Dragendorff's reagent: Historical perspectives and current status of a versatile reagent introduced over 150 years ago at the University of Dorpat, Tartu, Estonia.

The well-known Dragendorff's reagent (DR) was introduced by an Estonian-German Professor Johann Georg Noel Dragendorff (1836-1898) in the middle of the 19th century (1866). Dragendorff, who was a full-time professor in pharmacy at the university of Dorpat (Tartu) used his reagent originally for the rapid screening of herbal products to find traces of alkaloids. DR is a solution of potassium bismuth iodide composing of basic bismuth nitrate (Bi(NO3)3), tartaric acid, and potassium iodide (KI), and when contact with alkaloids DR produces an orange or orange red precipitate. In this review article, we make a short historical overview on the biography and scientific research work of Professor Dragendorff at the University of Dorpat. The chemistry, method of preparation, mechanism of action, and practical uses of DR in various disciplines in various European countries including the Baltic countries (Estonia, Latvia, Lithuania), Finland, Ukraine, Moldova, and in Asia (Vietnam), are also discussed. Over several decades, DR and its modifications have found uses in many new applications and disciplines, and a number of commercial DRs are also currently available on the market. Today, DR is used for example in the production of surfactants, where non-ionic surfactant is precipitated in water solution with modified DR (KBiI4+BaCl2+glacial acetic acid). Total six different potassium iodobismuthate (DR) solutions are also presented in the European Pharmacopoeia. In conclusion, DR (after more than 150 years of its invention in Estonia) has still an important role in pharmaceutical and related sciences all over the world.

Stable aqueous film coating dispersion of zein.

The effects of plasticizers, pH, and electrolytes on film formation and physical stability of aqueous film coating dispersions (pseudolatexes) of zein were evaluated. The influence of plasticizer on film formation mechanism and minimum film-formation temperature (MFT) were monitored by means of hot stage microscopy (HSM). Furthermore, the effects of pH and electrolytes on the short-term physical stability of pseudolatexes were investigated by measuring relative absorbance, zeta potential, and particle size of the dispersions. With aqueous coating dispersions of zein, stages of film formation were identified. The dispersions plasticized with 20% (w/w) PEG 400 or glycerol formed mechanically strong and flexible films with the lowest glass transition temperature (T(g)). Physical stability of the aqueous zein dispersions was dependent on both pH and electrolyte content. At a pH ranging from 3 to 4, the aqueous dispersions of zein were stable for at least 2 months exhibiting the highest values for zeta potential, the smallest particle size, and a low volume of aggregates. The stable dispersion could be obtained containing a lower concentration of electrolytes (e.g., 10(-5) M). The physical stability of aqueous zein dispersions can be determined by the combined measurements of relative absorbance, zeta potential, and particle size.

Chronic nicotine treatment changes differentially the effects of acute nicotine on the three main dopamine metabolites in mouse striatum.

The effect of chronic treatment with nicotine on striatal dopamine metabolism was studied in mice by measuring the striatal concentrations of dopamine and its metabolites 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). (-)-Nicotine was administered for 7 days using subcutaneously implanted nicotine releasing reservoirs. The release of nicotine was confirmed by measuring nicotine and cotinine concentrations in the plasma. To study the possible tolerance induced by chronic nicotine treatment, acute challenge doses of (-)-nicotine (either 3 mg/kg given once or 1 mg/kg repeated 4 times at 30 min intervals) were given to mice on the 7th day after the implantation. At an ambient temperature of 20-22 degrees C, acute nicotine treatment induced marked hypothermia (-5.2 to -6.7 degrees C) in both chronic nicotine treated and control mice, an effect that was prevented by elevating the ambient temperature to 32-34 degrees C. Chronic nicotine treatment did not per se alter striatal dopamine metabolism. Acute nicotine administration altered the striatal dopamine metabolism in a temperature-dependent manner. In mice kept at 20-22 degrees C, the DOPAC concentration rose slightly but concentrations of 3-MT and HVA fell, indicating a decrease in the release of dopamine. In contrast, in mice kept at 32-34 degrees C the DOPAC and HVA concentrations were clearly elevated by acute nicotine, whereas the concentration of 3-MT was not altered. In these normothermic mice chronic nicotine pretreatment did not alter the effects induced by acutely administered nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the centrifugal granulating process on the properties of layered pellets.

