Adamo Fini

Alginate/chitosan particulate systems for sodium diclofenac release

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

Solubility and solubilization properties of non-steroidal anti-inflammatory drugs

Abstract Ten non-steroidal anti-inflammatory drugs (NSAID) of the acetic and propionic classes were analyzed in the form of salts to disclose the solubilization property of their aqueous solutions toward a lipid probe (the azo-dye Orange OT). This property is related to the self-aggregation of the anions above a concentration value that differs for each drug: indomethacin and fenclofenac showed solubilization ability in the form of sodium salts in pure water (starting from 30 and 40 mM, respectively); these values decreased with increasing ionic strength. In the case of diclofenac it was necessary to use a salt prepared with an organic base, that displayed a solubility higher than that of the sodium salt, required to overcome the critical value (35 mM). Naproxen, sulindac, ketoprofen, indoprofen were used at high concentrations of their sodium salts (100–160 mM) and solubilize the dye in the presence of a high total ionic strength. Alclofenac did not display solubilization ability; fenbufen and ibuprofen were tested as salts of an organic base: results were not conclusive because the presence of the organic base in the salt form and in the solution, as added electrolyte for the ionic strength, affected the results of the solubilization tests. The results are briefly discussed in terms of hydrophilic/hydrophobic balance present on the anion of the NSAID examined, as evaluated by the fragment constant approach.

Description and preliminary evaluation of a new ultrasonic atomizer for spray-congealing processes

A new atomizer that operates with ultrasonic energy is described. This apparatus is intended to obtain microparticulate drug delivery systems through spray-congealing or spray-drying technologies. In this work, some experimental results are reported on model systems submitted to spray-congealing. The formulations under examination contained theophylline and fenbufen as model drugs and stearic acid, carnauba wax, Cutina HR(R) and Compritol 888 ATO(R) as low melting excipients. Non-aggregate and spherical-shaped microparticles were obtained with all the materials tested; moreover, they had smooth surface and good flowability. The particle sizes depend on the amount of drug present and in each case the maximum size value of the distribution frequency was found to be 375 mu. In vitro release of the drug depends on its solubility and on the excipient lipophilicity. The results suggest that the ultrasound-assisted atomizer could be proposed as a possible alternative to traditional atomizers used for spray-congealing in the pharmaceutical field.

CHEMISTRY BY MICROWAVES

The pioneers of the application of microwaves into more canonic systems thought that it could produce similar effects in assisting the reactions carried out in research laboratories. In most cases it was soon evident that reactions were more rapid, cleaner and with an easier workup of the final material, saving a great deal of time [1]. These findings stimulated the diffusion of microwave ovens in many laboratories to take advantage of this instrument for their reactions.

In vitro evaluation of alginate beads of a diclofenac salt

Abstract Alginate beads containing diclofenac hydroxyethylpyrrolidine were formulated with either Eudragit or chitosan in order to achieve an enteric formulation. In all cases, high entrapment efficiencies were obtained. The examination of fractured beads revealed an internal void in the Eudragit–alginate beads. In contrast, a dense homogeneous internal structure was observed in the chitosan–alginate beads due to interpolymeric complex. An interaction between chitosan and drug was also observed. Under conditions mimicking those in the stomach, a small amount of drug was released. The alginate–chitosan beads showed a release behaviour dependent on pH value and alginate–chitosan ratio.

Fast dispersible/slow releasing ibuprofen tablets

Eight formulations were developed containing ibuprofen in the form of orally disintegrating tablets. To prevent bitter taste and side effects of the drug, the drug was associated with Phospholipon 80H, a saturated lecithin, by wet granulation. The granules were then coated using different film forming agents (Kollicoat SR 30, Amprac 01, Kollidon 90F, Eudragit RD 100) obtaining four lots 1-4. Coated granules were then formulated with a sweetener (Aspartame), a mannitol-based diluent (Pearlitol SD 200) and Kollidon CL (1-4K) or Explotab (1-4E) were added as superdisintegrants and compacted under low compression force. The eight lots of tablets, 1-4K and 1-4E, were assessed if suitable as oral disintegrating tablets by determination of a range of technological parameters. Wetting and disintegregation time matched with the requirements of EP IV Ed., for almost all these formulations. Dissolution profiles suggested that the combined action of the hydrophobic lecithin and the coating delay the release of the drug from tablets with respect to when it is free or in the form of simple granules. By an appropriate combination of excipients it was thus possible to obtain orally disintegrating tablets and a delayed release of ibuprofen using simple and conventional techniques.

Formation of ion-pairs in aqueous solutions of diclofenac salts.

