Study of the influence of alkalizing components on matrix pellets prepared by extrusion/spheronization.

The aim of this study was to investigate the effects of alkalizing components and the nature of the wetting liquid on the properties of matrix pellets prepared by extrusion and spheronization. Atenolol was used as an active pharmaceutical ingredient, ethylcellulose as a matrix former, microcrystalline cellulose as a filler and disodium phosphate anhydrous and trisodium phosphate dodecahydrate as alkalizing materials. Water and a water-ethanol mixture served as granulation liquids. Pellet formation was evaluated via mechanical, dissolution and morphological studies. In order to enhance the dissolution of Atenolol from the pellets, alkalizing components were used and the influence of these components on the pH was tested. Investigations of the breaking hardness, the morphology and the dissolution revealed that the pellets containing trisodium phosphate dodecahydrate and prepared with a higher amount of water as binding liquid displayed the best physico-chemical parameters and uniform dissolution. In in vitro experiments, the dissolution release complied with the texture of the pellets and the effect of pH. The pellets have suitable shape and very good hardness for the coating process and are appropriate for subsequent in vivo experiments.

Evaluation of powder mixtures and hydrophilic gastroretentive drug delivery systems containing zinc acetate and sodium bicarbonate.

The aim of this study was to develop and study floating controlled drug delivery systems consisting of a model drug (zinc acetate dihydrate), different forms of a matrix-forming polymer (Metolose 90 SH) and sodium bicarbonate as an effervescent component. The proportions of Metolose and bicarbonate were varied, and the effects of the different ratios on the properties of the resulting powders and tablets were determined. The water uptakes of different powder mixtures were initially evaluated. These tests indicated the interaction of the active and effervescent agent, this phenomenon leading to an unpredicted increase in the amount of liquid taken up. This interaction was evaluated as concerns the degradation of the hydrophilic matrix system. The disintegration of tablets with different compositions revealed that this interaction increases the time required for the disintegration of these systems. The study demonstrated that the interaction of the components induced significant changes in the parameters of this new sensitive delivery system. In the last steps, the buoyancy and dissolution properties of tablets that appeared appropriate for the formulation of a controlled drug delivery system were investigated.

Role of surface free energy and spreading coefficient in the formulation of active agent-layered pellets.

Formulation of layered pellets can be a useful method for the preparation of multiparticulate systems. The aims of this work were to study the properties of hydrophilic active agent (pirenzepine dihydrochloride) layers formed on different pellet cores, the efficacy of layering and the connection between the core and the layers. The carrier pellets were prepared from mixtures of a hydrophilic (microcrystalline cellulose) and a hydrophobic (magnesium stearate) component in different ratios. These cores were coated in a fluid bed apparatus with an aqueous solution of active agent, with or without the addition of hydroxypropyl methyl cellulose (HPMC) as an adhesive component. The wettability of the pharmaceutical powders was assessed by means of Enslin number and contact angle measurements, and the surface energy was determined. Spreading coefficients of the components were also calculated and correlated with pellet properties such as the content of active agent, the friability and the morphological appearance of the layered product. An increased friability of the layer formed and the lower effectiveness of the process were experienced with a reduction in the wetting of the core. The efficiency of layering on a less polar core could be increased by the addition of HPMC, but the sensitivity of these pirenzepine layers to mechanical stress was higher. The type of the abrasion of these particles was dissimilar to that for samples prepared without HPMC. Peeling of the layers containing HPMC was observed for hydrophobic cores, but this phenomenon was not detected for the hydrophilic ones. These results can be explained by the spreading coefficients, which revealed an insufficient adhesion of layers for the samples that exhibited peeling.

Effect of lubricant on spreading of coating liquid on surface of tablets containing pancreatin.

The objective of this study was to evaluate the spreading of the coating liquid on different tablets containing pancreatin and microcrystalline cellulose. The effects of the ratio of the components, the presence of magnesium stearate and the blending circumstances were investigated. The contact angle of the liquids on the different tablets did not change linearly. For the mixture containing 50% pancreatin, the deviation of the measured value from the predicted one was more than 25%. This deterioration was also detected for mixtures containing 1% lubricant, but the extent was lower and was not modified by change of the mixing circumstances. This phenomenon was explained by the special microstructure of the surface of the tablet. This was predicted from the spreading coefficient, calculated from the surface free energy. The enrichment of pancreatin on the surface was preferred in binary mixtures. The spreading of magnesium stearate was most preferred for the powder mixture, and thus prediction of the properties of the tablet was easier for these mixtures. The extent of the effect of this excipient on the surface properties was very wide-ranging. The change in the spreading of the coating liquid was significant; however, the change in the work of friction was negligible.

Formulation of intelligent tablets with an antacid effect.

