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Titanate nanotubes (TNTs) are promising vectors for drug delivery due to their unique physicochemical properties such as biocompatibility, mechanical strength, and chemical resistivity. However, considering their strong hydrophilicity, pristine TNTs exert very limited permeability through the intestinal cell layer. The aim of this study was to turn the surface characteristics and thus enhance the permeability of TNTs by functionalization. TNTs were functionalized with trichloro(octyl)silane (TCOS) and magnesium stearate (MgSt). Carbon content and surface free energy of the functionalized TNTs were detected to evaluate the effectiveness of functionalization, by using CHNS analytical and optical contact angle (OCA) measurements, respectively. Caco-2 cell line was applied to test the permeability and the cytotoxicity of the samples. Cytotoxicity was evaluated by using MTT assay. The results revealed that the surface characteristics of TNTs may be adjusted in a wider range with TCOS-TNT than with St, but the samples show higher toxicity. Silane functionalized TNTs may be safe up to 1 mg/ml, while St functionalized TNTs up to 2 mg/ml concentration. The preparation method of MgSt-TNT was also superior from the aspect of environmental safety. The permeability was suitable for samples with moderate hydrophobicity (aqueous contact angle 60-90°).

Objectives The main objective of present review is to explore and evaluate the effectiveness of recently developed methods to improve the bioavailability of orally administered biopharmaceutical drugs. Methods A systematic search of sciencedirect, tandfonline and Google Scholar databases based on various sets of keywords was performed. All results were evaluated based on their abstracts, and irrelevant studies were neglected during further evaluation. Results At present, biopharmaceuticals are used as injectable therapies as they are not absorbed adequately from the different routes of drug administration, particularly the oral one. Their insufficient absorption is attributed to their high molecular weight, degradation by proteolytic enzymes, high hydrophilicity and rigidity of the absorptive tissues. From industrial aspect incorporation of enzyme inhibitors (EIs) and permeation enhancers (PEs) and mucoadhesive polymers into conventional dosage forms may be the easiest way of formulation of orally administered macromolecular drugs, but the effectiveness of protection and absorption enhancement here is the most questionable. Conjugation may be problematic from regulatory aspect. Encapsulation into lipid-based vesicles sufficiently protects the incorporated macromolecule and improves intestinal uptake but have considerable stability issues. In contrast, polymeric nanocarriers may provide good stability but provides lower internalization efficacy in comparison with the lipid-based carriers. Conclusion It can be concluded that the combination of the advantages of mucoadhesive polymeric and lid-based carriers in hybrid lipid/polymer nanoparticles may result in improved absorption and might represent a potential means for the oral administration of therapeutic proteins in the near future.

Currently, pharmaceutical companies are working on innovative methods, processes and products. Oral mucoadhesive systems, such as tablets, gels, and polymer films, are among these possible products. Oral mucoadhesive systems possess many advantages, including the possibility to be applied in swallowing problems. The present study focused on formulating buccal mucoadhesive polymer films and investigating the physical and physical–chemical properties of films. Sodium alginate (SA) and hydroxypropyl methylcellulose (HPMC) were used as film-forming agents, glycerol (GLY) was added as a plasticizer, and cetirizine dihydrochloride (CTZ) was used as an active pharmaceutical ingredient (API). The polymer films were prepared at room temperature with the solvent casting method by mixed two-level and three-level factorial designs. The thickness, tensile strength (hardness), mucoadhesivity, surface free energy (SFE), FTIR, and Raman spectra, as well as the dissolution of the prepared films, were investigated. The investigations showed that GLY can reduce the mucoadhesivity of films, and CTZ can increase the tensile strength of films. The distribution of CTZ proved to be homogeneous in the films. The API could dissolve completely from all the films. We can conclude that polymer films with 1% and 3% GLY concentrations are appropriate to be formulated for application on the buccal mucosa as a drug delivery system.

