Morphological evaluation of low-dose midazolam granules by laser Raman microscopy.

Raman analysis has higher sensitivity for the detection of active pharmaceutical ingredients (APIs) than additives; thus, it is expected to be used for the evaluation of low-content preparations. The purpose of this study was to clarify the usefulness of granule morphology assessment using Raman analysis in the development of low-content formulations. In this study, midazolam was used as a model drug to prepare granules as a low-content formulation. Raman images were used to visualize the distribution of ingredients on the surface of the granules, determine the particle size of midazolam bound to the granules, and investigate the types of excipient components to which midazolam is bound. It was suggested that midazolam particles of a certain size were difficult to bind to excipients and had particularly low adhesion to mannitol. It was revealed that this phenomenon caused the segregation of the content of midazolam particles in the granules. Therefore, to obtain granules with good content uniformity, it was considered necessary to control the particle size of the API and select an additive that does not differ in adhesiveness to the main drug. Additionally, the findings obtained by morphological observation could be clarified by the quantitative evaluation of additives using Raman.

Effect of the External Lubrication Method for a Rotary Tablet Press on the Adhesion of the Film Coating Layer.

External lubrication is a useful method which reduces the adhesion of powder to punches and dies by spraying lubricants during the tableting process. However, no information is available on whether the tablets prepared using an external lubrication system can be applicable for a film coating process. In this study, we evaluated the adhesion force of the film coating layer to the surface of tablets prepared using an external lubrication method, compared with those prepared using internal lubrication method. We also evaluated wettability, roughness and lubricant distribution state on the tablet surface before film coating, and investigated the relationship between peeling of the film coating layer and these tablet surface properties. Increasing lubrication through the external lubrication method decreased wettability of the tablet surface. However, no change was observed in the adhesion force of the film coating layer. On the other hand, increasing lubrication through the internal lubrication method, decreased both wettability of the tablet surface and the adhesion force of the film coating layer. The magnesium stearate distribution state on the tablet surface was assessed using an X-ray fluorescent analyzer and lubricant agglomerates were observed in the case of the internal lubrication method. However, the lubricant was uniformly dispersed in the external lubrication samples. These results indicate that the distribution state of the lubricant affects the adhesion force of the film coating layer, and external lubrication maintained sufficient lubricity and adhesion force of the film coating layer with a small amount of lubricant.