Drug-layered pellets based on microcrystalline cellulose (MCC) beads as substrates were prepared using a laboratory-scale centrifugal granulator. The effect of three independent process parameters (rotor rotation speed, slit air flow rate, and spray air rate) on responses describing the amount of drug loss during the process, amount of agglomerates, bulk density, flowability, friability, shape, and surface roughness were studied using a 3(3) full factorial experimental design. The variables studied were found to have a significant influence on the responses evaluated. Rotor rotation speed and slit air flow rate had a significant positive influence on the amount of drug loss during the process and the amount of agglomerates, whereas rotor rotation speed and spray air rate had the same effect on the bulk density, flowability, and the roundness of the pellets. The amount of agglomerates and the roundness value of the pellets were negatively affected by the spray air rate while the slit air flow rate showed the same effect on the bulk density and flow rate of the pellets. In addition to the main effects, there were some significant paired interactions between slit air flow rate and spray air rate as well as rotor rotation speed and slit air flow rate. Based on the results, the significance of these three parameters should be considered carefully for quality pellet preparation by the centrifugal granulating technique using MCC beads as substrates.

Development and characterization of aqueous amylose-rich maize starch dispersion for film formation.

Development and characterization of amylose-rich starch dispersion for film forming was performed. The influence of dispersion preparation temperature on amylose-rich maize starch (Hylon VII) film formation, and the physical properties of the films were investigated. The film-forming ability of the dispersions was evaluated with free films plasticized with glycerol and sorbitol, and the films were prepared at an elevated temperature (70 degrees C) by a casting technique. The solid-state and particle properties of dispersions were investigated by means of X-ray diffraction (XRD), Fourier transform near infrared (FT-NIR) spectroscopy and laser diffraction particle size analysis. Free films were characterized with respect to their appearance, by FT-NIR spectroscopy, and by XRD. Mechanical stress-strain properties were also studied. Increasing the temperature of dispersion preparation results in higher crystallinity, thus affecting the film forming ability. Mechanically strong and elastic films can be formed from amylose-rich starch dispersion formed at 40 degrees C. The more crystalline precipitate complex (obtained at 80 degrees C) and the entirely amorphous gel (obtained at 10 degrees C) formed non-continuous and cloudy films. The better film-forming properties of the dispersion formed at 40 degrees C are probably due to the highly amorphous structure and smaller particle size. The study shows the possibility of using ambient tempered amylose-starch dispersion for film forming.

Influence of neutron activation factors on matrix tablets for site specific delivery to the colon.

The impact of the neutron activation procedure, i.e. incorporation of samarium oxide (Sm(2)O(3)) and neutron irradiation, on the compression properties (including the crushing strength) and in vitro dissolution of potential colonic delivery systems based on matrix tablets of amidated pectin (Am.P) or two types of hydroxypropyl methylcellulose (HPMC) was investigated. The neutron activation factors did not influence the compression properties of the tablets. Replacement of magnesium stearate with samarium stearate in directly compressed Am.P tablets to achieve both radiolabelling and lubrication resulted in a greater extent of concentration-dependent reduction of the crushing strength. Dissolution tests demonstrated that irradiation increased the release of the model drug ropivacaine from the tablets. The extent of this increase was unexpectedly low considering the previously observed degradation of the polymer expressed as an irradiation-induced viscosity reduction in solutions prepared from the polymers. Delayed-release coating with Eudragit L 100 protected the HPMC tablets against the release-increasing effect of irradiation until the late phases of release. Sm(2)O(3) retarded the release to a varying extent depending on particle characteristics. Incorporation of Sm(2)O(3) in the coating layer did not influence the release. However, one-third of the radioactivity leached from the coating within 60 min in 0.1 M HCl.

Characterization of particle deformation during compression measured by confocal laser scanning microscopy.