The aim of this work was to discover the robustness of combined wet milling process to determine the interval of the Mel (meloxicam) amount and to predict the degree of crystallinity of the milled samples using DSC and XRPD measurements. The samples had the poly(vinyl alcohol) (PVA) as the stabilizing agent. By increasing the amount of the Mel, its crystallinity increased and close correlation was found between the degree of crystallinity and the Mel amount. To achieve the desired particle size range (100–500 nm), the Mel amount should be changed between 10.0 and 17.5% (w/w) and a PVA concentration should be used between 5.0 and 4.58% (w/w). In this specified range, the degree of crystallinity of Mel will be changed between 20 and 45%. The crystallinity of Mel investigated by DSC and XRPD did not show any significant difference at 95% significance level. During the milling process to predict the amorphous content of the active agent, the DSC method can be suggested for the fast quantification of the degree of crystallinity.

Orally disintegrating tablets (ODTs) are gaining importance and popularity due to their numerous advantages. Lysozyme, an enzyme with antibacterial properties, is currently only available as a conventional tablet and syrup. The main aims of this study were to formulate ODTs containing lysozyme using a variety of excipients and evaluate how formulation technology and excipient selection affected enzyme activity. Three different superdisintegrants in two concentrations, two different types of fillers, and three types of modern, ready-to-use co-processed excipients were investigated. The effect of the quality of the materials and the applied compression force were also studied. The investigated Critical Quality Attributes were disintegration time, dissolution profile and activity of lysozyme enzyme. A higher enzyme activity was found for ODTs with a higher hardness and density, containing the stabilizing agent in a smaller particle size. The structure of the superdisintegrant crystals had a greater impact on the disintegration time and dissolution profile of ODTs than the amount of superdisintegrants used. The results also revealed that despite the general advantages and effectiveness of ready-to-use excipients, the use of tailored formulations is more advantageous for sensitive drugs like enzymes.

The in-line control of pharmaceutical processes has become a necessary tool for the evaluation and follow-up of pharmaceutical dosage forms. In this study, a novel approach to the evaluation of conditions established in a conical fluid bed granulator during the in-situ and spray-on fluid bed melt granulation (FBMG) techniques was developed. The determination of temperature mappings allowed the characterization of the critical zones during the melt granulation and the prediction of the volume of the wetting zone, hence enabling the identification of the areas of optimal granule growth. Two grades of polyethylene glycol (PEG 2000 and 6000) were used as meltable binders in three binder spraying rates and droplet size fractions for spray-on and three binder particle sizes and contents for in-situ. The results showed the presence of intense heat exchange in the bottom of the bed during the in-situ technique and under the spraying nozzle during the spray-on technique, identified as the wetting zone. Isotherm maps enabled the identification of the transition between the wetting, cooling and consolidation zones for the spray-on and the cooling zone for the in-situ technique. The shape and volume of the wetting zone was highly dependent on binder spraying rate and spraying pressure for spray-on and binder particle size and content for in-situ FBMG. Granule size and size distribution were correlated to the volume of the wetting zone and an optimized wetting volume interval was determined for both spray-on and in-situ techniques for the optimal quality attributes of the granules.

Recently, there has been an increasing interest in the application of nanotubular structures for drug delivery. There are several promising results with carbon nanotubes, however, in light of some toxicity issues, the search for alternative materials has come into focus. The objective of the present study was to investigate the influence of the applied solvent on the composite formation of titanate nanotubes (TNTs) with various drugs in order to improve their pharmacokinetics, such as solubility, stability, and bioavailability. Composites were formed by the dissolution of atenolol (ATN) and hydrochlorothiazide (HCT) in ethanol, methanol, 0.01 M hydrochloric acid or in ethanol, 1M sodium hydroxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), respectively, and then they were mixed with a suspension of TNTs under sonication for 30 min and vacuum-dried for 24 h. The structural properties of composites were characterized by SEM, TEM, FT-IR, differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, and optical contact angle (OCA) measurements. Drug release was determined from the fast disintegrating tablets using a dissolution tester coupled with a UV&ndash, Vis spectrometer. The results revealed that not only the good solubility of the drug in the applied solvent, but also the high volatility of the solvent, is necessary for an optimal composite-formation process.

