Giovanni Filippo Palmieri

Colloidal soft matter as drug delivery system

Growing interest is being dedicated to soft matter because of its potential in delivering any type of drugs. Since hydrophilic, lipophilic, small and big molecules can be loaded into these colloidal systems and administered through the parenteral or nonparenteral route, soft matter systems have been used to solve many biomedical and pharmaceutical problems. In fact, they make possible to overcome difficulties in the formulation and delivery of poorly water-soluble drug molecules, settle some stability issues typical of biological drug molecules, design parenteral sustained release forms and provide functionalized soft particles that are very effective in drug targeting. This review deals with the important role that colloids play in the drug delivery and targeting, with particular attention to the more currently used systems such as microemulsions, organogels, liposomes, micelles, and dendrimers. Though significant progress has been made in drug targeting, some challenges still remain. Further efforts will be required to better understand the characteristics of targets and to discover new ones. In-depth knowledge of the physico-chemical structure and properties of the systems used for targeting is fundamental for understanding the mechanism of interaction with the biological substrate and the consequent drug release.

Spray-Drying as a Method for Microparticulate Controlled Release Systems Preparation: Advantages and Limits. I. Water-Soluble Drugs

Spray-drying was used for the preparation of paracetamol/eudragit RS or RL or ethylcellulose microspheres to verify the possibility of their use in controlled-release solid-dosage forms formulation and try to determine advantages and limits of the technique of such use. Microspheres were first characterized by scanning electron microscopy, differential scanning calorimetry, x-ray diffractometry, and in vitro dissolution studies and then used for the preparation of tablets. During this step, the compressibility of the spray-dried powders was also evaluated. In vitro dissolution studies were performed also on the tablets and their release control was accessed. Although powders were unable to slow down drug release, tablets obtained from microsphere compression showed a good capability of controlling paracetamol release when eudragit RS or ethylcellulose was used, even at low polymer amounts.

Improved Dissolution Behavior of Fenbufen by Spherical Crystallization

Fenbufen is an analgesic, antipyretic and anti-inflammatory drug that is characterized by poor water solubility, a defect increased by very low wettability. Poor water solubility, particularly at low pH, could decrease absorption in the upper part of the gastrointestinal tract, which would be inconvenient for good bioavailability. Different spherical crystallization processes have been considered as methods to improve fenbufen dissolution behavior. A two-solvent system, in the presence of a bridging liquid, is the only method capable of producing spherical fenbufen crystals. In a first step, fenbufen solubility was considered in different solvents. The drug crystals formed were typically needle shaped. This characteristic was considered as a favorable parameter to obtain spherical crystals. After the selection of the best fenbufen solvent, several ratios of solvent (S)-nonsolvent (NS) (tetrahydrofuran [THF]-demineralized water) were studied. The addition of a bridging liquid (isopropyl acetate) improved spherical crystallization. The results from this method were reproducible batch to batch. The spherical crystals obtained showed a clear improvement in dissolution capacity, probably due to better wettability. Dissolution studies were then carried out on these spherical crystals stored for 1 month at different relative humidities (RHs). The dissolution profiles remained unchanged.

Gastro-resistant microspheres containing ketoprofen

Ketoprofen gastroresistant microspheres were prepared by spray-drying using common pH dependent polymers, such as Eudragit S and L, CAP, CAT and HPMCP. The long ketoprofen recrystallization time was a serious hindrance to the preparation of microspheres having a drug content higher than 35%. Microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray diffractometry and in vitro dissolution studies, and used for the preparation of tablets. During this step, the compaction ability of the spray-dried powders was measured. While the compressibility of the microspheres containing the enteric cellulosic derivatives are not acceptable and different from those of the microcrystalline cellulose, the compaction properties of ketoprofen/Eudragit L or S microspheres are comparable to those of the Avicel PH 101. In vitro dissolution studies were performed on the microspheres and the tablets. All microspheres showed a good gastroresistance, but some differences among the five polymers in reducing drug release at low pH values are present. Acrylic polymers (Eudragit L or S) are considerably more effective than the cellulosic derivatives CAP and CAT, while the HPMCP profile is in an intermediate position. These differences are erased by the microspheres compression process. In HCl 0.1 N, the percentage of ketoprofen released from the tablets is always close to zero, independently from the polymer used.

Physical characterization of naproxen sodium hydrate and anhydrate forms

Naproxen sodium (NS) is a nonsteroidal anti-inflammatory drug used in painful and inflammatory diseases. By crystallization from water or by exposure to relative humidities over 43%, the anhydrate form can be hydrated to a dihydrate species. Different techniques have been used to characterize physically anhydrate naproxen sodium (ANS) and hydrate naproxen sodium (HNS): elemental analysis, atomic absorption, electron scanning microscopy, thermomicroscopy, differential scanning calorimetry, Karl Fishers titrimetry, thermogravimetry, spectrophotometric analysis and X-ray diffraction study. The hydration/dehydration mechanism, at different relative humidities, was investigated to evaluate their physical stability. When stored up to 43% relative humidity, ANS shows a good stability, whereas with an increase in relative humidity it is hydrated. HNS equilibrium solubility was determined at different temperatures (21, 26, 31, and 37 degrees C). Due to the metastability and the quick phase changes in the water of ANS, its solubility was calculated from intrinsic dissolution measurements at the same temperatures, as solubility measurements of HNS. Water solubility of ANS is greater than HNS, but the solubility difference decreases when the temperature decreases. This is due to the fact that at higher temperatures the intrinsic dissolution rates (IDR) of ANS are considerably faster and decrease as the temperature falls.

