlled release of the drug over time.

Milling and comilling Praziquantel at cryogenic and room temperatures: Assessment of the process-induced effects on drug properties.

This study is a comprehensive evaluation of praziquantel (PZQ) behavior upon grinding considering the influence of milling temperature (cryogenic vs room temperature), frequency and time and presence of polymers (milled raw PZQ vs comilled PZQ/povidone and PZQ/crospovidone at 50:50 w/w) on two experimental responses (residual crystallinity and PZQ recovery). To this aim a full factorial design was set up and the responses of the experimental design were statistically assessed. The powder temperature, measured in different milling conditions, was found to increase with increasing milling frequency and time, up to a maximum recorded value of 46.9 °C (after 90 min at R.T.), for all the three powder systems. When PZQ was ground in RT environment, the recovery was 100%, independently from frequency and time of milling. Its residual crystallinity remained pronounced (>70%) upon milling, even if treated at the most severe conditions. Conversely, when the drug was milled in presence of the polymers, it showed a higher tendency to degradation and amorphysation, independently from the choice of the polymer. The use of cryogenic conditions, operating at temperatures lower than PZQ glass transition, permitted to dramatically reduce PZQ residual crystallinity when the drug was ground by itself. In the case of binary mixtures, the switch to a cryogenic environment did not affect significantly the experimental responses, but permitted to obtain a more predictable trend of both drug recovery and residual crystallinity when varying time and frequency of milling.

A novel approach for dry powder coating of pellets with Ethylcellulose. Part I: Evaluation of film formulation and process set up.

An innovative dry powder coating technology was developed in a high-shear granulator using ethylcellulose (E10) as polymer. Several solid plasticizers were investigated with the aim of decreasing the polymer Tg at least to the highest possible working temperature (80°C). DSC analysis of physical mixtures of E10 and plasticizers evidenced that lauric acid (LA) was the most effective plasticizer. In order to reach the target temperature a liquid plasticizer, oleic acid (OA), was introduced in the coating formulation. Free films were then prepared and the target minimum film forming temperature (MFFT) was established in the range 70-80°C. Depending on the LA:OA weight ratio, Kollidon VA64 was included to decrease the LA recrystallization, while talc served as anti-sticking agent. Curing at the MFFT ensured the formation of homogeneous and stable films with good stability on storage. The dry powder coating process of placebo pellets was then developed, consisting of a combination of liquid assisted and thermal adhesion methods. The best coating formulations in terms of yields, coating efficiency (expressed as Relative Standard Deviation of the weight applied) and low pellets aggregation were based on E10:LA:OA in a weight ratio of 65:20:15 and 60:20:20. Moreover pellets remained stable after 1year of storage (25°C/60% R.H.).

Evaluation of melt granulation and ultrasonic spray congealing as techniques to enhance the dissolution of praziquantel.

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.

Ethylcellulose film coating of guaifenesin-loaded pellets: A comprehensive evaluation of the manufacturing process to prevent drug migration.

The aim of the research was to investigate the complete process of pellet production in a Wurster fluidized bed coater in order to determine the main factors affecting the migration phenomenon of a soluble API through the ethycellulose film coating (Surelease®) and hence the long-term stability of the controlled release pellets. Guaifenesin (GFN), as BCS class I model drug, was layered on sugar spheres using a binder-polymer solution containing the dissolved GFN. The drug loaded pellets were then coated with Surelease®. The influence of drug loading (4.5-20.0% w/w), curing conditions (40-60°C and dynamic-static equipment), coating level (12-20% theoretical weight gain) and composition of the binder-layering solution (hypromellose versus Na alginate) on process efficiency (RSDW%), GFN content uniformity (RSDC%), GFN solid state (DSC and XRD) and pellet release profiles was evaluated. The effectiveness of the Surelease film was strongly affected by the ability of GFN to cross the coating layer and to recrystallize on the pellet surface. Results indicated that this behaviour was dependent on the polymer used in the binder-layering solution. Using hypromellose as polymer, GFN recrystallized on the coated pellet surface at both drug loadings. The curing step was necessary to stabilize the film effectiveness at the higher drug loading. Increasing the coating level delayed but did not prevent the GFN diffusion. Replacing hypromellose with Na alginate, reduced the migration of GFN through the film to a negligible amount even after six months of storage and the curing step was not necessary to achieve stable controlled release profiles over storage.