This study describes a novel approach for the use of thermal analysis to study the aftermath of the fluid bed melt granulation process and to depict the growth mechanism of the granules by quantifying the enthalpies of the granules at every physicochemical change using DSC and their mass loss through TG coupled to MS for a qualitative determination of the composition and amount of the evolved gases for the corresponding fragment ion. The experiments were made in situ with lactose monohydrate and two viscosity grades of PEG (2000 and 6000) as meltable binders with different contents and size fractions. DSC showed the presence of a beta lactose endotherm peak after the melting of alpha lactose and a proportional increase in its intensity with the increase in the particle size and the content of the binder, which suggested a relation with the agglomeration growth. Interestingly, TG and MS showed a larger reduction in the water content from lactose with the increase in the binder particle size, making it possible to evaluate the dehydration during the melt granulation. Indeed, during the distribution mechanism the low binder particle size and viscosity exposed lactose to a high heat transfer from the fluidizing air. However, a high binder particle size results in lactose immersed in the PEG particles, causing water to be trapped inside the granules and hence a larger reduction in water mass loss indicating the immersion mechanism. Therefore, thermal analysis is a promising tool for granulation growth control.

As proven in clinical trials, superficial fungal infections can be effectively treated by single topical application of terbinafine hydrochloride (Ter-HCl) in a film forming system (FFS). Poly(lactic-co-glycolic acid) (PLGA) derivatives, originally synthesized with intention to get carriers with optimized properties for drug delivery, and multifunctional plasticizers - ethyl pyruvate, methyl salicylate, or triacetin - were used for formulation of Ter-HCl loaded FFSs. After spraying, a biodegradable, transparent, adhesive, and occlusive thin layer is formed on the skin, representing drug depot. In situ formed films were characterized by thermal, structural, viscoelastic, and antifungal properties as well as drug release and skin penetration. DSC and SEM showed fully amorphous films with Ter-HCl dissolved in PLGA in high concentration (up to 15%). FFSs are viscoelastic fluids with viscosity which can be easily adjusted by the type of plasticizer used and its concentration. The formulations showed excellent bioadhesion properties, thus ensuring persistence on the skin. In situ film based on branched PLGA/A plasticized with 10% of ethyl pyruvate allowed prolonged release of Ter-HCl by linear kinetics for the first 6 days with a total time of almost 14 days. During ex vivo human skin penetration experiment, Ter-HCl was found to be located only in its target layer, the epidermis. According to our results, plasticized branched PLGA derivatives loaded by Ter-HCl are suitable for the development of FFSs for superficial fungal infections treatment.

The oral delivery of biopharmaceuticals requires the including of absorption enhancer, protease inhibitor and a suitable carrier system. The aim of the present work was to formulate and characterize chitosan solutions/films incorporating citric acid (CA) as potential excipient in comparison to the well-known acetic acid (AA)-based films as a reference. Films were made by the solvent casting method with/without glycerol (G), propylene glycol (PG) and polyethylene glycol (PEG-400) as plasticizers. The minimum film forming temperature (MFFT) of the prepared solutions, film thickness, hardness/deformation, mucoadhesivity, moisture content, FT-IR spectra and surface free energy (SFE) were investigated. Chitosan has been reported as a safe and effective paracellular absorption enhancer for hydrophilic macromolecules, therefore there would be more rationale for incorporating CA as a solubility enhancer, a permeation enhancer and an enzyme inhibitor. CA shows good cross-linking, an ideal plasticizing property and increases both tensile strength and mucoadhesivity, thus its incorporation simplifies the formulation while improving effectiveness. We concluded that CA (3.5, 4 and 5 w/v %)-based chitosan solution could be used as a novel coating/subcoating polymer for oral macromolecule delivery, or as oral mucoadhesive films.