Matrix systems with a local antacid effect were produced in this study. Aluminium hydroxide and magnesium trisilicate in constant concentrations were used as active agents. Eudragit E PO was applied as a matrix former and sodium bicarbonate as a disintegrant (third antacid component), in different ratios. Their effects on the properties of the tablets were studied. Such formulated systems must be insoluble if the pH of the stomach is less acidic, but a rapid disintegration must occur if necessary. It can be concluded that Eudragit E PO in appropriate composition can ensure tablets with pH-dependent disintegration. Its binding effect allows tablet making from the elastic active component. The liberation of antacid materials from this system is controlled. If the pH reached 2.5, the erosion of the tablet was reduced. In contrast with expectations, the application of poorly compressible and effervescent sodium bicarbonate increased the time for disintegration of the tablets, because of its extended alkalizing effect around the tablet. This system with this acrylic component is appropriate to produce a controlled-release local antacid preparation.

[Evaluation of phenomena detected on the surface of stirred coating liquid]. / Felületen lejátszódó jelenségek szerepének vizsgálata a bevonó folyadékok eloállítása során.

The main objective of this work was to study the effect of conditions of coating fluids through the properties of the coating fluid, film and coated product. With a more accurate understanding of the process the effects of the factors can be defined and by means of this the optimal composition can be determined and problem-free coating can be carried out. In this work the evaporation was studied. The effects of different operational factors on evaporation were studied through fluids of different compositions. In case of fluids containing ethanol a significant loss can be detected after a short period of time and this fact cannot be changed by the use of an antifoaming agent. The highest difference in effect of a given factor was detected for the stirring rate. The effect of the operational factors changed depending on the Composition. Stirring rate showed the highest sensitivity to the presence of the volatile component. These results can help to determine the critical control points and the optimal stirring circumstances.

Evaluation of surface and microstructure of differently plasticized chitosan films.

Surface and structural investigations of natural biopolymer (chitosan) films containing various conventionally applied hydrophilic plasticizers (glycerol and poly(ethylene glycol) 400) were performed and the results were compared, with the aim of acquiring new information concerning the formation of these plasticized films. The surface tests revealed that the water uptake, the water-binding properties (moisture content) and the polarity were higher for the film containing glycerol as plasticizer. Positronium lifetime measurements and NMR studies performed to evaluate the effects of the plasticizer on the polymer structure demonstrated relevant differences in the effects of the plasticizers. The influence of glycerol on the structure of the film formed was more intensive than that of PEG 400. It can be concluded that the surface properties of the films, which are very important for their storage and application, cannot be established exactly by means of structural tests. Both surface and structural tests must be performed before the formulation of this type of plasticized mucoadhesive films.

Evaluation of the composition of the binder bridges in matrix granules prepared with a small-scale high-shear granulator.

The aim of this work was to evaluate the binder bridges which can form in hydrophilic matrix granules prepared with a small-scale high-shear granulator. Matrices contained hydroxypropyl methylcellulose (HPMC) as a matrix-forming agent, together with lactose monohydrate and microcrystalline cellulose as filler. Water was used as granulating liquid. A 2(4) full factorial design was used to evaluate the effects of the operational parameters (impeller speed, chopper speed, dosing speed and wet massing time) on the granulation process. The temperature of the sample increased relevantly during the preparation in the small-scale apparatus. The same setup induced different temperature increases for different amounts of powder. This alteration enhances the solubility of lactose and decreases that of HPMC, and thus the quantities of the dissolved components can vary. Accordingly, changes in composition of the binder bridge can occur. Since exact determination of the dissolution of these materials during granulation is difficult, the consequences of the changes in solubility were examined. Differential scanning calorimetry (DSC), thermomechanical analysis (TMA) and X-ray diffraction (XRD) measurements were made to evaluate the films prepared from liquids with different ratios of soluble materials. The DSC and XRD measurements confirmed that the lactose lost its crystalline state in the film. The TMA tests revealed that increase of the quantity of lactose in the film decreased the glass transition temperature of the film; this may be attributed to the interaction of the additives. At a lactose content of 37.5%, a second glass transition appeared. This phenomenon may be indicative of a separate amorphous lactose phase.

Evaluation of the binding effect of human serum albumin on the properties of granules.

The main objective of this study was the application of a solution of human serum albumin as a granulating fluid. The properties of the granules formed were evaluated and compared with those when a conventional binder was applied in the same concentration. The powder mixture contained a soluble (mannitol) and an insoluble component (different types of cellulose). The protein solution applied exerted an appropriate aggregating effect if the system contained microcrystalline celluloses. Powdered cellulose was not suitable for the granulation with human serum albumin solution. As compared with the same concentration of the conventionally applied cellulose ethers as binder, the prepared granules exhibited a larger particle size, a significantly better compressibility, a higher breaking hardness and a favourable deformation process. These findings mainly reflect the good adhesive properties of the protein. The best compressibility and mechanical behaviour were attained on the application of the microcrystalline cellulose Vivapur type 105. This favourable behaviour may be connected with the wettability of cellulose. These results suggest that the formulation of tablets may be easier from an active agent in the serum that binds to albumin (e.g. interferon) since the amount of additives (binder) can be reduced.

