Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism.

A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.

Effect of particle size on gastric emptying of enteric-coated granules in fasted beagle dogs: Relationship with interdigestive migrating motor complex.

This study investigates the particle size threshold at which the interdigestive migrating motor complex (IMMC) becomes active in gastric emptying for fasted beagle dogs. Enteric-coated granules containing cetirizine dihydrochloride (CET) were prepared in three particle sizes, 200, 660, and 1,200 µm (D50). To mark IMMC timing and water movement from the stomach, enteric-coated aspirin tablets and acetaminophen solution were used. To six fasted beagle dogs with 50 mL of acetaminophen solution was administered each granule size as a multiple-unit and a single enteric-coated aspirin tablet (3-period crossover study). No significant difference in pharmacokinetic parameters of CET after oral administration of different particle sizes was observed. However, the appearance time of CET in plasma with smaller granules (200 and 660 µm) was significantly faster than that of salicylic acid (a major metabolite of aspirin) in all dogs. In the case of the largest granules (1,200 µm), no significant time difference was observed in the appearance of both compounds in plasma. Furthermore, in two dogs, both compounds appeared at the same time, implying IMMC-regulated gastric emptying for the largest CET granules. These results support a particle size threshold between 660 and 1,200 µm for gastric emptying without IMMC action in fasted beagle dogs.

[Method for the evaluation of the stability and usability after opening packages of orally disintegrating tablets: case of amlodipine besilate products].

Orally disintegrating (OD) tablets are widely used in clinical practice. However, drug information on the choice and dispensing based on their stability after opening packages and usability in patients and dispensaries is not sufficient. The aim of this study was to investigate possible evaluation methods of the stability and usability of amlodipine OD tablets. Additives of the brand were changed in April 2009, and therefore the previous and current forms and two generics, current and newly marketed (in November 2009) products of different firms, were used. OD tablets were stored at 25 degrees C and 75% relative humidity for 3 months after opening the packages, and their physicochemical properties were evaluated. Their weight, diameter, thickness, and color difference increased slightly from the initial state. The extent of the change in their hardness, disintegration time, and friability was different among products. These physicochemical changes were acceptable in dispensary practice. Storage after opening the packages did not affect their dissolution rate. The dissolution rate at the initial state of the current brand was slower than that of the previous one. All products used were able to be dispensed by an automatic tablet-packing machine and applied to the so-called simple suspension method for intubational administration. Sensory evaluation tests revealed no major difference in the oral disintegration time, taste, impression, and preference among products. In conclusion, the stability and usability of amlodipine OD tablets used in this study were examined using several methods, and they can be used equivalently from the stability and usability viewpoints.