A new technology was developed to form extended release hard gelatin capsules, based on the lipid matrix formation of Gelucire 50/13 and cetostearyl alcohol. Matrices were formed in situ by filling pulverised lipids, ethylcellulose and active ingredients such as diclofenac sodium, acetaminophen and metronidazol into capsules and heating at 63°C for 11 min. Effects of heating were investigated also on the brittleness of capsule shells. Inhibition of the evaporation of water reduced capsule damage. Dissolution tests and texture analysis were performed to discover the release and mechanical profiles of the matrices. Tests were repeated after 1 month storage and results were compared. Gelucire 50/13 alone prolonged drug release but cetostearyl alcohol slowed drug liberation even further. Drug release from all compositions was found to follow first-order kinetic. Significant softening of the matrices was detected during storage in composition containing only Gelucire 50/13, ethylcellulose and diclofenac sodium. Thermal analysis and IR tests were also performed to discover physicochemical interactions between active pharmaceutical ingredients and excipients. Thermal analysis confirmed a notable interaction between diclofenac sodium and Gelucire 50/13 which could be the cause of the observed softening. In conclusion, modified release hard gelatin capsules were developed by a simple and fast monolithic lipid matrix formation method.

The excipients proved to exert strong effects on the physicochemical properties of the tested systems, and it is very important to study them intensively in preformulation studies in pharmaceutical technology. In our earlier paper, we already described the structure of Klucel®-containing films with various physicochemical examinations (tensile strength, surface properties and positron annihilation lifetime spectroscopy). The aim of our present investigations was to study the thermal behaviour of the film-forming polymers with two different chain lengths, of the taste-enhancing and plasticizing excipients and also of the films prepared from them. The thermal behaviour of Klucel® LF and Klucel® MF film-forming polymers was found to differ only in the range of 340–400 °C, which is due to the different chain lengths of the polymer molecules. Among the active ingredients and excipients used, glycerol had the smallest while xylitol showed the greatest thermal stability. The shape of the TG curves shows that the decomposition process changes with the increase in the concentration of the excipients. The TG curves open up more, which is probably due to the fact that the molecules built-in among the polymer chains loosen the structure, which in turn is decomposed more easily. The TG–MS examinations revealed that during decomposition, carbon dioxide was formed in the highest concentration and that acetic acid, isopropyl alcohol and acetone also developed. The shape of the TG curves shows that in the case of the 5 and 10 % systems, the presence of lidocaine did not result in a significant difference in thermal stability.

The aim of the present study was the development of directly compressed tablets for implantable delivery of risedronate sodium for osteoporosis treatment and the comparison of the mechanism and kinetics of drug release from biogradable (chitosan) and non-degradable (PVC) polymer matrices. The compositions and process parameters were optimized in accordance to a mixed 2 and 3 level full factorial design. Critical Quality Attributes (CQA), such as diametral breaking hardness, porosity and speed of drug dissolution were investigated. The results revealed significant differences between the behaviours of the two polymers. Chitosan exhibited poor compressibility, which resulted in poor mechanical properties and the fast disintegration of chitosan based tablets. Nevertheless, despite the fast disintegration, the chitosan based matrices exhibited one-week-long continuous drug release, which can be due to a strong drug-carrier interaction. The presence of intermolecular hydrogen bonds was confirmed with FT-IR and NIR measurements. In contrast, PVC based compositions exhibited excellent compressibility, good tablet hardness and low porosity. The tablets remained intact during the dissolution and exhibited a slower release rate than what was measured in the case of chitosan based matrices. There was no sign of intermolecular association on NIR spectra, suggesting that the dissolution rate is basically determined by the porosity of tablets, but FT-IR measurements revealed some details of the molecular background of drug release mechanism.

The distribution of the plasticizer triethyl citrate between the chains of the polymer ethylcellulose was determined in order to explain the mechanical properties. A knowledge of these properties is indispensable for preformulation studies. As preformulation, the relationship between the mechanical properties and the distribution of the plasticizer was studied. The distribution was investigated with positron annihilation lifetime spectroscopy, and the mechanical properties with breaking hardness tests. Two kinds of ethylcellulose were used. The best film-former with plasticizer was chosen with the optimal concentration. Selection of the optimum type and concentration of the plasticizer is essential in the formulation of pellets and coated dosage forms.

In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.