[Formulation of an oral solid dosage form containing human interferon-alpha]. / Humán interferon-alpha orális szilárd gyógyszerformába történo feldolgozása.

The main objective of this study was to process the human alpha-interferon for the solid dosage form. The first step was the preparation of the intermediate product for the tablet making. Fluid bed apparatus with top spray method was applied for the layering of powdered cellulose with human alpha-interferon solutions. The intermediate product was compressed into tablet and an enteric solvent coating of the tablets was made in a fluid bed apparatus with Wurster method. The physical parameters were detected. These fitted the Ph. Eur. and the mechanical properties of the tablets were appropriate for coating in fluid bed apparatus. The tablets agree with the requirements of Ph. Eur. and the active agent was not dissolved in gastric juice. An animal test was also performed. The human alpha-interferon in the blood of the animals was detected with ELISA method. The human alpha-interferon specific kit was used. The active ingredient dissolved from the tablets was absorbed from the ileum. The solid dosage form containing human alpha-interferon was prepared; this can make oral application of human alpha-interferon possible.

Formulation of an intermediate product from human serum albumin for the production of a solid dosage form.

The main objective of this study was to evaluate and to increase the processibility of a model protein (human serum albumin (HSA)) for preparation of an intermediate for a solid dosage form. The applicability of the solid forms is easier, and therefore their formulation is a promising method for the application of proteins. The layering of powdered cellulose with HSA solutions of different concentrations in a fluid bed apparatus with the top spray method was applied. The yield of this technique was very good, independently of the concentration of the applied solution. The HSA covered the particles (the HSA layer formed was smooth), but it caused aggregation of the cellulose particles, and spray-dried microparticles also formed. The proportion of optimum-sized particles (200-315 microm) decreased. The largest amount was detected for the samples prepared with liquid containing 15% HSA (about 2 times higher than the second best). Not only the size, but also the shape of the particles was changed. The alteration in this parameter caused a change in the flowability. This was likewise the best for the samples prepared with the liquid containing 15% HSA. The concentration of HSA in the fraction containing smaller particles was higher, because of the abrasion of the particles and the enrichment of the spray-dried HSA. The distribution of HSA in the large particles was uneven. The layering of powder cellulose can be applied to produce an intermediate from HSA for solid dosage forms, but the appropriate concentration of this protein solution must be optimized previously because HSA can act as a binder. The formation of large agglomerates must be eliminated, because the distribution of the active agent in these is very inhomogeneous. The present results indicated that the best value can be achieved with liquid containing between 12.5% (most homogeneous distribution of HSA) and 15% HSA (best flowability).

Rapid method to study the sedimentation of a pigment suspension prepared for coating fluids.

Film coating fluids commonly contain a pigment suspension. The sedimentation of insoluble particles in the coating suspension is one of the main problems during the formulation of the coating fluid. The aims of this work were to investigate the suitability of an energy-dispersive X-ray fluorescence analyser for rapid measurement of the sedimentation of titanium dioxide in aqueous suspensions. The suspensions were produced with a high-speed Ultra-Turrax. The process factors evaluated were the stirring rate, time and volume, and the process of sedimentation of the pigment. The enrichment of the pigment at the bottom of the sample holder was followed by means of the very rapid method of energy-dispersive X-ray fluorescence analysis. It can be concluded that the sedimentation of the particles is described by the Weibull equation. With an appropriate combination of the factors, a threefold increase in the sedimentation time was achieved. The mathematically based information (sedimentation time, kinetics of sedimentation, etc.) is essential for an exact evaluation of the preparation of the coating fluid. The understanding of the process through use of this test method leads to the ability to identify the critical control points of film coating.

Study of the effect of stirring on foam formation from various aqueous acrylic dispersions.

Acrylic polymers in aqueous dispersions are very often used to prepare coating suspensions which contain insoluble particles. The mixing of the pigment suspension and the polymer dispersion is a very important step in the preparation of the liquid. The stirring can cause precipitation of the polymer and foam formation. Foam formation from different Eudragit dispersions was evaluated in this study. A high-speed mixer was applied and the foam and liquid phases formed were separated. The changes in concentration of the polymer in the two phases were studied by FT-IR with a horizontal attenuated total reflection (HATR) accessory. The presence of shape-holding foam can be detected at very different rates of stirring. The most intensive foam formation was detected for Eudragit FS 30 D. The Eudragit RL 30 D dispersion was the least sensitive to high-speed mixing. The relative content of the polymer in the foam was higher than that in the liquid. This is indicated by the accumulation of surface-active agent on the surface of the bubbles formed in the foam. This phenomenon differed considerably for the various dispersions. An exact knowledge of the foam formation from aqueous acrylic dispersions is very important in order to determine the parameters of mixing and the quantity of antifoaming agent.

