Application of Terahertz Attenuated Total Reflection Spectroscopy to Detect Changes in the Physical Properties of Lactose during the Lubrication Process Required for Drug Formulation

Abstract

Manufacturing the solid dosage form of an orally administered drug requires lubrication to enhance manufacturability, ensuring that critical quality attributes such as disintegration and dissolution of the drug product are maintained during manufacture. Here, to evaluate lubrication performance during manufacture, we used terahertz attenuated total reflection (THz-ATR) spectroscopy to detect differences in the physical characteristics of the lubricated powder. We applied a simple formulation prepared by blending granulated lactose as filler with magnesium stearate as lubricant. A flat tablet was prepared using the lubricated powder to acquire sharp THz-ATR absorption peaks of the samples. First, we investigated the effects of lubricant concentration and compression pressure on preparation of the tablet and then determined the effect of the pressure applied to samples in contact with the ATR prism on sample absorption amplitude. We focused on the differences in the magnitudes of spectra at the lactose-specific frequency. Second, we conducted the dynamic lubrication process using a 120-L mixer to investigate differences in the magnitudes of absorption corresponding to the lactose-specific frequency during lubrication. In both studies, enriching the lubricated powder with a higher concentration of magnesium stearate or prolonging blending time correlated with higher magnitudes of spectra at the lactose-specific frequency. Further, in the dynamic lubrication study, the wettability and disintegration time of the tablets were compared with the absorption spectra amplitudes at the lactose-specific frequency. We conclude that THz-ATR spectroscopy is useful for detecting differences in densities caused by a change in the physical properties of lactose during lubrication.Key words terahertz pulsed spectroscopy; attenuated total reflection; lubrication; lactose; magnesium stearate; evanescent waveThe manufacture of the tablet or capsule form of an orally administered drug requires blending of a lubricant with granules or other excipients, including the active pharmaceutical ingredient (API). This important process enhances the flow of the powder, 1) and thereby helps optimize manufacturing processes such as tableting and encapsulation. Factors such as the type of blender, rotation speed, lubrication time, batch and equipment size can affect the quality attribute of a drug product.2,3) The factors are generally determined according to scale-up theories to maintain the same physicochemical properties of a lubricated powder when changes are made to the equipment or production scale of the lubrication process. 4-7)However, even when using the same manufacturing conditions, we must consider variations in lubrication performance among batches of lubricated powders that are caused, for example, by differences in the physical characteristics of the lubricant or the physical characteristics of granules that are manufactured before the lubrication process. 8)To conduct real-time monitoring of the uniformity of the blended powder dur...