Spectroscopic insight for tablet compression.

Tablet compression process has been studied over the years from various perspectives. However what exactly happens to material during compression is still unknown. In this study a novel compression die which enables real-time spectroscopic measurements during the compression of material is represented. Both near infrared and Raman spectroscope probes can be attached to the die. In this study the usage of the die is demonstrated by using Raman spectroscopy. Eicosane, d-glucose anhydrate, α-lactose monohydrate and xylitol were used in the study because their compression behavior and bonding properties during compression were assumed to be different. The intensity of the Raman signal changed during compression with all of the materials. However, the intensity changes were different within the materials. The biggest differences were within the xylitol spectra. It was noticed that some peaks disappeared with higher compression pressures indicating that the pressure affected variously on different bonds in xylitol structure. These reversible changes were supposed to relate the changes in conformation and crystal structure. As a conclusion, the die was found to be a significant addition for studying compression process in real-time. It can help to reveal Process induced transformations (PITs) occurring during powder compaction.

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.

New insights into segregation during tabletting.

The aim of this study was to evaluate how different granule size distributions affect the tablet compression process. The emphasis was on developing new analytic methods for compression data for entire batch. In all, 18 batches of granules containing theophylline and lactose were tabletted, using an instrumented eccentric tabletting machine. During tablet compression, upper and lower punch forces were recorded. Mathematical methods were developed for analysing the compression data during tabletting. The results suggested two types of undulation in the tabletting data: (1) short-time scale variation or tablet-to-tablet changes in force data and (2) long-time scale undulation describing the changes occurring throughout the tabletting process, such as segregation. These undulation phenomena were analysed, using various mathematical methods. In addition the results suggest that smaller particles have better tabletting properties, to a certain limit. However particle size alone cannot explain the tabletability of granules.

Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy.

Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the alpha-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.

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.

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.

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.

Effect of beta-sitosterol on precipitation of cholesterol from non-aqueous and aqueous solutions.

The aim of the present work was to study the solubility and phase behaviour of the beta-sitosterol-cholesterol mixed crystals in the presence and absence of water. Cholesterol, beta-sitosterol and 3:1, 1:1 and 1:3 mixtures of these were co-precipitated from acetone and acetone-water solutions. Precipitated crystals were analysed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), optical microscopy and Karl-Fischer titrimetry. The quantification of the sterols in solutions was preformed using GC-MS. The solubility of the sterols was mutually limiting. In the aqueous system, the solubility of both the sterols were significantly lower than in the absence of water, but the decrease in the solubility was considerably greater with the more hydrophobic beta-sitosterol. In the aqueous system, the total sterol solubility decreased with the increasing proportion of beta-sitosterol. The formation of new crystal structures, solid solutions of cholesterol and beta-sitosterol, was observed in non-aqueous as well as in aqueous environments except with the lowest cholesterol proportion in the system, in which case mixed crystals with eutectic behaviour were formed.

Development of indomethacin Carbopol ETD 2001 gels and the influence of storage time and temperature on their stability.

We investigated the development of a topical indomethacin gel formulation of suitable consistency using Carbopol ETD 2001 as the gelling agent. Topical gel formulations containing 1% w/w indomethacin (IND), 1% w/w Carbopol ETD 2001 (C2001), 1% of trethanolamine (TEA), 30% hexylene glycol (HG) and 10% polyethylene glycol (PEG 300) were prepared with excipients Tween 80, PVP 25, both Tween 80 and PVP 25 or neither agent. These four gel formulations were tested after a period of 1 and 4 weeks at storage temperature of 6 degrees C, 20 +/- 2 degrees C and 45 degrees C. Physical evaluation of the stability of these gels was carried out by microscopic and rheological tests, measurement of pH and by visual inspection. Rheological properties were studied using the cone and plate method at shear rates of 600 to 6000 1/s. Viscosities corresponding to shear rates were also calculated. Our results indicated that C2001 could be used as a gelling agent for IND in topical preparations. IND-C2001 gels were clear and exhibited an acceptable appearance; gel behaviour was non-Newtonian and pseudoplastic. The addition of either Tween 80 or PVP 25 to the base gel formulation significantly increased the shear stresses and viscosity of the gels. These novel formulations exhibited good physical stability throughout the 4-week examination periods as inferred from pH measurements and microscopic examination. Additionally, the non-Newtonian pseudoplastic behaviour of the gels was maintained throughout storage, with only a minimal decrease in gel viscosity after 4 weeks. Differences in consistencies of the four formulations, although initially apparent, were no longer evident after 4 weeks of storage for all temperature conditions examined. Gels stored at high temperature (45 degrees C) developed a dark yellow color and decreased in viscosity compared to other storage temperature.