Direct compression of riboflavin sodium phosphate tablets was studied by confocal laser scanning microscopy (CLSM). The technique is non-invasive and generates three-dimensional (3D) images. Tablets of 1% riboflavin sodium phosphate with two grades of microcrystalline cellulose (MCC) were individually compressed at compression forces of 1.0 and 26.8 kN. The behaviour and deformation of drug particles on the upper and lower surfaces of the tablets were studied under compression forces. Even at the lower compression force, distinct recrystallized areas in the riboflavin sodium phosphate particles were observed in both Avicel PH-101 and Avicel PH-102 tablets. At the higher compression force, the recrystallization of riboflavin sodium phosphate was more extensive on the upper surface of the Avicel PH-102 tablet than the Avicel PH-101 tablet. The plastic deformation properties of both MCC grades reduced the fragmentation of riboflavin sodium phosphate particles. When compressed with MCC, riboflavin sodium phosphate behaved as a plastic material. The riboflavin sodium phosphate particles were more tightly bound on the upper surface of the tablet than on the lower surface, and this could also be clearly distinguished by CLSM. Drug deformation could not be visualized by other techniques. Confocal laser scanning microscopy provides valuable information on the internal mechanisms of direct compression of tablets.

Amylopectin as a subcoating material improves the acidic resistance of enteric-coated pellets containing a freely soluble drug.

The effect of an aqueous amylopectin subcoating on the acidic resistance and dissolution behaviour of enteric-coated pellets was studied. Freely water-soluble riboflavin sodium phosphate (RSP) was used as a model drug, and microcrystalline cellulose (MCC) and lactose as fillers in the pellet cores. The pellets were subcoated with 5% aqueous amylopectin solution or with 5% hydroxypropyl methylcellulose (HPMC) solution, and subsequently film-coated with aqueous dispersion of cellulose acetate phthalate (CAP). Drug release of enteric-coated pellets was investigated by confocal laser scanning microscopy (CLSM). Dissolution tests showed that amylopectin subcoating improved the acidic resistance of the enteric-coated pellets in 0.1 N hydrochloric acid (HCl) compared with HPMC subcoating. As the amylopectin subcoating load was increased to 4% and the aqueous CAP coating load to 35%, the coated pellets resisted in 0.1 N HCl solution for approximately 1 h (the amount of drug released was below 10%), and they dissolved in the SIF without enzymes in less than 10 min. Confocal microscopy images and profiles of mean fluorescence intensities of RSP (obtained in the range of the interface of the pellet core and the film and the film coating surface) showed consistent results with dissolution tests. It seems that amylopectin subcoating can prevent the influx of the dissolution medium into the pellet core, and thus decrease the premature dissolution and release of the drug from the enteric-coated pellets in 0.1 N HCl solution. The drug release mechanism appeared to be osmotically driven release, and followed by diffusion through the polymer film.

Extrusion-spheronization of pH-sensitive polymeric matrix pellets for possible colonic drug delivery.

The aim of this study was to investigate extrusion-spheronization pelletization for preparing pH-sensitive matrix pellets for colon-specific drug delivery. The effects of three independent variables (amounts of Eudragit S, citric acid and spheronizing time) on pellet size, shape (roundness and aspect ratio), and drug release were studied with central composite design. The pellets contained ibuprofen as a model drug, citric acid as a pH-adjusting agent, Eudragit S as a pH-sensitive binder and microcrystalline cellulose (MCC). The pellets were prepared with Nica extrusion-spheronizing equipment and subsequently enteric-coated using an air-suspension technique. Eudragit S as a pH-sensitive matrix former in pellets increased the pellet size and influenced pellet roundness. In small amounts Eudragit S increased pellet roundness but in larger amounts pellet roundness was reduced. Citric acid promoted the pelletization process resulting in a narrower area distribution. The pH-sensitive matrix pellet failed to delay the drug release. The combination of citric acid and enteric coating, however, delayed the drug release for 15 min in a pH 7.4 phosphate buffer.

Enhanced stability of rubbery amylose-rich maize starch films plasticized with a combination of sorbitol and glycerol.