Development of microparticles for oral administration of the non-conventional radical scavenger IAC and testing in an inflammatory rat model.

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol(®) HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals.

Evaluation of ultrasonic atomization as a new approach to prepare ionically cross-linked chitosan microparticles.

Ultrasonic atomization was evaluated as a new approach for the preparation of ionically cross-linked controlled-release chitosan microparticles loaded with theophylline as the model drug, using tripolyphosphate (TPP) as counter-ion. It was possible to nebulize both 2% and 3% (w/v) chitosan solutions as a function of their viscosity, usually not processed by employing the conventional nebulizer. The results of the chitosan molecular characterization using the SEC-MALS analysis revealed that ultrasonic atomization caused a certain depolymerization, probably due to the main chain scission of the 1,4-glycosidic bond; however, Fourier transform-infrared spectroscopy revealed the absence of other chemical modifications. The ultrasonic atomization allowed preparation of TPP cross-linked chitosan microparticles mostly ranging between 50 and 200 mum. As regards manufacturing parameters, the linking time and washing medium were found to affect the properties of the microparticles, while the stirring rate of the TPP solution did not show any influence. The evaluation of the formulation variables revealed that chitosan concentration strongly affected both the feasibility of the ultrasonic atomization and the drug release. All the microparticles showed an encapsulation efficiency of > 50 % and, after an initial burst effect, a controlled release of drug for 48 h. In conclusion, the ultrasonic atomization could be proposed as a robust and innovative single-step procedure with scale-up potential to successfully prepare ionically cross-linked chitosan microparticles.

Effect of Aerosil on the properties of lipid controlled release microparticles.

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.

Evaluation of beta-lactose, PVP K12 and PVP K90 as excipients to prepare piroxicam granules using two wet granulation techniques.

The present investigation aimed at evaluating the use of different excipients, beta-lactose and polyvinylpyrrolidone of two molecular weights (PVP K12 and PVP K90), in the production of improved release piroxicam granules, by wet granulation using both water and steam as granulation liquid. The formulations examined were: piroxicam (Px)/beta-lactose; Px/PVP K12 and Px/PVP K90, each one at a 1:9 weight ratio. The most significant difference between beta-lactose and PVP is that, using the first excipient, both steam and water granules were produced while, when PVP were employed, only steam granules were obtained. Image analysis revealed that beta-lactose steam granules had a larger surface area with respect to water granules, whereas lower values of this parameter were observed in PVP-s granules, confirming the Scanning Electron Microscopy micrographs and the fractal analysis results. As regards the enhancement of the dissolution profiles, the best result was obtained using beta-lactose steam granules followed by PVP K12 ones, even if the reactive dimension values indicated that during the dissolution process PVP K12 granules modified the surface more than beta-lactose granules. As regards PVP K90, this excipient was the one less influencing the granule morphology and the dissolution behaviour. Differential Scanning Calorimetry analysis suggested the partial amorphisation of the drug in the granules containing the three excipients. This result was then confirmed by X-ray powder diffraction analysis. Therefore, beta-lactose and PVP K12 could be proposed as useful excipients to enhance the dissolution rate of Px from granules prepared using the steam granulation technique.

Characterization and taste-masking evaluation of acetaminophen granules: comparison between different preparation methods in a high-shear mixer.