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.

Influence of storage time and temperature on the stability of indomethacin Pluronic F-127 gels.

The stability of 20 topical gel formulations containing drug, 1% w/w indomethacin (IND), and 20% w/w Pluronic (PF-127) as a gel-forming agent, hexylene glycol (HG) and polyethylene glycol 300 (PEG) in different amounts (16, 20 and 24% w/w) as solvents and 1% w/w polyvinyl pyrrolidone (PVP, K-25) and Tween as excipients was determined by appearance and consistency of the gels, microscopy, pH and rheological measurements after 1 and 4 weeks storage, at 6 degrees C, 20 +/- 2 degrees C and 45 degrees C. Viscosity values were determined from rheograms by a Haake Rotovisco sensor at shear rates of 1000 to 10,000 l/s. The relationship between effectors (temperature and storage time) and response (viscosity) was determined using multiple regression analysis. All formulations were stable at room temperature (20 +/- 2 degrees C). The consistency of the gels containing HG and PEG decreased during storage at 6 degrees C. Storing the gels at 6 degrees C resulted in the precipitation of IND, but when PVP was incorporated into the IND-PF-127 gels, the stability of the gels was improved. All IND gels sustained their pseudoplastic flow behaviour. The viscosity decreased as storage time increased. A statistically significant model was obtained, showing that the effect of storage temperatures on the viscosity was much less than the effect of storage time.

Pluronic F-127 gels as a vehicle for topical formulations of indomethacin and rheological behaviour of these formulations.

Topical gel formulations containing a non-steroidal anti-inflammatory drug, indomethacin (IND), were prepared using 20% w/w Lutrol PF-127 as a gel-forming agent, and 16, 20 and 24% w/w Hexylene glycol (HG) or polyethylene glycol 300 (PEG) as solvents. 1% w/w Tween 80 and 1% w/w PVP 25 were added as excipients. The effects of the amounts of solvent and excipients on the physical characteristics of IND gel such as consistency, appearance, crystallization, pH and viscosity were studied. The results indicated that 1% w/w IND is able to form a structural gel. The viscosity values were calculated from the rheograms which were determined by a Haake Rotovisco sensor at a shear rate of 10,000 l/s. Viscosities corresponding to shear rates of 1000, 3000, 6000 and 9000 l/s were also calculated. Yield points were approximated from the rheograms. Although all IND gels maintained their pseudoplastic flow behaviour, their viscosities decreased markedly with increasing shear rates. Furthermore, increasing the amount of HG or PEG gave a more viscous gel except for the 24 w/w% HG gels which turned a jelly with or without either Tween or PVP. The difference in viscosities was explained by the changes in the gel compositions. 20% of PEG-1% PVP ranked first in viscosity followed by 16% PEG-1% PVP, 16% PEG-1% Tween, 24% PEG, 20% PEG-1% Tween and 16% HG-1% PVP. The results indicate that the excipients influence the physical characteristics of the gels. The optimum concentration for gels manifesting as strength of gel was 20% PEG in combination with 1% PVP which had the highest viscosity and yield value at a low shear rate.

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.

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.

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.

Cholesterol-lowering effect of spreads enriched with microcrystalline plant sterols in hypercholesterolemic subjects.

BACKGROUND: Plant sterols have been shown to reduce serum lipid concentrations. The effectiveness is highly dependent on the physical state of the plant sterols. By means of a new crystallizing method, plant sterols can be added into dietary fats and oils homogeneously. In this fat ingredient, plant sterols are in a microcrystalline form. AIMS OF THE STUDY: We investigated the cholesterol-lowering effect and possible side effects of vegetable oil-based spreads fortified with two different doses of microcrystalline plant sterols. METHODS: This double-blind randomized, placebo-controlled study consisted of a 6-wk run-in and a 6-month experimental period. During the run-in period, all 155 hypercholesterolemic subjects received rapeseed oil-based control spread. In the beginning of the experimental period subjects were randomly assigned into one of three experimental groups. The control group continued to use control spread, and the two test groups used spreads with added plant sterols of either 1.5 g/d or 3.0 g/d. The subjects consumed test spreads as a part of their normal diet without any restrictions in lifestyle and diet. RESULTS: Plasma total- and LDL-cholesterol concentrations were significantly reduced by 7.5-11.6% (0.46-0.62 mmol/1) in groups consuming margarine enriched with free plant sterols, compared with the control group. The effects were similar between the two groups consuming either 1.5g or 3.0 g plant sterols per day. No effect on HDL-cholesterol or triacylglycerol concentrations occurred. The test spreads did not induce any adverse effects in blood clinical chemistry, hematology or decreases in serum concentrations of lipid soluble vitamins. CONCLUSIONS: Microcrystalline plant sterols are effective in lowering serum total- and LDL-cholesterol concentrations without obvious side effects. The daily dose of 1.5 g plant sterols is enough to reach the maximum effect.

