Mixing efficiency of pharmaceutical powders in an intensive mixer with rotating mixing vessel
The mixing of ductile lubricant particles is known to have several negative effects on tablet properties, such as decreased hardness and delayed disintegration. This study investigated the usefulness of a mixing system using an intensive mixer with a rotating mixing vessel (EIRICH Intensive Mixer) for blending lubricants.
To confirm the suitability of lubricant-mixing conditions (rotor types, rotation speed, and mixing time), we mixed lactose/cornstarch with two types of lubricants (magnesium stearate and sodium stearyl fumarate), prepared tablets made from the mixtures, and evaluated their properties. Mixing with a star rotor suppressed the negative effects of lubricants on tablet properties more effectively than mixing with a microgranulation rotor (Z rotor). To verify the usefulness of this mixing system in direct tableting, the formulations for direct compression with SuperTab®14SD or SmartEx® as excipients and acetaminophen (AAP) (10%) as an active pharmaceutical ingredient were used. The results confirmed the effectiveness of lubrication for tableting by evaluating the ratio of lower punch pressure to upper punch pressure and the uniform dispersion of AAP using near-infrared (NIR) spectroscopy. Finally, the process of mixing lubricants collectively with the active pharmaceutical ingredient and other ingredients was evaluated. The results showed that this mixing system using an intensive mixer effectively mixed all the ingredients in the formulation. This study clarified the usefulness of an intensive mixer in blending lubricants for pharmaceutical formulations.
Introduction
Tablets are the most popular vehicle for oral dosage due to their convenient administration and relatively low manufacturing costs [1]. Usually, tablet manufacturing involves the mixing of APIs and pharmaceutical additives such as fillers, disintegrants, lubricants, and so on. Direct compression, where blended formulation powders are fed directly to a tablet machine, is the simplest method of manufacturing tablets, as it does not require intermediate processes such as granulation, extrusion, or spray drying [2]. The use of lubricants in the formulations is necessary for ensuring the stable production of pharmaceutical tablets.
Lubricants reduce the friction between the die wall and powder bed during tableting and tablet ejection [3], [4]. It is common that a lubricant is mixed separately from other ingredients in a relatively short time just before feeding the tablet machine, because mixing ductile lubricant particles has several negative effects on tablet properties, such as decreased hardness and delayed disintegration [3]. Magnesium stearate (Mg-St) is the most frequently used lubricant due to its excellent lubrication properties and low cost, despite its negative effects.
Several papers have reported on the ductile properties of Mg-St during mixing using different types of mixers, such as a V-type mixer and a high-shear mixer [3], [5], [6], [7]. To avoid the negative effects of Mg-St on tablet properties, several trials have been reported. For example, sodium stearyl fumarate (SSF) was used instead of Mg-St as a lubricant [8]. Wang et al. reviewed that SSF shows less interference with tablet strength and has a less negative effect on tablet dissolution compared to Mg-St [9].
To achieve direct compression, novel types of excipients were designed. Excipients with favorable flow and compression properties were developed [10]. Spray-dried lactose, a lactose form created over 50 years ago, is designed specifically for direct compression [10], [11]. Recently, many excipients for the direct compression method for orally disintegrating tablets (ODTs) have been developed [12], [13]. Co-processed excipients (CPE) for ODT manufacturing serve various functions, such as promoting rapid disintegration and enhancing the compaction properties of powders. CPEs containing fillers, binders, disintegrants, and other additives are granulated [10], [12], [14].
The mixing process of pharmaceuticals depends on the mixer types, mixing conditions, and powder formulation [5], [15]. Generally, V-type mixers and high-shear mixers are used. With V-type mixers, the mixing powders including APIs need relatively long mixing times. Conversely, utilizing a high-shear mixer with a stationary mixing vessel and a concentric rotor tool typically mixes ingredients uniformly in a short time and with good dispersion of the lubricant. One of the defects of a high-shear mixer is to induce the excessive spread of lubricant during mixing. An intensive mixer with a rotating mixing vessel and an eccentrically mounted mixing tool is expected to moderate mixing behaviors compared to high-shear mixers and V-type mixers when blending lubricants. The tilt of a rotating mixing vessel adds a rolling effect to the material flow. Different types of rotors with different shapes can optimize shear introduction into the mix [16]. The EIRICH Intensive Mixer has long been used primarily for processing inorganic materials [16], and it has recently found application in the battery industry [17]. However, few applications of this mixer in the pharmaceutical industry have been reported [18].
The purpose of this study was to clarify the suitability of this intensive mixer to blend pharmaceutical powders. A standard formulation, consisting of a lactose/cornstarch mixture [19] with lubricants, was mixed under various conditions, then compacted into tablets for evaluating mixing properties. Formulations containing excipients for direct compression and a model API (acetaminophen) were also used to evaluate the uniformity of the mixing. The results were used to investigate the possibility of one-step mixing (collective mixing of APIs, fillers, lubricants, and other additives) using an intensive mixer to reduce the number of mixing steps in the conventional method, which is typically more than two steps.
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Materials
Lactose (Pharmatose®200M, DFE Pharma, Goch, Germany; D50: 40 μm) and corn starch (Nippon Cornstarch, Tokyo; D50: 20 μm) were used as fillers after passing through a 710 μm screen. As direct tableting fillers, co-processed mannitol (SmartEx®, Shin-Etsu Chemical, Tokyo; D50: 55 μm) and spray-dried lactose (SuperTab®14SD, DFE Pharma, Goch; D50: 130 μm) were used without sieving. Magnesium stearate (Mg-St, Mallinckrodt Pharma, Tokyo; D50: 6.0-14.0 μm; mp: 120-130°C) and sodium stearyl fumarate (SSF).
Hana Kato, Yoshiko Takeuchi, Hirofumi Takeuchi,
Mixing efficiency of pharmaceutical powders in an intensive mixer with rotating mixing vessel (EIRICH Intensive Mixer),
Journal of Drug Delivery Science and Technology, 2025, 106845, ISSN 1773-2247,
https://doi.org/10.1016/j.jddst.2025.106845.