The effect of the solvent on the film-forming parameters of hydroxypropyl-cellulose.

In pharmaceutical technology, film-forming agents are often applied in solution during the preparation of solid dosage forms. A wide range of polymers have already been examined, but many of the effects of the applied solvent on the properties of the film are still not fully known. The study of these phenomena might be of great help in the preparation of better films. In the present study, the frequently used polymer hydroxypropyl-cellulose was examined in water and ethanol. The latter solvent exhibits better wetting properties for this polymer. It was found that the use of ethanol enhanced the processibility because of the easier atomization and the shorter drying period. Properties characteristic of the chemical nature (wetting, surface free energy and thermal properties) and the physical behaviour (deformation process) of the poured films were studied. Relevant differences were detected only in the mechanical parameters. The sizes of the free volume holes in the differently prepared polymers were also determined, but this parameter proved irrelevant as concerns alterations of the breaking process. The explanation of the differences processibility of the films might be the different strengths of binding between the macromolecular chains. This phenomenon can also explain the different degrees of hydration of the polymer and the changes in the drying process.

Surface treatment of indomethacin agglomerates with eudragit.

Indomethacin is a widely used anti-inflammatory drug with serious side-effects. This drug was used as a model drug for the coating of agglomerates with a permeable film (Eudragit NE). The agglomeration of the crystals increased the flowability of the bulk crystals. The coating further improved the flowability, and also the uniformity of the mass of the filled capsules. The coating film also influenced the wetting of the samples. The coating decreased the surface free energy and therefore reduced the adhesion forces between both the dry and the wet particles. The modification of the flow properties and the even capsule filling can be explained by this phenomenon. Since coating film does not dissolve in the artificial gastric juice, the dissolution test was performed only in the artificial intestinal juice. The dissolution of indomethacin from the coated sample was changed significantly. Accordingly, coating of the crystals can be performed in order to protect the mucosa of the gastrointestinal tract or to promote the preparation of solid dosage form.

Film coating as a method to enhance the preparation of tablets from dimenhydrinate crystals.

Crystals of dimenhydrinate as a model drug were used for crystal coating, a method that can be applied to increase the flowability of a material and facilitate the tablet making. An increase in particle size was observed during the film coating. The change in shape of the coated particles was also examined. Some physicochemical parameters changed during coating, e.g. the surface free energy parameters and the wetting of the samples. The amount of coating material (and therefore the coating time) influenced several parameters (the shape of the particles, the flow properties and surface free energy parameters, compressibility and compactibility). Several parameters of prepared tablet (porosity, breaking hardness) were examined. Accordingly, coating of the crystals can be performed in order to enhance the handling of a material with insufficient properties for tablet making.

[The effect of surface phenomena on the processing of solid materials. I. Theoretical basis of surface phenomena of solid materials]. / A felületi jelenségek szerepe a szilárd anyagok feldolgozása során. I. Rész. A jelenségek elméleti háttere.

The functions of friction and adhesion in the processing of solid materials were evaluated in our work. The first part of our study dealt with the theoretical basis of these phenomena. The work of Podczek was used as a guideline. The negative and positive effects of these parameters were emphasized. The types of adhesion were discussed. The different types of forces (capillary, Lifshitz-van der Waals, electrical, etc.) and several other parameters (surface free energy, roughness, particle size and shape) causing these effects were analysed. Different mathematical models which can be used for the determination of surface free energy, adhesion force and spreading coefficient were considered.

[The effect of surface phenomena on the processing of solid materials. II. Experimental evaluation of surface phenomena of solid materials]. / A felületi jelenségek szerepe a szilárd anyagok feldolgozása során. II. Rész. A szilárd anyagok határfelületi jelenségeinek kísérleti vizsgálata.

The functions of friction and adhesion in the processing of solid materials were evaluated in our work. The second part of our study dealt with some practical examples from our practice. Indomethacin was used for the examination of adhesion, dimenhydrinate for the study of friction, and metronidazole for the determination of the spreading coefficient. Several technological methods (coating, granulation, pelletization and tableting) were used. The positive effects of the processes on the various phenomena (surface free energy, adhesion force and spreading coefficient) were emphasized. The influences of alteration in the parameters on the flowability, compressibility, compact texture, etc. were assessed.