Well known aging problems with rubbery starch films are the migration of plasticizer and increased crystallinity leading to embrittlement. The effects of a combination of sorbitol and glycerol used as plasticizers on mechanical, moisture permeability and solid-state properties of rubbery amylose maize starch (Hylon VII) films were studied. The films were prepared by casting and were exposed to conditions of 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH for 9 months. The starch films plasticized with a combination of sorbitol and glycerol (1:1) at equal amount to the polymer weight, were shown to be the most stable alternative of the studied films during the 9 months storage period. The water vapor transmission (WVTR) of the films did not change during the period of storage and neither did the elongation at break, but the tensile strength increased. X-ray diffraction (XRD) results showed that during storage no crystallization had occurred. The combination of sorbitol and glycerol prevented the migration of the plasticizer molecules out of the film.

Organic acids as excipients in matrix granules for colon-specific drug delivery.

Interest exists in developing site-specific systems for release of a drug in the lower part of the small intestine or in the colon. The aim of this study was to investigate whether drug release rates from enteric matrix granules could be influenced by using organic acids as excipients. Ibuprofen was used as a model drug and Eudragit S and Aqoat AS-HF as enteric polymers. The dissolution rates of the drug were investigated at different levels of pH (5.8, 6.8 and 7. 4). Drug absorption was studied in bioavailability tests in healthy volunteers. In vitro/in vivo correlation was also investigated. It was concluded that although inclusion of an organic acid in a formulation retarded in vitro release of the model drug, no corresponding effect was evident in in vivo studies. Bioavailability tests are therefore important early on during development of new dosage forms or formulations. Although no correlation between in vitro and in vivo results was generally evident correlation could be demonstrated for individual formulations following mathematical transformation of data.

Determination of tackiness of chitosan film-coated pellets exploiting minimum fluidization velocity.

The tackiness of aqueous chitosan film coatings and effects of anti-sticking agents on sticking tendency, were evaluated. A novel rapid method exploiting minimum fluidization velocity to determine tackiness was introduced and tested. The pressure difference over the miniaturized fluidized-bed was precisely recorded as a function of velocity of fluidization air. High molecular weight chitosan plasticized with glycerol was used as a film-forming agent. Magnesium stearate, titanium dioxide, colloidal silicon dioxide and glyceryl-1-monostearate (GMS) were studied as anti-sticking agents. Film coatings were performed in a miniaturized top-spray coater. The incorporation of anti-sticking agents led to a clear decrease in tackiness of the chitosan films, and magnesium stearate and GMS were shown the most effective. Film-coated pellets containing magnesium stearate and GMS as an anti-sticking agent were very easily fluidized (showing very low values of minimum fluidization velocity) and were thus classified as the best flowing and the least sticking samples. Both these additives were found anti-sticking agents of choice for aqueous chitosan film coatings. Determination of the experimental minimum fluidization velocity in a fluidized bed, is a useful and sensitive method of measuring the tackiness tendency of film-coated pellets.

Diffusion of a freely water-soluble drug in aqueous enteric-coated pellets.

The effects of filler used in the pellet cores (ie, waxy cornstarch or lactose) and the enteric film coat thickness on the diffusion and dissolution of a freely soluble drug were studied. Two kinds of pellet cores containing riboflavin sodium phosphate as a model drug, microcrystalline cellulose (MCC) as a basic filler, and waxy cornstarch or lactose as a cofiller were film coated (theoretically weight increase 20% or 30%) with an aqueous dispersion of cellulose acetate phthalate (CAP). The diffusion of riboflavin sodium phosphate in aqueous enteric-coated pellets was investigated using noninvasive confocal laser scanning microscopy (CLSM). The in vitro release tests were performed using a USP apparatus I (basket method). Diffusion of drug from the core to the film coat was found to be greater with lactose-containing pellets than with waxy cornstarch-containing pellets. The dissolution test showed that 30% enteric-coated waxy cornstarch pellets had a good acidic resistance in 0.1 N HCl solution for at least 1 hour, while the other enteric pellet formulations failed the test. The waxy cornstarch-containing enteric pellets dissolved at SIF in less than 10 minutes. Confocal images of film-coated pellets showed that waxy cornstarch-containing pellets had less drug dissolved than respective lactose-containing pellets. The observations were further confirmed by measurement of fluorescence intensity of riboflavin sodium phosphate in the film coat. The dissolution test was consistent with the confocal microscopy results. In conclusion, waxy cornstarch as a cofiller in the pellet cores minimizes premature drug diffusion from the core into the film coat layer.