The physicochemical properties of polymers planned to be applied as mucoadhesive films were studied. Two types of Klucel® hydroxypropylcellulose (LF and MF) were used as film-forming polymers. Hydroxypropylcellulose was incorporated in 2 w/w% with glycerol and xylitol as excipients and lidocaine base as an active ingredient at 5, 10 or 15 w/w% of the mass of the film-forming polymer. The free volume changes of the films were investigated by positron annihilation lifetime spectroscopy, the mechanical properties of the samples were measured with a tensile strength tester and contact angles were determined to assess the surface properties of the films. It was found that the Klucel® MF films had better physicochemical properties than those of the LF films. Klucel® MF as a film-forming polymer with lidocaine base and both excipients at 5 w/w% exhibited physicochemical properties and good workability. The excipients proved to exert strong effects on the physicochemical properties of the tested systems and it is very important to study them intensively in preformulation studies in the pharmaceutical technology in order to utilise their benefits and to avoid any disadvantageous effects.

XRPD is the method of choice to determine crystalline content in an amorphous environment. While several studies describe its use on powders, little information is available on its performance on finished products. The method's use may be limited not only by the need of sample pretreatment and its validation but also by the propensity of some materials to recrystallize when exposed to heat or mechanical stress. In this work the authors describe an attempt at constructing a model based on the XRPD measurement of intact layered pellets using univariate methods based on peak heights and PLS regression. Results indicate that neither the goodness-of-fit (below 0.9 for all tested variables), nor the RMSEC values (above 5 for all tested variables) of any model based on peak height were good enough to consider them for everyday use. PLS regression however provided a model with improved characteristics (R(2)=0.9581, RMSEC=3.04) despite the low API content and individual loading characteristics also reflected the validity of the model. PLS analysis also indicated that a specific sample may be different in some formulation characteristic that did not register on other examinations. This further indicates the method's usefulness in the analysis of intact dosage forms.

The aim of this study was to develop, evaluate and compare extended release mini-matrices based on metoprolol tartrate (MPT) and either glyceryl behenate (GB) or glyceryl palmitostearate (GPS). Mini-matrices were produced by three different techniques: hot melt extrusion, compression of melt granulates and prilling. Hot-melt extrusion and compression of granules obtained from melted material proved to be reliable, robust and reproducible techniques with aim of obtaining extended release matrices. Prilling tended to be susceptible to increased melt viscosity. Direct compression was not applicable for mini-matrix production due to poor powder flow. In general MPT release from all matrices was affected by its loading and the size of the units/particles. Processing of GB-MPT mixtures by different techniques did not lead to different drug release rates and patterns, while in case of GPS differently obtained matrices provided diverse MPT release outcomes. Matrices based on GB tended to have higher porosity compared to ones composed of GPS and thus most of the GB-based formulations showed faster drug delivery. FT-IR analysis revealed no interactions between primary components used for matrix production and Raman mapping outlined uniform MPT distribution throughout the units. DSC and X-ray studies revealed significant changes in the crystallinity of glycerides after storage under room conditions (GPS samples) and at increased temperature (GB and GPS samples), which was correlated to the changes seen in drug release rate and pattern after storage. Media composition in general tended to insignificantly affect GB matrices, while in case of GPS matrices increasing the pH and presence of biorelevant compounds induced faster drug release.

The aim of our research was to investigate the effect of the length of the polymer chain and the concentration of triethyl citrate used as a plasticizer on the thermal stability of the film structure in the case of two ethyl cellulose films (EC 10 and EC 45) used for preparing MR dosage forms. The influence of storage time was studied by monitoring the changes in the thermoanalytical parameters and by performing TG–MS examinations. It was found that the decomposition of the plasticizer from the arising film structure is retarded and a more homogeneous sample, therefore a better film can be prepared from EC 45. Mass spectrography performed as a coupled technique also proved that the films stayed stable until approximately 200 °C. Based on the above results, the composition prepared from EC 45 polymer with 5% triethyl citrate as plasticizer is recommended for making MR dosage forms.

