M.J. Fernández-Hervás

Pectin/chitosan mixtures as coatings for colon-specific drug delivery : an in vitro evaluation

The ability of a multiple-unit dosage form to reach the colon intact has been investigated, in vitro, using conditions chosen to simulate the pH and times likely to be encountered during transit to the colon. Small tablets were coated with either pectin USP or pectin in a 1:10 mixture with chitosan. Indomethacin and paracetamol were used as model drugs to represent poorly soluble and soluble compounds. Pectin alone was able to protect the cores from premature release, but only when a substantially thick coat was present. Pectin/chitosan mixtures achieved better protection at a lower coat weight. The use of pectinolytic enzymes to simulate breakdown in the colon showed that the pectin/chitosan mixture was susceptible to enzymic breakdown and allowed drug release to occur. The importance of pre-exposure of the tablets to conditions in the upper gastro-intestinal tract prior to exposure to the enzyme was noted.

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.

Characterization study of a diclofenac salt by means of SEM and fractal analysis

Abstract In this paper, the morphological and surface characteristics of five samples from different batches of the same salt, diclofenac/ N -(2-hydroxyethyl)pyrrolidine, were investigated using SEM descriptors and fractal dimensions. Two samples were crystallized from organic solvents; the others from water. This elementary difference is suitable to introduce differences in their behaviours. Salt particles obtained from organic solvents present cubic shapes and smooth surfaces. On the other hand, salt particles obtained from aqueous solutions exhibit irregular forms and rugged surfaces. Furthermore, solvent molecules are adsorbed on the particle surface during the synthesis process or become incorporated into the bulk. When these substances are subjected to thermal treatment, the solvent molecules are lost, causing a change in the external morphology of the particles. The fractal dimensions calculated from the slope of a Richardson plot were 1.14, 1.04, 1.09, 1.05 and 1.10. These results seem to indicate that the D values are not greatly affected by the mode of synthesis and solvent employed.

Influence of diluents and manufacturing method on the in vitro dissolution of carteolol hydrochloride matrix tablets

Abstract The release behaviour of carteolol hydrochloride matrix tablets was investigated as a function of filler nature (Emcompress®, mannitol, PEG 6000 and lactose), type of wetting liquid (Eudragit ® L 12.5% and isopropanol-acetone mixture 6:4) and mode of filler incorporation. The values of the technological parameters suggest that hardness was the most significantly affected by the three formulation factors considered. The strongest influence over the technological parameters was exerted by the mode of filler incorporation. The kinetic data conformed with the Higuchi square root equation, except for the lots containing mannitol and isopropanol-acetone mixture that conformed to a first-order plot. The lot containing Emcompress® and isopropanol-acetone mixture displayed acceptable linearity with both plots. Therefore, a non-linear regression procedure and reduced time method were used to define with precision the kinetic model followed by this formulation. Release parameters such as the Higuchi rate constant, ts0 and dissolution efficiency were calculated. Lots containing mannitol presented more rapid release rates due to the high solubility of this filler. On the other hand, the use of PEG 6000 as diluent significantly decreased drug release. The influence of technological parameters on the release of these systems was also examined, an inverse relationship between hardness and dissolution efficiency being found.

Determination of percolation thresholds in matrix-type controlled release systems: Application of a resistance analysis technique

Abstract In this work, matrix tablets have been prepared with binary mixtures of the inert polymer Eudragit ® RS 100 and a soluble, power-conductor model substance, sodium chloride. The sodium chloride content comprised between 20 and 80% w/w. A technique based on the measurement of the resistance of the matrix tablets has been used to achieve easy estimation of the values of the percolation thresholds, as a function of the sodium chloride loadings. The results obtained have been expressed in terms of resistivity and evaluated on the basis of percolation theory. The tablet resistivity has been considered as a critical property of the system. A change in this property and the presence of the percolation threshold were observed to appear simultaneously. From the data obtained, we have determined a first percolation threshold comprising between 30 and 40% (w/w) sodium chloride loading. The tablets made with a sodium chloride charge higher than 70% (w/w) undergo a disintegration process. The results obtained have been corroborated by scanning electron microscopy.