Real-time image-based investigation of spheronization and drying phenomena using different pellet formulations.

Extrusion-spheronization (ES) is a frequently used agglomeration process in the pharmaceutical industry to manufacture spherical solid units or pellets with a narrow size and shape distribution. In this study, photometric stereo imaging was applied in real-time during the final steps of the ES process, being spheronization and drying. In addition to the pellet size distribution of undispersed (wet) samples, the imaging technique captures visual information on pellet shape and surface brightness. Pellet samples were taken at 20 time points during spheronization and were imaged at-line (during spheronization) and off-line (after spheronization). Particle size distributions and visual image information were both used to characterise the spheronization behaviour of different formulations. Next, particle size distributions and surface brightness values calculated from the at-line obtained images during fluid bed drying of pellets were analysed. The particle size distribution and brightness value changes occurring during pellet drying were explained both by the reduction in residual moisture content and drug solid-state transition. Due to the rapidness of the technique with regard to sample preparation, sample measurement and the acquisition of results in combination with the possibility to measure undispersed (wet) samples, valuable information on spheronization and drying characteristics of different formulations was obtained in real-time.

Aqueous coating dispersion (pseudolatex) of zein improves formulation of sustained-release tablets containing very water-soluble drug.

Zein is an alcohol soluble protein of corn origin that exhibits hydrophobic properties. Pseudolatexes are colloidal dispersions containing spherical solid or semisolid particles less than 1 microm in diameter and can be prepared from any existing thermoplastic water-insoluble polymer. The novel plasticized film-coating pseudolatex of zein was studied in formulation of sustained-release tablets containing very water-soluble drug. Film formation of plasticized aqueous dispersion was compared with film forming properties of plasticized organic solvent system (ethanol) of zein. The water vapor permeability (WVP), water uptake and erosion, and moisture sorption were evaluated with free films. The tablets containing metoprolol tartrate as a model drug were used in pan-coating experiments. Aqueous film coatings plasticized with PEG 400 exhibited very low water uptake. No significant difference in WVP, moisture sorption and erosion were found between aqueous films and organic solvent-based films of zein plasticized with PEG 400. The atomic force microscopy (AFM) images on microstructure of films showed that colloidal particle size of zein in the aqueous films was smaller than that observed in the solvent-based films. In addition, the aqueous-based films were more compact and smoother than the respective solvent-based films. The aqueous zein-coated tablets containing very water-soluble drug (metoprolol tartrate) exhibited clear sustained-release dissolution profiles in vitro, while the respective solvent-based film-coated tablets showed much faster drug release. Furthermore, aqueous zein-coated tablets had lower water absorption at high humidity conditions. In conclusion, the plasticized aqueous dispersion (pseudolatex) of zein can be used for moisture resistant film coating of sustained-release tablets containing very water-soluble drug.

Analysis of sustained-release tablet film coats using terahertz pulsed imaging.

The coating quality of a batch of lab-scale, sustained-release coated tablets was analysed by terahertz pulsed imaging (TPI). Terahertz radiation (2 to 120 cm(-1)) is particularly interesting for coating analysis as it has the capability to penetrate through most pharmaceutical excipients, and hence allows non-destructive coating analysis. Terahertz pulsed spectroscopy (TPS) was employed for the determination of the terahertz refractive indices (RI) on the respective sustained-release excipients used in this study. The whole surface of ten tablets with 10 mg/cm(2) coating was imaged using the fully-automated TPI imaga2000 system. Multidimensional coating thickness or signal intensity maps were reconstructed for the analysis of coating layer thickness, reproducibility, and uniformity. The results from the TPI measurements were validated with optical microscopy imaging and were found to be in good agreement with this destructive analytical technique. The coating thickness around the central band was generally 33% thinner than that on the tablet surfaces. Bimodal coating thickness distribution was detected in some tablets, with thicker coatings around the edges relative to the centre. Aspects of coating defects along with their site, depth and size were identified with virtual terahertz cross-sections. The inter-day precision of the TPI measurement was found to be within 0.5%.

Effects of process variables on the size, shape, and surface characteristics of microcrystalline cellulose beads prepared in a centrifugal granulator.