The aim of the present study was to investigate the structure of free films of Eudragit ® L 30D-55 containing different concentrations (0%, 1% or 5%) of diclofenac sodium by positron annihilation spectroscopy. The data revealed that the size of the free-volume holes and the lifetimes of ortho -positronium atoms decreased with increase of the API concentration. Films containing 5% of the API exhibited a different behavior during storage (17 °C, 65% relative humidity (RH)) in consequence of the uptake of water from the air.

In the course of film coat preparation it is very important to carry out preformulation investigations. The film formed by Metolose® SM-4 polymer containing Macrogol 2000 (polyethylene glycol) as plasticizer showed structure changes depending on the concentration of the plasticizer during storage. This could be explained by the fact that the small quantity of plasticizer can be built in among the methyl cellulose molecules more easily, while the greater amount of plasticizer forms a separate phase in the beginning and can be built in into the film structure only later. On the other hand, the water bound by the hygroscopic property of the plasticizer can further influence the properties of the film as water also serves to function as a plasticizer. The increase in the quantity of the plasticizer enhanced the tensile strength of the film: the resulting film was less breakable and easier to handle mechanically. The studied films proved to be suitable for forming a protective coat of different solid dosage fo...

The aim of the present work was the characterization of the myometrial samples of healthy control and chronic inflammation-exposed rats as a function of gestational stage by means of differential scanning calorimetry (DSC). Non-pregnant, mid-pregnant (day 14) and late-pregnant (day 21) animals were included. The spontaneous, KCl-stimulated as well as maximal motor activity was additionally recorded in vitro. Calorimetric enthalpy (ΔH) normalised on wet mass significantly increased as pregnancy progressed in case of non-inflamed uteri. Inflammation resulted in a significant decrease in ΔH/m of samples from non-pregnant till pregnant rats. Maximal contractility increased by inflammation in all tested stages of gestation. Our present results indicate that DSC can be considered as a useful tool for the investigation of the uterine function modified by gestation or a pathological condition.

The aim of the present work was the characterization of nonpregnant and early pregnant myometrium (days 3–6) of the rat by means of differential scanning calorimetry (DSC). The spontaneous motor activity as well as the KCl-evoked contractions of isolated uterine rings was additionally recorded. A relatively close correlation was found between calorimetric enthalpy (ΔH) and the contractility of the uterus samples. Our results indicate that DSC is a useful tool for the investigation of the functions of developing myometrium and it can be considered as supplementing the traditional structural and functional methods.

Nutritional-physiological research of near past decades had established the real nutritional value of fats and oils. In the former theory the nutritional value of fats and oils is influenced mainly by the rate of saturated/unsaturated fats. It was ruled out, and positive, inert or risk physiological effect of every single fatty acid had been established. The health-care effect of omega-3 fatty acid mainly by the favourable (

Differential scanning calorimetry (DSC) was used in the investigation of the behaviour of coating free films. The films were produced from two film-forming polymers which are chemically different but equally used for producing controlled-release dosage forms: Eudragit NE 30 D (synthetically produced polymethacrylate copolymer) and LustreClear product (mixture containing natural and semi-synthetic components: microcrystalline cellulose, hydroxy-ethyl cellulose, carrageenan and polyethylene glycol). During their comparative analysis the characteristic parameters of the DSC curves obtained with dynamic measurement method were used and their changes as a function of storage conditions and storage time were observed. It was found that the thermoanalytical behaviour of the examined methacrylate-based Eudragit NE and cellulose-based LustreClear films was different. The specific enthalpy change of Eudragit NE fresh films was very little, but it increased considerably during storage. The specific enthalpy change of LustreClear films was much greater but its value shows only a slight further increase during storage. The results obtained help to choose the proper temperature for coating and drying.

The main purpose of our study was to produce microspheres containing diltiazem hydrochloride and to perform the thermoanalytical examination of the components and microspheres. Thermal analysis is a very frequently used method in the preformulation tests of solid dosage forms.