Rheological properties of creams with four different surfactant combinations - effect of storage time and conditions.

Changes in the rheological properties of four o/w cream formulations differing in the combination of surfactants were studied. The non-ionic surfactants used were soybean derivatives, polyethylene glycol 10 and 25 soya sterol, and sorbitol derivatives, sorbitan monooleate and trioleate. Combinations of the soybean and sorbitol derivatives were used. The rheological properties were tested during a 28-day storage period at three different storage conditions (cold, room temperature and accelerated conditions). In addition to dynamic and static rheological tests, droplet size distributions and conductivities of the creams were also determined. The consistency of the creams containing polyethylene glycol 10 soya sterol decreased during storage. Despite the greatest decreases in consistency, the creams containing polyethylene glycol 10 soya sterol exhibited the most viscoelastic structures with linear viscoelastic behaviour. Storing the creams for 28 days in the three different storage conditions made the differences in the consistency of the formulations smaller. All three storage conditions were involved when the conditions of the most viscoelastic cream of each formulation was specified. In the case of linearly viscoelastically behaving creams containing polyethylene glycol 10 soya sterol, all the rheological tests correlated with the droplet size distributions and the conductivity tests.

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.

Characterization of microcrystalline cellulose and silicified microcrystalline cellulose wet masses using a powder rheometer.

A powder rheometer has been used to study the properties of wet powder masses and the results have been compared to the mixer torque rheometer (MTR). Two different microcrystalline cellulose (MCC) grades (Avicel and Emcocel) and silicified microcrystalline cellulose (SMCC, Prosolv) were used as model powders. The wet massing behaviour of one material (Prosolv) was studied by the powder rheometer using liquid addition experiments, while the rheological properties of wet granules were studied using both the powder rheometer and the MTR. In water addition measurements the torque behaved in a similar way to MTR measurements and the maximum value of ZTL (zero torque limit) was achieved at the capillary state of wet mass. The wet granules exhibited different behaviour in the powder rheometer and the MTR experiments, which indicates that these rheometers involve different shear forces or they measure different properties of the wet granules. Emcocel wet masses achieved the capillary state at lower liquid amount than Avicel and Prosolv masses, which indicates that Emcocel is not able to hold as much water in the internal structure as Avicel and Prosolv. The powder rheometer proved to be a sensitive piece of equipment, which can be used to study both dry and wet powder masses. It was able to distinguish wet granules from wet powder masses after liquid addition, whereas the MTR could not. However, before the powder rheometer can be properly utilised in wet powder mass studies, the problem of torque overload requires resolution.

Use of a capillary rheometer to evaluate the rheological properties of microcrystalline cellulose and silicified microcrystalline cellulose wet masses.

The influence of microcrystalline cellulose (MCC) type and water content on the rheological properties of the wet powder masses were studied using two different MCC grades (Avicel and Emcocel) and silicified microcrystalline cellulose (SMCC, Prosolv). A ram extruder was used as a capillary rheometer and unique flow curves for each cellulose grade and moisture content were derived. In addition, the elastic parameters of recoverable shear and compliance were determined. From different flow curve models evaluated, it was not possible to obtain clear evidence, which model best described the rheological properties of each cellulose grade at each water level. Furthermore, the residuals were shear rate dependent, which indicates that the models do not perfectly agree with physical properties of the wet masses. The elastic properties of wet masses increased with increasing water content and decreased with increasing shear stresses. SMCC grade proved to be more elastic than the simple MCC grades at each moisture content. Thus, the rheological properties of MCC and SMCC wet masses were different and changed with water content. Consequently, it was not possible to achieve similar rheological properties between different grades of cellulose by altering the water content of the wet mass.