The spray drying of acetazolamide as method to modify crystal properties and to improve compression behaviour

Acetazolamide shows a very poor compression ability and tablets must usually be produced through a wet granulation process. However, the possibility to obtain pure acetazolamide for direct compression could be interesting for industrial application. With the scope to obtain a material for direct compression, three different crystallisation methods were chosen, with respect to acetazolamide solvent solubility. (a) Acetazolamide was dissolved in an ammonia solution and then spray dried. It was possible to characterise the spherical particles as a mixture of two polymorphic forms, I and II by Powder X-ray diffraction study. (b) Pure form I was obtained by slowly cooling to room temperature a boiling water solution. (c) Pure form II, the marketed form, was obtained by neutralisation of an ammonia solution. Their compression behaviour was investigated firstly by a rotary press. Whilst pure polymorphic forms I and II could not be compressed, the spray dried particles showed very good compression properties. In fact, tablets were obtained only by spray dried particles, which show very good properties under compression and the absence of capping tendency. On the other hand, it was impossible to obtain tablets from polymorphic forms I and II, whatever compression pressures were used. In order to explain their densification mechanism, a single-punch tablet machine, equipped for the measurement of the upper punch displacement in the die, was used. From calculated Heckels parameters, it was demonstrated that the spray dried material shows a greater particle rearrangement in the initial stage of compression due to its spherical habit and minor wrinkledness of particle surface. The crystalline structure due to the presence of polymorphic forms I and II concur to lowering the intrinsic elasticity of the material. This fact avoids the risk of the rupturing the interpaticulate bonds, which are formed during the compression, concurring to the consolidation of the tablet.

Influence of crystal habit on the compression and densification mechanism of ibuprofen

Abstract Ibuprofen was recrystallized from several solvents by two different methods: addition of a non-solvent to a drug solution and cooling of a drug solution. Four samples, characterized by different crystal habit, were selected: sample A, sample E and sample T, recrystallized respectively from acetone, ethanol and THF by addition of water as non-solvent and sample M recrystallized from methanol by temperature decrease. By SEM analysis, sample were characterized with the respect of their crystal habit, mean particle diameter and elongation ratio. Sample A appears stick-shaped, sample E acicular with lamellar characteristics, samples T and M polyhedral. DSC and X-ray diffraction studies permit to exclude a polymorphic modification of ibuprofen during crystallization. For all samples micromeritics properties, densification behaviour and compression ability was analysed. Sample M shows a higher densification tendency, evidenciated by its higher apparent and tapped particle density. The ability to densificate is also pointed out by D0’ value of Heckels plot, which indicate the rearrangement of original particles at the initial stage of compression. This fact is related to the crystal habit of sample M, which is characterized by strongly smoothed coins. The increase in powder bed porosity permits a particle–particle interaction of greater extent during the subsequent stage of compression, which allows higher tabletability and compressibility.

Polymers with pH-dependent solubility : Possibility of use in the formulation of gastroresistant and controlled-release matrix tablets

Polymers usually utilized for gastroresistant film coating of tablets or pellets such as cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), and Eudragit L and S were used in the preparation of drug/polymer matrix tablets. These tablets were prepared either by direct compression of both powders or by the formulation of microspheres that were then compressed. The microspheres were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffractometry analyses. Dissolution studies were finally carried out to verify if the tablets possessed gastroresistant or controlled-release characteristics. Except for Eudragit L, the polymers can be used under certain conditions in the formulation of modified-release tablets.

Gelatin-Acacia Complex Coacervation as a Method for Ketoprofen Microencapsulation

AbstractKetoprofen microcapsules were prepared by complex coacervation between gelatin and acacia, and dried with different methods: isopropanol addition, spray-drying, and freeze-drying, Successively, microparticles were analyzed by infrared thembalance, ultraviolet spectroscopy, optical and scanning electron microscopy, and sieves; and subjected to dissolution studies in order to examine parameters such as yield, moisture content, encapsulation percentage, morphology of solid particles, particle size, and dissolution behavior. Provided that encapsulation and drying methods did not affect ketoprofen dissolution profiles, the most appropriate drying method for industrial purposes was spray-drying.

Tabletted polylactide microspheres prepared by a w/o emulsion-spray drying method.

An emulsification-spray drying technique is used to prepare poly(D, L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal antiinflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30min. The matrix tablets release the drug in 8-10h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.An emulsification-spray drying technique is used to prepare poly(D,L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal anti-inflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30 min. The matrix tablets release the drug in 8-10 h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.