Preparation of microcrystalline cellulose (MCC) beads with a laboratory-scale centrifugal granulating apparatus was studied, and the pharmaceutical quality of the beads was characterized with respect to the subsequent drug layering. Five process parameters of potential importance, including rotor rotation speed X1, slit air X2, spray air pressure X3, spray air rate X4, and height of nozzle setting X5, were evaluated using a fractional factorial design (FFD 2(5-2)) as the experimental design. The responses evaluated were expected yield, mean size, size distribution, shape characteristics (including roundness, circularity, elongation, rectangularity, and modelx), and friability. All five process parameters studied were found to have an influence on the selected properties of the beads, but the effects of rotor rotation speed, slit air flow rate, and spray air rate were statistically significant (p < .05). The effect of the rotor rotation speed was found to be the most potent on all the responses studied. The results also show some significant interactions between the parameters tested. The most significant interactions were between rotor rotation speed and slit air, rotor rotation speed and spray air, and slit air and spray air.

Optimization of aqueous-based film coating of tablets performed by a side-vented pan-coating system.

The purpose of this research was to characterize the aqueous-based hydroxypropylmethylcellulose (HPMC) film coating of tablets utilizing a laboratory-scale side-vented pan-coating apparatus (Thai coater). The process and apparatus parameters of potential importance with respect to the final film quality were evaluated by using fractional factorial design (2(6-2)IV) and the process was optimized using response surface methodology (central composite design). Rotating speed of the pan was identified as a major parameter with respect to film thickness (weight increase; p < 0.05) and breaking strength (p < 0.05) of the aqueous HPMC film-coated tablets. Increasing the rotating speed from 5 rpm to 10 rpm resulted in a mean relative change of -43.9% and 2.4% of film thickness (weight increase) and breaking strength, respectively. As expected, inlet air temperature significantly affected the moisture content of the final film-coated tablets (p < 0.01) and the film thickness (weight increase; p < 0.05), but the effects on the other responses studied were minimal or negligible. Pneumatic spraying pressure and position of the spray gun (excluding angle of the gun) did not affect the responses studied. The process parameters relevant to a side-vented pan-coating process can be identified (by fractional factorial design) and, consequently, optimized (by central composite design) by using the factorial design approach.

Corn starches as film formers in aqueous-based film coating.

The purpose of this study was to evaluate the film formation ability and mechanical stress-strain properties of aqueous native corn starches, using free films and film coatings applied to tablets. Free films were prepared from high-amylose corn (Hylon VII), corn and waxy corn starches, using sorbitol and glycerol as plasticizers. The tablets and pellets were film-coated using an air-suspension coater, and characterized with respect to the film coating surface topography, cross-sectional structure and thickness (SEM), and dissolution in vitro. The amylose content of the starch film formers affected both the tensile strength and the elongation. The elongations were under 5% for even the plasticized starches, and in most cases, no plasticization effect was seen by either of the plasticizers. Dissolution of native corn starch film-coated tablets (weight gain 1%) did not differ from uncoated ones. A notable delay in dissolution of the drug was found by increasing Hylon VII film coating thickness, suggesting controlled-release characteristics.

Waxy corn starch: a potent cofiller in pellets produced by extrusion-spheronization.

The purpose of this study was to assess the usefulness of waxy corn (maize) starch as a cofiller and diluent in pellets produced by aqueous extrusion-spheronization. Waxy corn starch was combined with microcrystalline cellulose (MCC) in the range of 20-50% of the entire composition. Pellets containing ordinary corn starch or lactose with MCC were used as reference. The shape of pellets was characterized using an optical microscopic image analysis system. The surface and cross-sectional structure were investigated by means of scanning electron microscopy (SEM). The replacement of ordinary corn starch by waxy corn starch made it possible to increase the amount of starch from 20 to 40%. The pellets containing 50% waxy corn starch were of poorer quality but superior to those containing 30% corn starch. The surface structure became slightly more irregular with respect to the amount of either starch, and a cavity was formed inside the pellet during the spheronization. The origin of starch did not affect the surface structure of the pellets. Waxy corn starch is a potential cofiller: the amount of MCC can be reduced in pellets produced by extrusion-spheronization by using waxy corn starch as a cofiller. This enables the reduction of the manufacturing cost of pellets with low drug load.