In this work we studied the ability of the diclofenac anion to form ion-pairs in aqueous solution in the presence of organic and inorganic cations: ion-pairs have a polarity and hydrophobicity more suitable to the partition than each ion considered separately and can be extracted by a lipid phase. The cations considered were those of the organic bases diethylamine, diethanolamine, pyrrolidine, N-(2-hydroxyethyl) pyrrolidine and N-(2-hydroxyethyl) piperidine; the inorganic cations studied were Li(+), Na(+), K(+), Rb(+), Cs(+). Related to each cation we determined the equilibrium constant (K(XD)) for the ion-pair formation with the diclofenac anion in aqueous solution and the water/n-octanol partition coefficient (P(XD)) for each type of ion-pair formed. Among the alkali metal cations, only Li(+) shows some interaction with the diclofenac anion, in agreement with its physiological behaviour of increasing clearance during the administration of diclofenac. The influence of the ionic radius and desolvation enthalpy of the alkali metal cations on the ion-pair formation and partition was briefly discussed. Organic cations promote the formation of ion-pairs with the diclofenac anion better than the inorganic ones, and improve the partition of the ion-pair according to their hydrophobicity. The values of the equilibrium parameters for the formation and partition of ion-pairs are not high enough to allow the direct detection of their presence in the aqueous solution. Their formation can be appreciated in the presence of a lipid phase that continuously extracts the ion-pair. Extraction constants (E(XD)=P(XD) times K(XD)) increase passing from inorga to organic cations. This study could help to clarify the mechanism of the percutaneous absorption of diclofenac in the form of a salt, a route where the formation of ion-pairs appears to play an important role.

The Role of Chitosan in Drug Delivery

Chitosan, obtained by deacetylation of chitin, is a natural, hydrophilic, nontoxic, biocompatible, and biodegradable polysaccharide suitable for applications in pharmaceutical technology. Its role in drug delivery systems was examined by considering the chemical and biologic properties of the polymer.Chitosan is a nonbranched homopolymer formed by β-(1,4)-linked glucosamine units; hydroxyls and the amino groups are substrates for chemical modifications aimed at obtaining suitable materials for different purposes.Chitosan is soluble at acidic pH, forming gels; hydrogels are also formed in the presence of negatively charged drugs or polyanions, and represent a sustained drug release form. The bioadhesive nature of chitosan can be attributed to the same type of ionic interactions with mucosal membrane components. Mucoadhesive formulations have been developed for ocular, nasal, buccal, gastrointestinal, and vaginal drug administration. Chitosan is able to promote transmucosal absorption of small polar drugs, including peptides, inducing a transient opening of the tight junctions of the cell membrane.Due to its polymeric nature, chitosan has been widely investigated for a variety of microparticulate pharmaceutical forms. Chitosan is also a candidate for potential applications in the delivery of radiopharmaceuticals, genes and peptides.

Raman and thermal analysis of indomethacin/PVP solid dispersion enteric microparticles

Indomethacin (IMC) and three types of poly-(vinylpyrrolidone) (PVP 12PF, PVP K30 and PVP K90) were studied in the form of solid dispersion, prepared with the solvent evaporation method, by spectroscopic (Raman, FT-IR, X-ray diffraction), thermal (differential scanning calorimetry, thermogravimetry, hot-stage microscopy), fractal and image analysis. Raman and FT-IR micro-spectroscopy indicated the occurrence of drug/polymer interaction and the presence of an amorphous form of IMC, as also resulting from X-ray diffractometry. Hot-stage microscopy suggested that the interaction between IMC and the polymer occurring on heating of a physical mixture, is common to other acidic compounds and causes a depression of the temperature of the appearance of a molten phase. Co-evaporated particles were coated by spray-congealing process with molten stearic acid for gastroprotection, but also for stabilization of the amorphous structure of the drug: the final particles were spherically shaped. Dissolution tests carried out on the final microparticles showed that the coating with stearic acid prevents IMC release at acidic pH and also protects against recovery of the IMC crystallinity, at least after 9 months of aging: the extent and mode of the release, before and after aging, overlap perfectly. The test revealed a notable improvement of the drug release rate from the solid dispersion at suitable pH, with respect to pure IMC. The comparison of the present solid dispersion with IMC/PVP (surface) solid dispersion obtained by freeze-drying of an aqueous suspension, where IMC maintained its crystalline state, revealed that there was no difference concerning the release rate, but suggested a superior quality of this last process as a mean of improving IMC availability for the easiness of preparation and stability, due to the absence of the amorphous state of the drug, as a possible instability source of the system. Finally, the coating with stearic acid is discussed as a determining process for the practical application of solid dispersions.

Ultrasound-compacted and spray-congealed indomethacin/polyethyleneglycol systems

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