The manufacture of highly drug-loaded fine globular granules eventually applied for orally disintegrating tablets has been investigated using a unique multi-functional rotor processor with acetaminophen, which was used as a model drug substance. Experimental design and statistical analysis were used to evaluate potential relationships between three key operating parameters (i.e., the binder flow rate, atomization pressure and rotating speed) and a series of associated micromeritics (i.e., granule mean size, proportion of fine particles (106-212 µm), flowability, roundness and water content). The results of multiple linear regression analysis revealed several trends, including (1) the binder flow rate and atomization pressure had significant positive and negative effects on the granule mean size value, Carr's flowability index, granular roundness and water content, respectively; (2) the proportion of fine particles was positively affected by the product of interaction between the binder flow rate and atomization pressure; and (3) the granular roundness was negatively and positively affected by the product of interactions between the binder flow rate and the atomization pressure, and the binder flow rate and rotating speed, respectively. The results of this study led to the identification of optimal operating conditions for the preparation of granules, and could therefore be used to provide important information for the development of processes for the manufacture of highly drug-loaded fine globular granules. Key words fine globular granule; high drug loading; fluidized-bed rotogranulationOrally disintegrating tablets (ODTs) are solid dosage forms that are placed in the mouth, rapidly disintegrate/dissolve when in contact with the saliva and then easily swallowed without the need for water. Recently, a great deal of interest has been directed towards incorporating multiparticulate drug delivery system in ODT formulations.1) The multiparticulate drug delivery system comprises of functional granules with sustained release, delayed release, and taste-masking properties. One of the easiest ways of introducing specific functionalities to granules involves the application of a film coating, where a functional polymer layer is used to cover the drugloaded core particles. This particular technique is especially useful when the core particles are spherical, because it is then possible to apply a uniform coating to the particles.2) Furthermore, in cases where the particle size is less than 200 µm, improvements in the taste and texture of the powders can also be expected. However, in the case of even smaller particles (i.e., <100 µm), it can become increasingly difficult to apply a uniform coating because of the aggregation of the smaller particles resulting from static electrical charges. Therefore, the development of manufacturing processes capable of producing spherical particles with a narrow particle size distribution range of about 100-200 µm is therefore very important.Layering and wet granulation are two of the most ...
The effect of some drug properties (wettability and particle size distribution) on granule properties (mean particle size, particle size distribution, sphericity, and granule strength) were investigated in a high (>97%) drug-loading formulation using fluidized bed rotor granulation. Three drugs: acetaminophen (APAP); ibuprofen (IBU); and ethenzamide (ETZ) were used as model drugs based on their differences in wettability and particle size distribution. Granules with mean particle sizes of 100-200 µm and a narrow particle size distribution (PSD) could be prepared regardless of the drug used. IBU and ETZ granules showed a higher sphericity than APAP granules, while APAP and ETZ granules exhibited higher granule strength than IBU. The relationship between drug and granule properties suggested that the wettability and the PSD of the drugs were critical parameters affecting sphericity and granule strength, respectively. Furthermore, the dissolution profiles of granules prepared with poorly water-soluble drugs (IBU and ETZ) showed a rapid release (80% release in 20 min) because of the improved wettability with granulation. The present study demonstrated for the first time that fluidized bed rotor granulation can prepare high drugloaded (>97%) globular granules with a mean particle size of less than 200 µm and the relationship between physicochemical drug properties and the properties of the granules obtained could be readily determined, indicating the potential for further application of this methodology to various drugs.Key words high drug-loading; globular fine granule; fluidized bed rotor granulation; wettability Wet granulation is a technique to enlarge particle size by the coalescence of primary particles with the binder liquid and contributes to improved powder flowability, compaction behavior, and uniformity of drug content. In particular, high drug-loading wet granulation has recently gathered special interest as it can enhance patient compliance through reduction of dosage size, save manufacturing costs, and simplify the granulation process. In addition, if the particle size is less than 200 µm, improvements in the taste and texture of the powders would also be expected. Alternatively, if the particle size is too small, especially if it is less than 100 µm, uniform coating is difficult because of the aggregation of smaller particles via static electrical charge. Therefore, manufacturing high drug-loaded granules with a narrow particle size distribution of approximately 100-200 µm is critically important. To date, there have been many reports of drug-loaded granules prepared using high shear mixing and surfactants 1) ; however, the particle sizes of these granules were mostly over 200 µm, and it would be technically quite difficult to prepare high drugloaded fine granules using just a basic granulation technique.In the present study, we tried to investigate whether fluidized bed rotor granulation using the multi-functional rotor processor "Granurex ® (GX)" can prepare fine granules of a high (> 97%) drug-loadi...
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