Influence of crystallization solvent and dissolution behaviour for a diclofenac salt

Abstract 11 samples of diclofenac/ N -(2-hydroxyethyl)pyrrolidine salt obtained by crystallization from alcohol-type solvents or mixtures with triacetin were analyzed by scanning electron microscopy and differential scanning calorimetry. Few differences were found concerning the size parameters of particles obtained from different solvents, while the shape parameters displayed major differences depending on the crystallization solvent. Most of the samples showed simple thermograms while in the case of those obtained from isopropanol and 1,3-butanediol, the presence of the solvent inside the mass of the crystals was recorded. Dissolution profiles were found to be different for all the samples (due also to different sizes of the dissolving particles). An interesting linear relationship was found between the efficiency of dissolution and the shape factor of the dissolving particles, suggesting the relevant importance of shape irregularity in affecting dissolution rate differences.

Use of fractal dimensions in the study of excipients: application to the characterization of modified lactoses

In this paper, the morphological and surface characteristics of lactose and coated lactose particles are investigated, continuing with the use of SEM descriptors and fractal dimensions to characterize powder particles. The coating materials were different acrylic polymers of the Eudragit® type. The size parameters of lactose and coated lactoses indicated that the particle forms deviated from irregular or acicular forms. Shape factor data of coated substances obtained demonstrated that these particles presented regular contours. This fact signifies that lactose particles without coating treatment present irregular profiles with patent edges implying poor flow properties. The aspect ratio values of coated lactoses were close to unity and smaller than that showed by lactose. It is concluded that the polymer particles are placed on the irregularities of lactose particles, smoothing the roughness of the excipient surface. The fractal dimensions calculated from the slope of Richardson plots were 1.11 for lactose and 1.04, 1.05 and 1.08 for coated lactoses. These results are consistent with the shape parameters and flow properties. Some interesting relationships between SEM descriptors and a number of rheological properties have been found.

Design and evaluation of a new central core matrix tablet

In this paper, a study of the influence that two formulation variables exert on the drug release process from a new controlled drug delivery system has been realized in order to obtain a constant release rate during a prolonged period of time, and a programmed drug release. The drug release profiles obtained for the different batches have shown an interesting relationship between the particle size of the channeling agent used and the length of the zero-order periods. Furthermore, it is possible to modify the lag-times by using different granulometric fractions of the channeling agent. Similar results have been obtained by changing the weight of the assayed tablets.

Effect of the temperature on a hydrate diclofenac salt

The salt Diclofenac/N-(2-hydroxyethyl) pyrrolidine when crystallizes from water forms a di-hydrate, which looses the crystallization water molecules on heating or in the presence of silica gel, undergoing a phase transition. The two processes were followed at room temperature, at 40 and 50 degrees C by thermal analysis and analyzing the dimensional parameters obtained by scanning electron microscopy as a function of the changes occurring in the solid state. The fractal dimension of the particle surface (DS) was determined for the di-hydrate, the anhydrate and the anhydrous forms: DS values are close together suggesting that the processes modify only slightly the external morphology of the particles. The reactive dimension (DR) to dissolution suggests that the salt after the thermal treatment has a dissolution behaviour identical to that observed for the salt obtained from organic solvents. The two processes de-hydration and phase transition can be carried out at relatively low temperature, suggesting an important pathway to obtain the anhydrous form starting from the di-hydrate one.

Thermal analysis of the dehydrated form of a diclofenac salt

Abstract Thermogravimetric (TG) and differential thermal analysis (DTA) were used to follow the extent of the dehydration of three samples of diclofenac/N-(2-hydroxyethyl) pyrrolidine salt (DHEP) obtained from different batches of the preparation from water at industrial level. The dihydrate salt formed from water, and the anhydrous form obtained from organic solvents, have different crystal structures. The dehydration process carried out at a low temperature is not readily accompanied by the phase transition toward the crystal form of the anhydrous salt. DTA measurements on the dehydrated form of different samples showed an endotherm in the range 73–78°C that represents in all cases the phase transitions from the dehydrated toward the anhydrous form, while the endotherm at a higher temperature (98–111°C) is associated with the melting of the anhydrous form. A small loss of weight on TG profiles (at 68–78°C) was interpreted as a small amount of crystallisation water retained after the dehydration process and released after heating. According to the water amount, thermogram profiles of the examined samples appear modified with respect to the reference compounds. All these aspects suggest that industrial process of the dehydration of a large mass of the dihydrate diclofenac salt cannot be so accurate as the treatment at lab-level, and the small amounts of residual water do not prevent the phase transition.