The permeable polymer film-formation behavior of a Eudragit RS dispersion was investigated in response to stirring at various rates and for various times in an Ultra Turrax instrument. No additives were used. The minimum film-forming temperature of the liquid, the thermal behavior of the film and the compositions of the dispersion and the foam arising were investigated. It was found that, at a given mixing time, shape-retaining foam formation could be detected at over 17,500 rpm. The polymer was enriched in the foam, while its quantity was decreased in the liquid. The minimum film-forming temperature of the liquid phase did not vary significantly, with the exception of the rate of 24,000 rpm, when a uniform film was not formed because of the bubbles. The glass-transition temperatures of the films formed did not exhibit any differences. Film formation was not influenced by the stirring time at a given rate. It was found that the efficiency of homogenization should not be increased by using a high stirring rate, as a uniform, smooth film did not develop, such a film being indispensable to ensure appropriate drug release. Copyright © 2006 John Wiley & Sons, Ltd.

Pellets containing metronidazole were produced in a centrifugal granulator, with hydroxypropylcellulose (Klucel LF®) as binding agent, and corn starch, microcrystalline cellulose (Vivapur 101®) and lactose as excipients. The wettability of the pharmaceutical powders was assessed by means of contact angle measurements, and the dispersive and polar surface energies were determined. The spreading coefficients, the work of adhesion and the work of cohesion were calculated and correlated with the pellet properties (friability, bulk and tapped density, and porosity). The aim was to investigate the role of the surface free energy of one- and two-component powder compositions in pellet production. The interactions between the particles were found to be connected with the measured pellet parameters. It was concluded that, in the course of the growth of the pellets, the particle sizes of the pharmaceutical powders and the interactions between them are important. If the work of cohesion of the binder is lower than the work of cohesion of the substrate and the work of adhesion, then the optimal amount of the binding agent is that which coats the particles uniformly in minimal quantity and in continuous layer.

Cyclization of tert-anilines with a properly substituted vinyl moiety by the tert-amino effect affords fused pyridines. This type of ring closure reaction of 5-morpholino-4-vinylpyridazinones and a benzene analogue was investigated by differential scanning calorimetry (DSC) measurements. The structure of products was confirmed by spectroscopic and microanalytical methods. The enthalpy values and heats of reactions were obtained from the thermograms by integrating the peak area corresponding to the ring-closure reaction, and by semiempirical (PM3) and DFT (density function theory) calculations, respectively.

Mannitol and sorbitol are widely used in the pharmaceutical and food industry. There are some technological procedures such as spray-drying, freeze-drying, tablet compression, during which there is a possibility of heat effect. The purpose of this work was to study the thermal properties of sorbitol, mannitol and their mixtures. Furthermore, these materials and their tablet pressing were studied after melting and solidification. The results of the study prove that the use of sorbitol or mannitol alone is disadvantageous in melt technology. The use of mannitol is limited because of its high melting point (165°C) and the polymorph transition after melting. Sorbitol (melting point: 96.8°C) vitrifies from melt, therefore it is hard to handle during further processing. The melting point of the eutectic mixture (1.8% mannitol and 98.2% sorbitol) was 93.6°C. This mixture was unsuited for pressing because of its glassy property. Our results showed that the most favourable composition was the mixture of 30% mannitol and 70% sorbitol (melting point: 131.8°C) for tablet formulation. This mixture can be recommended for the formulation of such lozenge and hard candy tablets, where the active ingredient decomposes at higher temperature (>131.8°C).

In pharmaceutical practice it is important and useful to know the crystallinity of materials and to monitor it during formulation development, production processes and storage. The purpose of this study was to assess the quantitative capability of DSC for determining crystallinity in crystalline/amorphous powder mixtures and to compare the accuracy of the DSC method with that of conventional powder X-ray diffraction. Alpha-lactose monohydrate was chosen as the model material. On the basis of this study it can be concluded, that DSC method can be applied safely for semiquantitative evaluation of the crystallinity of lactose samples consisting of an amorphous content higher than 20%.

Cyclodextrin complexation was applied to achieve better aqueous solubility of the drug and to formulate suppositories. Binary products were prepared in several mole ratios by two different methods. The dissolution profiles and in vitro membrane diffusion behaviour of the compositions were investigated. Thermoanalytical studies were performed in order to confirm inclusion complex formation. Compositions were selected for further detailed investigations and for incorporation into suppository dosage form.

