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.

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.

Microscale granulation in a fluid bed powder processor using electrostatic atomisation.

The aim of this study was to use the electrostatic atomisation in miniaturised fluid bed granulation process and define the effect of process parameters. The process parameters included in the study were granulation liquid flow rate, atomisation voltage and binder concentration in the granulation liquid. Altogether 22 batches were granulated in Multichamber Microscale Fluid bed powder Processor (MMFP). Granule size distributions were measured with both sieves and image analyses. With these process conditions, the atomisation liquid flow rate had a strong positive correlation with the granule size. Increasing the atomisation voltage increased the granule size, which is contradictory with the expectations. The effect of the binder concentration remained unclear. Although it is challenging to model the fluid bed granulation process in micro-scale, multivariate methods such as principal component analysis (PCA) are helpful in studying the most important phenomena.

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 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.

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.

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.

Visualization of fluid-bed granulation with self-organizing maps.

The degree of the instrumentation of pharmaceutical unit operations has increased. This instrumentation provides information of the state of the process and can be used for both process control and research. However, on-line process data is usually multidimensional, and is difficult to study with traditional trends and scatter plots. The Self-Organizing Map (SOM) is a recognized tool for dimension reduction and process state monitoring. The basics of the SOM and the application to on-line data collected from a fluid-bed granulation process are presented. As a batch process, granulation traversed through a number of process states, which was visualized with SOM as a two-dimensional map. In addition, it is demonstrated how the differences between granulation batches can be studied. The results suggest that SOM together with new in-line process analytical solutions support the in-process control of the pharmaceutical unit operations. Further, a novel research tool for understanding the phenomena during processing is achieved.

Process analysis of fluidized bed granulation.

This study assesses the fluidized bed granulation process for the optimization of a model formulation using in-line near-infrared (NIR) spectroscopy for moisture determination. The granulation process was analyzed using an automated granulator and optimization of the verapamil hydrochloride formulation was performed using a mixture design. The NIR setup with a fixed wavelength detector was applied for moisture measurement. Information from other process measurements, temperature difference between process inlet air and granules (T(diff)), and water content of process air (AH), was also analyzed. The application of in-line NIR provided information related to the amount of water throughout the whole granulation process. This information combined with trend charts of T(diff) and AH enabled the analysis of the different process phases. By this means, we can obtain in-line documentation from all the steps of the processing. The choice of the excipient affected the nature of the solid-water interactions; this resulted in varying process times. NIR moisture measurement combined with temperature and humidity measurements provides a tool for the control of water during fluid bed granulation.

Content-based image retrieval: a new promising technique in powder technology.

The aim of the present study was to introduce a new technique for analyzing powders by examining the content information of images of pharmaceutical powder systems. Texture features of images of microcrystalline cellulose were compared by using a content-based image retrieval system (CBIR), QBIC (Query-by-Image-Content). The rank order and image similarities were compared to particle sizes and appearances of different mixtures. The image order of the similarity values was in close agreement with the appearance and particle size of the mixtures. When the image of pure Avicel PH 101 was used as a query image, the most similar images were always from images of mixtures with a large number of particles with smaller particle mean sizes. When images of pure Avicel PH 200 were used as a query image, the closest matches of image similarity were from images of mixtures with a larger amount of larger particles. The results show that the CBIR system extracts applicable content information on images of powders, but the texture features used were not totally adequate for analysis of the powders used. In general, content-based image retrieval seems to be a promising approach to efficiently use the vast image information that is available from pharmaceutical powders. Nevertheless, to achieve an efficient CBIR tool for powder technology requires development of substantial algorithms for feature extraction.

Use of the near-infrared reflectance method for measurement of moisture content during granulation.

The purpose of this study was to demonstrate the use of a near-infrared (NIR) method for in-process control of a placebo formulation. An NIR setup with a multichannel detector was applied in the measurement of water during fluidized bed granulation. The effects of two critical granulation parameters were studied using the central composite design. The present NIR setup with three wavelengths proved applicable for in-line moisture measurement. The 1990 nm signal was used for measurement of water and the 1745 and 2145 nm signals were used to correct the change in spectra baseline during granulation. Variations in inlet air conditions proved to be critical factors, explaining differences in the granule size distributions. Differences in granule moistening and drying rates resulting from varying inlet air conditions could be measured with the NIR setup. The moisture content of granules at the end of the spraying phase explained part of the differences in granule size distributions. The moisture content of granules at the end of the drying phase affected the tableting behavior of granules. The results suggested that direct measurement of granule moisture content facilitates the in-process control of the granulation.

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.

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.

The effect of compression force on surface structure, crushing strength, friability and disintegration time of erythromycin acistrate tablets.

The surface roughness of erythromycin acistrate tablets was studied by non-contact laser profilometry. Seven roughness parameters and 3D fractal dimension were examined. The mechanical properties (including crushing strength, friability and disintegration time) were determined, and SEM data were taken from the tablets. According to the results, the crushing strength and the disintegration time of the tablets increased with increasing compression force. At higher compression forces the crushing strength reached a constant level. The friability of the tablets behaved quite unexpectedly and minimum friability was observed at a compression force of 14 kN. Except for fractal dimension, the roughness parameters behaved very much in the same way as the friability of the tablets. The SEM data supported the friability and surface roughness data of the tablets.

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.