The aim of this study was to prepare and to investigate acetaminophen taste-masked granules obtained in a high-shear mixer using three different wet granulation methods (method A: water granulation, method B: granulation with a polyvinylpyrrolidone (PVP) binding solution and method C: steam granulation). The studied formulation was: acetaminophen 15%, alpha-lactose monohydrate 30%, cornstarch 45%, polyvinylpyrrolidone K30 5% and orange flavour 5% (w/w). In vitro dissolution studies, performed at pH 6.8, showed that steam granules enabled the lower dissolution rate in comparison to the water and binding solution granules; these results were then confirmed by their lower surface reactivity (D(R)) during the dissolution process. Moreover, the results of the gustatory sensation test performed by six volunteers confirmed the taste-masking effects of the granules, especially steam granules (P<0.001). Morphological, fractal and porosity analysis were then performed to explain the dissolution profiles and the results of the gustatory sensation test. Scanning electron microscopy (SEM) analysis revealed the smoother and the more regular surface of steam granules with respect to the samples obtained using methods A and B; these results were also confirmed by their lower fractal dimension (D(s)) and porosity values. Finally, differential scanning calorimetry (DSC) results showed a shift of the melting point of the drug, which was due to the simple mixing of the components and not to the granulation processes. In conclusion, the steam granulation technique resulted a suitable method to comply the purpose of this work, without modifying the availability of the drug.

Preparation and characterisation of ibuprofen-poloxamer 188 granules obtained by melt granulation.

The aim of this study was to prepare, by melt granulation, granules containing ibuprofen as a poorly water soluble model drug in order to improve its dissolution rate and its availability; lactose as a diluent and poloxamer 188 (Lutrol F68), as a new meltable hydrophilic binder, were used. The granules were prepared in a laboratory-scale high-shear mixer, using a jacket temperature of 50 degrees C and an impeller speed of 500 rpm. The particle size analysis shows that the main fraction was between 200 and 500 microm, while the determination of drug content indicated that ibuprofen was quite uniformly distributed in all the fractions. Scanning Electron Microscopy (SEM), image and fractal analysis revealed that the granules did not have a perfect spherical shape and a rugged surface (D(s)=2.6475). The in vitro dissolution tests showed an increase in the dissolution rate of granules compared to pure drug and physical mixture. The characterisation of the samples, performed by Differential Scanning Calorimetry (DSC) and X-ray powder diffraction (XRD), suggests that the improvement of dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the binder. Stability studies indicated that the granule properties do not change, at least after 1 year of storage at 25 degrees C. In conclusion, the results of this work suggest that the melt granulation technique is an easy and fast method to improve the dissolution rate of ibuprofen, using poloxamer 188 as a new hydrophilic meltable binder.

Novel multifunctional platforms for potential treatment of cutaneous wounds: development and in vitro characterization.

An original formulative/manufacturing approach for the development of a multi-composite wound dressing able to control the release of a water soluble API (lidocaine HCl) for several days was evaluated. The prepared multi-composite wound dressing is a microstructured spongy matrix, which embeds solid lipid microparticles (SLMs). The matrices were obtained by freeze drying of polyelectrolyte complexes made up two biopolymers: three different chitosan to alginate weight ratios (1:1, 3:1 and 1:3) were studied. The drug-loaded matrices were investigated as regards water uptake ability, swelling, drug loading, morphology and release profiles. SLMs were prepared at two different drug loadings (5% and 25%, w/w) by the spray congealing technology and were then incorporated in the spongy matrices. The characterization of the SLMs evidenced their spherical shape, mean dimensions lower than 20 µm, controlled release and the modification of the drug crystalline state. Comparing the release profiles of the SLMs-loaded sponges, the matrices with 1:3 chitosan/alginate ratio displayed a sustained release profile with the lower burst effect. Then hyaluronan and cysteine were embedded into the matrix to enhance the wound healing properties of the dressing. The final multi-composite platform was able to promote the growth of fibroblasts maintaining its prolonged release characteristic.