Improvement of fluconazole flowability and its effect on dissolution from tablets and capsules (original) (raw)
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Pharmaceutical granulation processes, mechanism and the use of binders
Pharmaceutical …, 2008
The user has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Cantor et al. flow better and are usually more compactible than the original powders. Granulation also permits handling of powders without loss of blend quality, since after blending particles are locked in-place within granules in a form of ordered mix.
Asian Journal of Pharmaceutics, 2014
I n the present investigation, suitability of a cost-effective and convenient granulation technique that is, moisture activated dry granulation (MADG) process for high drug loading in tablet formulation was studied. In this work, effect of the amount of water on flow properties of granules as well as an effect of mixing time on surface morphology of granules was studied. Paracetamol (PCM) immediate release granules were prepared using conventional excipients such as polyvinylpyrrolidone K-30, Kollidon VA 64 (as binders), and simple equipments by MADG technique. The prepared granules were evaluated for flow properties and tablets were compressed using optimized granule formulation. The prepared granules possessed good flow properties that is, angle of repose was 32.11 and percent compressibility index was 19.44. Tablets disintegrated in 2.08 min and 89% of the drug was released within 30 min. All the results were comparable with PCM tablets prepared by wet granulation method. Therefore, from the above studies it was concluded that MADG process may be effectively adopted by using Kollidon VA 64 as a binder in tablet formulations where high drug loading is to be achieved, where all the parameters of the formulation can be obtained within specified limits using this simple, convenient, less time consuming, economical, and efficient method of granulation.
Advanced Powder Technology, 2011
Understanding the relationship between high shear wet granulation processing parameters and the characteristics of intermediate and final products is crucial in the ability to apply quality by design (QbD) and process analytical technologies (PAT) to secondary pharmaceutical processes. This research examined a high shear wet granulation process and subsequent manufacturing of a tablet containing a biopharmaceutics classification system (BCS) class II drug, gliclazide (low solubility, high permeability). Previous studies have concentrated on either granulation or tabletting but not both together; this work brings together the analysis as a single large multivariate process. The design of experiment (DoE) was performed according to an L9 Taguchi method with three replications, in total; thirty-six runs were performed. A full statistical analysis relating both granule and tablet properties to selected process parameters were carried out. The research illustrates that mapping a highly multivariate process is possible. Statistically significant critical process parameters were identified for granule hardness, granule density and granule particle size. These granule properties were also identified as contributing to the dissolution release characteristics. Dissolution modeling and prediction was achieved within the DoE structure. Process noise was identified and measured across the entire production and specifically with respect to the milling process.
International Journal of Pharmaceutics, 2009
The purpose of this study was to establish a relationship between the material properties of an active pharmaceutical ingredient (API) and its behavior during high-shear wet granulation. Using several actives and excipients as material probes, the influence of aqueous solubility, wettability, water holding capacity, mean and width of the particle size distribution, and surface area was examined. The effect of these variables on the processibility and performance of the granulations was evaluated by monitoring such responses as granule growth, compactability and flow changes upon wet granulation. The prominent findings from this study include: (a) controlled growth is highest in readily wettable APIs with low surface area, (b) uncontrolled growth is high in APIs of high solubility and low water holding capacity, (c) polydisperse granulations are produced from APIs of high contact angle and surface area, (d) improvement in compactability is high in APIs with large surface area and broader size distributions and (e) flow enhancement as a result of wet granulation is highest in APIs of large size distributions. These results are physically interpreted in this manuscript based on the prevailing wet granulation theories. Findings from this study are useful in mapping a new material to predict its performance in a high-shear wet granulation process.
Advanced Granulation Techniques for Pharmaceutical Formulations Overview
2013
INTRODUCTION Active pharmaceutical compounds (drugs) are used for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical ingredient may exist in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without adding excipients, since the desired effect may not be obtained. Earlier, it was thought that excipients are inert in nature but, in recent time it is well known that excipients can greatly modify the intended effect of a drug. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution, ABSTRACT The Present study was focus on different techniques adopted while formulating solid dosage forms like tablets, Capsules and Granules etc. The ideal characteristics of granules include uniformity, good flow and compatibility. Nowadays the agglomeration process used in pharmaceutical industry for granulation. Based on the characteristics, suitable excipients were selected for the formulation of dosage forms. Physiological properties like bulk density, tapped density, hausners ratio and compressibility index have to evaluated and optimized for good pharmaceutical formulations. Apart from Physiological properties we have to consider evaluation parameters of finished products such as disintegration time and In-vitro release studies. Here we are mainly focusing on different types of granulation technique.
International Journal of Pharmaceutics, 2011
The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches. A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale highshear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis). Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.