The extents of the protective effects of coating films on the surface of crystals were determined. Three different samples were made with different quantities of coating fluid (Sepifilm LP 010 in 10% aqueous solution). Since the atomizing rate was constant, the coating time increased in parallel with the volume of coating fluid applied. The direct measurement of film thickness and smoothness is very difficult, and therefore indirect methods were used. Dimenhydrinate was chosen as model drug; this is a heat-sensitive antihistamine with a low melting point. This temperature can be reached during the tableting process. The behaviour of samples on exposure to heat was examined by differential scanning calorimetry. The water uptakes of the samples were determined with an Enslin apparatus. Plasticity was studied with an instrumented tablet machine. These indirect methods (thermal conductivity, water uptake and plasticity measurements) revealed connections between the results of the various experiments. An overlong coating time decreased the protective effect of the coating film.

The determination of film thickness is of prime importance in the quality assurance of coated pharmaceutical preparations. The rapid measurement of this parameter is problematic for multi-particulate pellet systems. The aim of this study was to apply the Raman spectroscopic method for the determination of the thickness of polymer coating on pellets. The change of Raman intensity was compared with measured film thickness, which was calculated from the change of the geometric parameters of the pellets, measured with an image-analyzing system. The results revealed that despite some difficulties Raman spectroscopy is a suitable method for the fast and accurate determination of film thickness on multi-particulate systems.

Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets.To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy.Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards.Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value.The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.

Sugar esters (SEs) are widely used in the pharmaceutical and food industries. They have a wide range of HLB values (1–16), and hence they can be applied as surfactants, or as solubility or penetration enhancers. SEs can be employed in hot-melt technology, because their melting points are low and they decompose only above 220 °C. The aims of this work were to study the thermal properties of SEs and to demonstrate differences between SEs with various HLB values. The results revealed that SEs with high or medium HLB values were vitrified by melting. Their glass transitions ( T g ) were determined by modulated differential scanning calorimetry. To visualize the changes in the samples during heating, hot-stage microscopy was used. Hydrophilic SEs were only softened, while lipophilic SEs were melted by heating. After melting and solidification, SEs have partially amorphous layered structures which slowly crystallize in time. Time-dependent solid-state changes (crystalline and amorphous phases) were observed, and analysed by means of differential scanning calorimetry and X-ray powder diffraction.

The plasticizing effects of poly(ethylene glycol) (PEG 400) on methylcellulose (Metolose) cast films were studied by conventional physicochemical methods and positron annihilation spectroscopy. The PEG concentrations relative to the total polymer content were varied within the range 0–75% (w/w). At low concentrations (below 33.3%, w/w), the plasticizer was found to build in into the methylcellulose structure. On the other hand, at higher concentrations (above 50%, w/w), it formed small separate phases in the films. Positron annihilation spectroscopy (PALS) was applied to track the Metolose–PEG interaction. Controlled ageing of Metolose–PEG films at room temperature and at 75% RH revealed a significant difference between the ageing processes of the monophase and those of the separate phase films. The ageing involves two steps in both cases: a fast and a slow one. The PALS measurements demonstrated that the slow process is hindered in the phase-separated samples.

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.

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.

Our research has a double purpose. On the one hand, doctors have expressed the need to formulate a rectal suppository dosage form from diuretic ethacrynic acid, which would add to the choice of treatment methods and thereby increase the possibilities of individual cure. On the other hand, the liberation and thereby the bioavailability of poorly-soluble ethacrynic acid needs to be enhanced, and for this purpose solubility-increasing additives new to rectal therapy were used. Solutol HS 15, Cremophor RH 40, and Cremophor RH 60 were used as additives in concentrations of 1, 3, 5, and 10%. The quantity of drug released changed as a function of additive concentration. Depending on the acceptor phase, the best results were achieved with an additive concentration of 1-3%, which is related to the optimal additive quantity accumulated on the boundary surface.

Coated multiparticulate systems are increasingly popular on the market. Their manufacture in a fluid bed often requires polymer binders. [...]