Effect of formulation hydrophobicity on drug distribution in wet granulation
Chemical Engineering Journal, 2010
Wet granulation is a process of enhancing the powder properties by producing larger particles from the agglomeration of agitated fine particles with liquid. The production of enlarged "granules" is often carried out in high-shear granulators, an equipment item prevalent in the pharmaceutical and food industries. In the pharmaceutical industry, good wettability between the liquid binder and the powder components in the formulation are relied upon to produce strong granules with a narrow size distribution. The wettability of hydrophobic drugs in the formulation is often improved by the use of surfactants; but this may not always be possible. Previous work on heterogeneous-wetting granulation [1-3] has found that as the formulation hydrophobicity increases, the average granule size decreases. The decreasing proportion of hydrophilic component available for granulation may influence the decreasing average granule size, however an explanation for this has not been clearly proposed. The observation and reasoning behind the granulation behaviour for heterogeneous-wetting powders forms the basis of this paper. Granulation experiments were carried out on varying degrees of formulation hydrophobicity and the granulation batch is sieved into different size fractions for sieve fraction assay analysis to determine the average granule composition and the drug distribution throughout the granulation batch. The sieve fraction assay analysis revealed that the drug distribution in the granular batch is strongly dependent upon the formulation wettability. This was seen for batches with water as the granulating fluid where the drug distribution was uneven and resulted in some sieve fractions being enriched or deficient of drug content. When the wettability of the formulation was improved a more uniform distribution of drug was achieved across all sieve fractions and formulation hydrophobicity. The average granule size decreased as the formulation hydrophobicity increased, supporting previous works, and this is due to the decreasing liquid bridge strength between the particles.
DPC 963 is a non-nucleoside reverse transcriptase inhibitor with low aqueous solubility. The effect of DPC 963 drug substance particle size on the characteristics of granules manufactured by high-shear wet granulation was evaluated. The wet granulation process was used to manufacture a DPC 963 formulation with high drug loading. The formulation was manufactured using drug substance lots with different particle size distributions. Granulation particle size distribution, porosity, and compressibility were determined. A uniaxial compression test was also performed on moist compacts of the formulation prepared with different particle size distributions. Particle agglomeration behavior was affected by drug substance particle size. Granulation geometric mean diameter and fraction with particle size greater than 250 µm was inversely proportional to the drug substance particle size. Mercury intrusion porosimetry revealed higher pore volumes for the granules manufactured using the drug substance with the smaller particle size, suggesting lower tendency for granule densification than for that manufactured with the larger drug substance particle size. Granulation compressibility was also sensitive to changes in drug substance particle size. A decreased drug substance particle size led to increased granulation compressibility. Results from the uniaxial compression experiments suggested that the effect of particle size on granulation growth is the result of increased densification propensity, which in turn results from increased drug substance particle size.
Five primary methods exist to form an agglomerated granule. They are formation of solid bridges, sintering, chemical reaction, crystallization, or deposition of colloidal particles. Binding can also be achieved through adhesion and cohesion forces in highly viscous binders. Successful processing for the agglomeration of primary particles depends on proper control of the adhesional forces between particles, which encourage agglomerate formation and growth and provide adequate mechanical strength in the product. Furthermore, the rheology of the particulate system can be critical to the rearrangement of particles necessary to permit densification of the agglomerate and the development of an agglomerate structure appropriate for the end-use requirements. If the particles are close enough then the surface forces such as van der Waals forces (short-range) and electrostatic forces can interact to bond particles. Decreasing particle size increases surface-mass ratio and favors the bonding. van der Waals forces are sevenfold stronger than electrostatic forces and increase substantially when the distance between them is reduced, which can be achieved by applying pressure as in dry granulation method. The cohesive forces that operate during the moist agglomerates are mainly due to the liquid bridges that develop between the solid particles. Electrostatic forces keep particles in contact long enough for another mechanism to govern the agglomeration process. The processing of drug substance with the excipients can be achieved without going through the granulation steps. By simply mixing in a blender, a directly compressible formulation can be processed and compressed in tablets or filled in the hard gelatin capsules. In the 1970s, microcrystalline cellulose as a directly compressible vehicle was introduced. The compressible formulation containing microcrystalline cellulose is suitable for a number of products. This has several obvious advantages, such as lower equipment cost, faster process time, and efficient operation involving only two process steps. Sometimes excipient costs may have to be compared against the savings in the processing steps and equipment by using alternate methods. There are, however, a number of products that require low dose of drug substance, where the blend uniformity and the content uniformity in the drug product are critical. Traditionally, the assessment of the blend uniformity is done after the blending process is complete. This required considerable delays in obtaining results, and the sampling techniques and product discharge from the blender required consistency to obtain satisfactory results. However, with the current interest in process analytical technology (PAT) on-line measurement of ingredients is possible. The U.S. Food and Drug Administration (FDA) has recently released guidance for industry detailing the current thinking on PAT (7). Other than content uniformity of a low-dose drug substance there are a number of reasons why direct compression may not be suitable for a wide array of products. These include the required flow properties; the amount of drug substance in a dosage form may require it to be densified to reduce the size of the drug product, obtain the required hardness, friability, disintegration/dissolution, and other attributes. Another approach which is becoming popular is to use traditional spray-drying process to produce drum to hopper granulation bypassing the conventional granulation process. This process may be suitable for large-volume products such as overthe-counter tablets or capsules.